trattamento dell'ipertensione polmonarecongresso2014.neonatologia.it/dia/8784.pdf ·...
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Trattamento dellipertensione polmonare
Paolo Tagliabue
Neonatologia e Terapia Intensiva Neonatale Fondazione MBBM- Ospedale SGerardo Monza
Definition
bull Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome characterized by sustained elevation of pulmonary vascular resistance (PVR) and is often associated with normal or low systemic vascular resistance (SVR)
bull This leads to extrapulmonary shunting from right to left across persistent fetal channels patent ductus arteriosus (PDA) and patent foramen ovale (PFO) leading to labile hypoxemia
Epidemiology
bull Pulmonary hypertension of the newborn
occurs in 19 permil live births (043ndash682 permil)
bull The mortality rate is 11 (50 for SGB sepsis)
bull Outcome (BPD neurologic impairment due to hypoxia)
bull PPHN can be primary ( Persistence of Fetal Circulation)
bull Male gender Black or Asian maternal race High prepregnancy BMI Maternal Diabetes and Asthma
bull Genetics (Mutation in FOXF1 Gene Mutation in TMEM70)
bull Or secondary to Cardiac (CHD) and pulmonary (RDS MAS)
diseases acute and chronic hypoxia infection pulmonary hypoplasia policithemia diaphragmatic hernia vein misalignement drug therapy
Hernandez-Dıaz S et al Risk Factors for Persistent Pulmonary Hypertension of the Newborn Pediatrics 2007120e272-e282
Diagnosis bull Clinical diagnosis should be considered when
ndash hypoxemia is disproportioned to chest-X ray abnormalities ndash pre- and post-ductal saturations discrepancy ndash PaO2 difference of at least 20 mmHg between the pre (right
radial) and post (umbilical) ductal arterial blood sample ndash response to Hyperoxia (100 Oxygen)
bull in congenital heart disease PaO2 does not rise above 5ndash6 KPa bull in some infants with PHN the PaO2 will rise to above 14 Kpa but not
in those infants with PHN due to sepsis or associated with pulmonary hypoplasia
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Definition
bull Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome characterized by sustained elevation of pulmonary vascular resistance (PVR) and is often associated with normal or low systemic vascular resistance (SVR)
bull This leads to extrapulmonary shunting from right to left across persistent fetal channels patent ductus arteriosus (PDA) and patent foramen ovale (PFO) leading to labile hypoxemia
Epidemiology
bull Pulmonary hypertension of the newborn
occurs in 19 permil live births (043ndash682 permil)
bull The mortality rate is 11 (50 for SGB sepsis)
bull Outcome (BPD neurologic impairment due to hypoxia)
bull PPHN can be primary ( Persistence of Fetal Circulation)
bull Male gender Black or Asian maternal race High prepregnancy BMI Maternal Diabetes and Asthma
bull Genetics (Mutation in FOXF1 Gene Mutation in TMEM70)
bull Or secondary to Cardiac (CHD) and pulmonary (RDS MAS)
diseases acute and chronic hypoxia infection pulmonary hypoplasia policithemia diaphragmatic hernia vein misalignement drug therapy
Hernandez-Dıaz S et al Risk Factors for Persistent Pulmonary Hypertension of the Newborn Pediatrics 2007120e272-e282
Diagnosis bull Clinical diagnosis should be considered when
ndash hypoxemia is disproportioned to chest-X ray abnormalities ndash pre- and post-ductal saturations discrepancy ndash PaO2 difference of at least 20 mmHg between the pre (right
radial) and post (umbilical) ductal arterial blood sample ndash response to Hyperoxia (100 Oxygen)
bull in congenital heart disease PaO2 does not rise above 5ndash6 KPa bull in some infants with PHN the PaO2 will rise to above 14 Kpa but not
in those infants with PHN due to sepsis or associated with pulmonary hypoplasia
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Epidemiology
bull Pulmonary hypertension of the newborn
occurs in 19 permil live births (043ndash682 permil)
bull The mortality rate is 11 (50 for SGB sepsis)
bull Outcome (BPD neurologic impairment due to hypoxia)
bull PPHN can be primary ( Persistence of Fetal Circulation)
bull Male gender Black or Asian maternal race High prepregnancy BMI Maternal Diabetes and Asthma
bull Genetics (Mutation in FOXF1 Gene Mutation in TMEM70)
bull Or secondary to Cardiac (CHD) and pulmonary (RDS MAS)
diseases acute and chronic hypoxia infection pulmonary hypoplasia policithemia diaphragmatic hernia vein misalignement drug therapy
Hernandez-Dıaz S et al Risk Factors for Persistent Pulmonary Hypertension of the Newborn Pediatrics 2007120e272-e282
Diagnosis bull Clinical diagnosis should be considered when
ndash hypoxemia is disproportioned to chest-X ray abnormalities ndash pre- and post-ductal saturations discrepancy ndash PaO2 difference of at least 20 mmHg between the pre (right
radial) and post (umbilical) ductal arterial blood sample ndash response to Hyperoxia (100 Oxygen)
bull in congenital heart disease PaO2 does not rise above 5ndash6 KPa bull in some infants with PHN the PaO2 will rise to above 14 Kpa but not
in those infants with PHN due to sepsis or associated with pulmonary hypoplasia
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
bull PPHN can be primary ( Persistence of Fetal Circulation)
bull Male gender Black or Asian maternal race High prepregnancy BMI Maternal Diabetes and Asthma
bull Genetics (Mutation in FOXF1 Gene Mutation in TMEM70)
bull Or secondary to Cardiac (CHD) and pulmonary (RDS MAS)
diseases acute and chronic hypoxia infection pulmonary hypoplasia policithemia diaphragmatic hernia vein misalignement drug therapy
Hernandez-Dıaz S et al Risk Factors for Persistent Pulmonary Hypertension of the Newborn Pediatrics 2007120e272-e282
Diagnosis bull Clinical diagnosis should be considered when
ndash hypoxemia is disproportioned to chest-X ray abnormalities ndash pre- and post-ductal saturations discrepancy ndash PaO2 difference of at least 20 mmHg between the pre (right
radial) and post (umbilical) ductal arterial blood sample ndash response to Hyperoxia (100 Oxygen)
bull in congenital heart disease PaO2 does not rise above 5ndash6 KPa bull in some infants with PHN the PaO2 will rise to above 14 Kpa but not
in those infants with PHN due to sepsis or associated with pulmonary hypoplasia
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Diagnosis bull Clinical diagnosis should be considered when
ndash hypoxemia is disproportioned to chest-X ray abnormalities ndash pre- and post-ductal saturations discrepancy ndash PaO2 difference of at least 20 mmHg between the pre (right
radial) and post (umbilical) ductal arterial blood sample ndash response to Hyperoxia (100 Oxygen)
bull in congenital heart disease PaO2 does not rise above 5ndash6 KPa bull in some infants with PHN the PaO2 will rise to above 14 Kpa but not
in those infants with PHN due to sepsis or associated with pulmonary hypoplasia
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Echocardiography il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
dP (gradiente Vdx-adx) + pressione atrio dx Pressione atrio destro nei neonati= 5mmHg
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Echocardiography Il rigurgito della valvola tricuspide che stima un gradiente di pressione tra ventricolo e atrio destro al quale va sommata la pressione atriale destra
Dotto arterioso con shunt esclusivo destro gtsinistro ampio in questo caso bisogna essere in grado di escludere le Cardiopatie Congenite dotto dipendenti
Equazione di Bernoulli semplificata dP (mmHg) = 4 (V max)2
PAP dP (gradiente Vdx-adx) + pressione atrio dx (5mmHg)
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Supportive measures bull To maintain normothermia
bull To correct metabolic and hematologic abnormalities (hypoglycemia hypocalcemia acidosis and polycythemia)
bull Intravenous nutrition preferably through a central line
bull To ensure minimal stimulation (covering eyes and ears and maintaining a low-noise environment)
bull Sedation (morphinefentanyl or benzodiazepines)
bull Paralysis should be avoided
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Cardiovascular system The aim is to maintain systemic blood pressure higher than the pulmonary pressures and to ensure optimum tissue oxygenation
bull In case of hypotension or poor perfusion ndash repeated (1-2 ) fluid bolusess (consider normal saline or packed RBCs)
ndash Hb level should be kept gt 13 gdL to optimise oxygen delivery to the tissues
ndash inotropic agents (dopamine dobutamineepinephrine milrinone)
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
SURFACTANT REPLACEMENT THERAPY FOR RESPIRATORY DISORDERS OTHER THAN RDS Surfactant inactivation and secondary dysfunction may occur with
bull meconium aspiration syndrome bull persistent pulmonary hypertension bull neonatal pneumonia bull pulmonary hemorrhage
Surfactant administration techniques surfactant dosage patient populations entry criteria and study outcomes in the small randomized trials and case series of surfactant replacement in neonates with secondary surfactant deficiency vary considerably Effctiveness of surfactant administration was demonstrated in Meconium Aspiration Syndrome Pneumonia and Pulmonary Haemorrrage The surfactant use in Congenital Diaphragmatic Hernia is controversial
Richard A Polin Waldemar A Carlo and COMMITTEE ON FETUS AND NEWBORN
Surfactant Replacement Therapy for Preterm and Term Neonates WithRespiratory Distress Pediatrics 2014133156
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Respiratory support
bull Surfactant replacement
bull Mechanical Ventilation
ndash Hyperventilation
ndash Gentle ventilation
ndash HFOV
bull ECMO
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash Hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Drummond WH Gregory GA Heymann MA Phibbs RA
The independent effects of hyperventilation tolazoline and dopamine on infants with persistent pulmonary hypertension J Pediatr 198198603-1
The ratio of pulmonary artery to systemic artery pressure averaged 114 with standard therapy but decreased to 098 following respiratory alkalosis alone to 087 following drug infusions and to 070 following the combination of alkalosis and drug infusion (5 infants)
Peckham GJ Fox WW
Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension J Pediatr 1978 931005-10
During the study period when the infants (10) were hyperventilated as the Paco2 decreased from 489 to 283 mm Hg (P less than 002) the mean pulmonary artery pressure decreased by 36 mm Hg (P less than 0001) to subsystemic pressure levels and the mean AadeltaO2 decreased by 146 mm Hg (P less than 0001)
Gordon JB1 Rehorst-Paea LA Hoffman GM Nelin LD
Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets Pediatr Res 1999 Dec46(6)735-41
Alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hyperventilation
1) In uncontrolled small studies hyperventilation has been associated with a reduction in the pulmonary artery pressure and improvement in oxygenation
2) Concerns on hyperventilation ndash reduction in cerebral blood flow that can occur if the PaCO2 is lowered to 25ndash35 Kpa
(50)
ndash hypocarbia has been associated with the development of periventricular leukomalacia and cerebral palsy in prematurely born infants
ndash hyperventilation may also cause barotrauma resulting in airleaks and the subsequent development of bronchopulmonary dysplasia
bull Alkali infusion would seem a logical treatment but ndash It may not reduce mortality
ndash It may be associated with an increased risk for the use of extracorporeal membrane oxygenation and prolonged oxygen dependency
ndash It increases the hypoxic reactivity of the pulmonary vascular bed perpetuating the pathophysiology of PHN
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Anju Gupta et al Inhaled Nitric Oxide and Gentle Ventilation in the Treatment of Pulmonary Hypertension of the Newborn mdash a Single-Center 5-Year Experience Journal of Perinatology 2002 22435ndash 441
The principles of gentle ventilation are to use Low ventilatory settings while preserving spontaneous respiration
bullPaO2 between 50 and 70 mm Hg bullPaCO2 between 40 and 60 mm Hg
Ventilator time - cycled pressure -limited constant ndash flow Initial Setting PIP to produce adequate chest excursion and air entry PEEP 5 cm H2O Rate lt 40min IT 05 sec If the infant shows excessively labored spontaneous respiration or the PaCO2 remains above 60 mm Hg high- frequency positive pressure ventilation (HFPPV) is used by setting the ventilator rate at 100min with inspiratory time of 03 seconds and PEEP of 0 cm H2O Minimal sedation with low- dose phenobarbital or rarely midazolam is used Paralysis opiate infusions deliberate respiratory or metabolic alkalosis are not attempted If the infant fails above management andor the PaCO2 remains elevated (gt60 mm Hg) the infant is given a trial on HFOV Infants with persistent PH and severe hypoxemia with PaO2 lt40 mm Hg and preductal oxygen saturation lt80 were started on INO therapy at 25 ppm
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Despite the limitations of not being a randomized controlled trial this study clearly shows that INO is an effective and well - tolerated therapy for infants with severe PH without using hyperventilation
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Henderson-Smart DJ De Paoli AG Clark RH Bhuta T
High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term (Review) Cochrane Database of Systematic Reviews 2009 Issue 3 Art No CD002974 DOI 10100214651858CD002974pub2
Conclusions There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant inhaled nitric oxide inotropes) Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants
HFOV if a high volume strategy is used can however improve oxygenation and carbon dioxide elimination both outcomes being useful in the management of infants with PHN (Anne Greenough and Babita Khetriwal Pulmonary hypertension in the newborn Pediatr Resp Rev 20056 111ndash116)
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
J Pediatr 1997 13155-6
Conclusions treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN Differences in responses are partly related to the specific disease associated with PPHN
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Susan R Hintz et al
Decreased Use of Neonatal Extracorporeal Membrane Oxygenation (ECMO) How New Treatment Modalities Have Affected ECMO Utilization Pediatrics 20001061339-1343
ECMO was used less frequently when HFOV beractant and iNO was more commonly used The differences in treatment modalities used and subsequent use of ECMO were statistically significant We speculate that in this patient population the diagnostic composition of neonatal ECMO patients has changed over time
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Background
Design
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
An AaDO2[561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 specificity 95 positive predictive value 78 )
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
iNO
The biologic effects of NO depends upon
bull direct activation of soluble guanylate cyclase (sGC) bull sGC converts GTP to cGMP
bull relaxes SMC through stimulation of cGMP-gated ion
channels and activation of cGMP-dependent protein kinase type I
bull the actions of cGMP are limited through catabolism by
phosphodiesterases (PDE) especially by type 5 cGMP-dependent PDE (PDE5)
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
iNO
bull Inhaled NO is a selective pulmonary vasodilator
bull NO is rapidly metabolized to nitrate with formation of met-Hgb which is rapidly reduced to ferrous-Hgb by met-Hb reductase in red blood cells
bull NO has the unique ability to regulate the distribution of pulmonary blood flow in the setting of parenchymal lung disease including acute respiratory distress syndrome (ARDS)
bull Abrupt discontinuation of NO inhalation can result in ldquoreboundrdquo pulmonary hypertension leading to a decreased cardiac output and systemic hypotension
Da Steven H Abman M Humbert et al (eds) Pharmacotherapy of Pulmonary Hypertension Handbook of ExperimentalPharmacology 218 DOI 101007978-3-642-38664-0_11 copy Springer-Verlag Berlin Heidelberg 2013257
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Inhaled nitric oxide reduced the use of extracorporeal membrane oxygenation in critically ill neonates born at or near term with hypoxic respiratory failure who had received maximal conventional therapy Nitric oxide therapy was safe well tolerated and relatively easy to administer
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Inhaled nitric oxide improves outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO The reduction seems to be entirely a reduction in need for ECMO mortality is not reduced Oxygenation improves in approximately 50 of infants receiving nitric oxide (The Oxygenation
Index decreases by a (weighted) mean of 151 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg)
The outcome of infants with diaphragmatic hernia was not improved indeed there is a suggestion that outcome was slightly worsened The incidence of disability incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not Conclusion it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia
Neil Finer Keith J Barrington
Nitric oxide for respiratory failure in infants born at or near term Cochrane Database of Systematic Reviews 2006 Issue 4 Art No CD000399 DOI 101002 14651858 CD000399pub2
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Lisa M Askie et al on behalf of the Meta-analysis of Preterm Patients on Inhaled Nitric Oxide (MAPPiNO) Collaboration
Inhaled Nitric Oxide in Preterm Infants An Individual-Patient Data Meta-analysis of Randomized Trials
PEDIATRICS 2011128729
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Cole FS et al
NIH Consensus Development Conference Statement Inhaled Nitric-Oxide Therapy for Premature Infants Pediatrics 2011127363
1 The evidence does not support use of iNO in the care of premature infants of lt34 weeks gestation who require respiratory support
2 iNO may have benefit in infants of lt34 weeks gestation with pulmonary hypertension or hypoplasia In such situations clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties
3 Future research should seek to understand the gap between benefits on lung development and function in infants at high risk of BPD suggested by basic research and animal studies and the results of clinical trials to date
4 Previous strategies shown to be ineffective are discouraged unless new evidence emerges
5 On the basis of assessment of currently available data hospitals clinicians and the pharmaceutical industry should avoid marketing iNO for premature infants of lt34 weeks gestation
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
PM Mourani
Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease J Pediatr 2009154379-84
We found that chronic sildenafil therapy as part of an aggressive treatment program to treat underlying lung disease and PH was well-tolerated had few adverse events and was related to progressive improvement in PH in most patients
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Dopo che i soggetti che avevano partecipato allo studio avevano completato 3 e in alcuni casi 7 anni di trattamento egrave stato riscontrato un numero piugrave elevato di decessi nel gruppo trattato con le dosi alte
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
This study was a proof-of-concept randomized masked study in infants 355 weeksrsquo GA and 3 days old with severe PPHN and oxygenation index (OI) 25 admitted to the NICU
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hernando Baquero
Newborn A Pilot Randomized Blinded Study Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn Pediatrics 20061171077
The study shows that oral sildenafil may be of benefit in improving oxygenation in such infants and therefore can serve as the basis for planning the initiation of larger clinical studies of oral sildenafil in neonates with severe neonatal hypoxemic respiratory failure and severe PPHN
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Jaclyn E Lee et al
Use of Sildenafil to Facilitate Weaning From Inhaled Nitric Oxide in Children With PulmonaryHypertension Following Surgery for Congenital Heart Disease J Intensive Care Med 2008 23 329-334
Inhaled nitric oxide was weaned from 298 plusmn 59 ppm prior to sildenafil initiation to 122 plusmn 34 ppm (mean plusmn SE P = 024) in the 24 hours after sildenafil The mean time to discontinuation of iNO after sildenafil initiation was 44 days
Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Shah PS Ohlsson A
Sildenafil for pulmonary hypertension in neonates (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005494 DOI 10100214651858CD005494pub2
Authorsrsquo conclusions The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) con soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare con buona risposta clinica
bull Dopo 4 giorni in fase di divezzamento dallrsquoiNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alciuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Ripresa della dose piena di iNO senza effetto (PAP 70 mmHg) e
quindi Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Caso clinico NC outpatient giunto tramite STEN per per sofferenza perinatale grave in nato a termine Quadro polmonare compatibile con
ldquoSindrome da Aspirazione di Meconiordquo
bull Paziente in ventilazione HFO con CDP elevate (gt 20 cmH2O) dopo alcuni giorni di soddisfacente scambio dei gas
bull iNO iniziato a 4 giorni di vita per ipossia ed sospetta ipertensione polmonare
bull Dopo 4 giorni di iNO segni clinici di scompenso cardio-circolatorio (amentato fabbisogno di O2 epatomegalia edemi ipotensione arteriosa)
bull Sildenafil ev continuo 07 mgkgdie
bull iNO sospeso dopo 4 giorni dallrsquoinizio del Sildenafil (attualmente in scalo)
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Gaffuri M1 Cristofaletti A2 Mansoldo C3 Biban P
Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease
BMJ Case Rep 2014 Jun 32014
We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant after a therapeutic course with sildenafil The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids no visual recovery was noticed at 2-year follow-up NAION has been associated with PDE5i therapy in adults but to the best of our knowledge it is almost unheard of in children We suggest close monitoring of visual function in children undergoing treatment with sildenafil
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
A metabolite of arachidonic acid prostacyclin is endogenously produced by vascular endothelium It is a potent vasodilator in both the pulmonary and systemic circulations and has antiplatelet aggregatory activity A relative deficiency of prostacyclin may contribute to the pathogenesis of pulmonary arterial hypertension (PAH)
David B Badesch
Prostanoid Therapy for Pulmonary Arterial Hypertension J Am Coll Cardiol 20044356Sndash 61S
bullEpoprostenolo
bullTreprostinil
bullInhaled Iloprost
bullBeraprost
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
The use of PGI2 for neonatal PH 1) The use of epoprostenol led to improved oxygenation and decreased pulmonary artery pressures in eight infants with PPHN all 8 infants survived without requiring ECMO and two infants subsequently developed BPD (Eronen Pediatr Cardiol 1997)
2) The use of beraprost in 7 infants with PPHN showed a significant improvement including hospital discharge for all patients (Nakwan Neonatology 20119932ndash37)
3) Deluca (Paediatr Anaesth 200616596ndash602) published a case report of the use of epoprostenol in an infant with CDH showing a transient but unsustained benefit leading to treatment failure 4) Golzand (Isr Med Assoc J 20057408ndash409) reported on the use of epoprostenol in an infant with PPHN refractory to iNO with good response leading to discontinuation of both PH-specific agents 5) Kovach (Congenit Heart Dis 20072194ndash198) reported on the use of inhaled epoprostenol in an infant with CHD refractory to iNO that resulted in dramatic improvements in ventilation and oxygenation leading to discontinuation of both PH-specific agents
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
WARICHA JANJINDAMAI
Effectiveness and Safety of Intravenous Iloprost for Severe Persistent Pulmonary Hypertension of the Newborn Indian Pediatrics 2013 50 835
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Intravenous iloprost continuous infusion could be a promising therapy for severe pulmonary hypertension of the newborn as an adjunctive therapy in case iNO or ECMO is not available
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
Monocenter retrospective uncontrolled review of ex-preterm babies aged lt18 months admitted to a Pediatric Intensive Care Unit
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Marco Piastra et al
Nebulized Iloprost and Noninvasive Respiratory Suppor for Impending Hypoxaemic Respiratory Failure in Formerly Preterm Infants A Case Series Pediatric Pulmonology 47757ndash762 (2012)
In conclusion noninvasive respiratory support and nebILO in ex-preterm infants with impending HRF and PH are feasible and safe No clinically significant complications have been noticed while significant oxygenationand hemodynamic improvements have been achieved Larger controlled studies are needed to further confirm the clinical usefulness of this approach
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Retrospective comparative study PPHN was treated with inhaled iloprost in 20 newborns and with oral sildenafil in 27 newborns in the absence of inhaled iloprost in the hospital
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Hasan Kahveci
Oral Sildenafil and Inhaled Iloprost in the Treatment of Pulmonary Hypertension of the Newborn Pediatric Pulmonology 2014
Inhalation of iloprost a prostacyclin analog is effective and safe it is potently vasoreactive and well tolerable when used for critically ill patients with PPHN in developing countries Iloprost seems to be more effective than oral sildenafil in terms of the time required for improvement of OI AndashaDO2
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Inotrops
bull PPHN is frequently associated with low systemic pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction
bull PPHN-induced circulatory failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity in newborn infants with PPHN
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
PIERRE TOURNEUX et al
Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatr 2008153345-9
Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary systemic artery pressure ratio and improved cardiac performance
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Eleven neonates with a diagnosis of persistent pulmonary hypertension Dose intravenous loading dose of milrinone (50 μgkg) over 60 mins followed by a maintenance infusion (033-099 μgkgmin) for 24-72 hrs Results bullan improvement in PaO2 (p = 0002) bull a sustained reduction in FIO2 (p lt 0001) and oxygenation index (p lt 0001) bull reduction of mean airway pressure (p = 003) bull reduction of inhaled nitric oxide dose (p lt 0001) bullSerial echocardiography revealed bulllower pulmonary artery pressure bullimproved right and left ventricular output bullreduced bidirectional or right-left shunting (p lt 005)
The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide These data support the need for a randomized controlled trial in neonates
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Bassler D Kreutzer K McNamara P Kirpalani H
Milrinone for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2010 Issue 11 Art No CD007802 DOI 10100214651858CD007802pub2
Milrinone is a selective inhibitor of type III cAMP phosphodiesterase isoenzyme in cardiac and vascular muscle It has both positive inotrope and vasodilator effects
Authorsrsquo conclusions The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or in well resourced countries should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
McNamara PJ et al
Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxi de Pediatr Crit Care Med 2013 Jan14(1)74-84
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Aim to investigate the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration (with pigs)
MAP mean arterial pressure PAPM mean pulmonary arterial pressure PVRI pulmonary vascular resistance index SVRI systemic vascular resistance index
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration Inhaled ILO improves gas exchange only thereby reducing intrapulmonary shunt blood flow Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity
Ralf Geigeret al
Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration
Intensive Care Med (2008) 34368ndash376
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Wu TJ1 Teng RJ Tsou KI
Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates
Pediatrics 1995 96472-4 Seven premature neonates with PPHN
Six cases responded clinically The decrease of AaDO2 reached significance at 36 hours but the decrease of oxygenation index was not significant over 72 hours Four infants survived No significant side effects were encountered MgSO4 may be considered as an alternative treatment of PPHN in premature infants
Nine newborn infants with severe persistent pulmonary hypertension MgSO47H20 solution (200 mgkg) was given intravenously over20-30 minutes PaO2 and SaO2 values increased at 6 hours and PCO2 dereased secondary to a decreasein pulmonary vascular resistence
Yousef K Abu-Osba Treatment of seyere persistent pulmonary hypertension of the newborn with magnesium sulphate
Archives ofDisease in Childhood 1992 67 31-35
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Maurice Beghetti
Effects of inhaled nitric oxide and intravenous magnesium sulphate alone and in combination in a porcine model of hypoxic pulmonary hypertension Med Sci Monit 2003 9(6) BR233-238
inhaled NO is a selective pulmonary vasodilator in a pig model of hypoxic
pulmonary hypertension and show that the simultaneous administration
of intravenous Mg does not enhance either the hemodynamic effect or the
plasma cGMP levels induced by NO inhalation Based on our results there
isno rationale for using Mg at least at the doses tested as a pulmonary
vasodilator either alone or in combination with NO to treat pulmonary
hypertension
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Ho JJ Rasa G
Magnesium sulfate for persistent pulmonary hypertension of the newborn (Review) Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD005588 DOI 10100214651858CD005588pub2
Authorsrsquo conclusions On the basis of the current lack of evidence the use of magnesium sulphate cannot be recommended in the treatment of PPHN Randomised controlled trials are recommended
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Aim to evaluate the acute hemodynamic effects of nifedipine in infants and children with BPD and pulmonary artery hypertension and to compare these effects to those achieved by administering a high concentration of inspired oxygen
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
JOHN R BROWNLEE et al
Acute Hemodynamic Effects of Nifedipine in Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension
Pediatr Res 198824 186
Thus nifedipine is an acute pulmonary vasodilator in some children with bronchopulmonary dysplasia Should future studies document that these acute effects are sustained and that long-term administration in childhood is safe
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Pulmonary vasodilators drugs
bull iNO
bull Phosphodiesterase-inhibitors
bull Prostanoids
bull Inotrops
bull Endhotelin-blockers
bull Magnesium sulfate
bull Calcium channel blockers
bull Tolazoline
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Tolazoline is a potent non-specific vasodilator which acts primarily as a competitive a-adrenergic antagonist In an early study oxygenation improved in only 67 of the infants with severe pulmonary disease treated with intravenous tolazoline There is a high rate (82) of side-effects bullsystemic hypotension bullgastrointestinal haemorrhage bullrenal failure An alternative method of trying to avoid the unwanted systemic effects is to give tolazoline directly into the lungs Via the endotracheal tube can improve oxygenation without side effects
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Deirdra Hartigan Is nebulised tolazoline an effective treatment for persistent pulmonary hypertension of the newborn
Arch Dis Child 20038882ndash86
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Take Home Message
bull Surfactant can be usefull ( avoid it in CDH)
bull HFOV + iNO could be the best respiratory strategy
bull There is a strong evidence for the effectiveness and the safety of iNO in term and near term infants
bull There is evidence for the effectiveness but not for the safety of Sildenafil bull Promising drugs can be considered (but there is no evidence from controlled studies)
Milrinone Inhaled Iloprost Endhotelin blockersNifedipine
bull Magnesium sulfate Talazoline should not be used for PPHN
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale
Ospedale San Gerardo- Fondazione MBBM MONZA