patent ductus arteriosus in the preterm infant (pda) clinical dilemma rudolph am, drorbaugh je, auld...
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Patent Ductus Arteriosus inthe Preterm Infant
(PDA)
Clinical dilemma
Rudolph AM, Drorbaugh JE, Auld PAM, et al. Studies on the circulation in the neonatal period. Pediatrics. 1961;27: 551–556
Burnard ED. The cardiac murmur in relation to symptoms in the newborn. Br Med J. 1939;1:134
What is PDA?
Fetal DA maintain by PGE2 +NO
Functional closure Fetal circulation & PDA Patency (PGE2, No )
After Birth INCREASE PaO2
, Cytochrome-P450, inhibits K+)
Pulmonary Vascular resistance Circulating PGE2 and Its receptors
Bouayad et al, am J physiol Heart Circ 380:2001
Antenatal Steroid Am J Physiol Heart Circ Physiol, Sep 1981; 241: H415 - H420
Vitamin AWu GR et al, pediat res 49,:747-754; 2001 ,
Anatomical closure &
Remodeling Constrictive effect of O2 Loss of responsiveness to PGE2 Obliteration of vessel lumen Reduction in intramural vasa vasorum blood
flow Ductus wall hypoxia lead to reduction PGE2
and NO production (Apoptosis VEGF) Preterm infant fail in this remodeling
mechanism
Kajino et al, Factors that increase the contractile tone of DA Am j physiol 281 ;2001
Patency of the preterm fetal ductus arteriosus
The preterm DA is morphologically and biochemically immature Edward M 2007
Poorly responsive to contractile stimuli Low oxygen tension Vasodilators ( adenosine, PGE, NO ) The excessive inhibitory effects of endogenous
PGE and NO + a weaker intrinsic DA tone
Am J Physiol 287: R652–R660, 2004.
INCIDENCE (%)
GEST(WEEK)
Healthy RDS Healthy RDS Healthy RDS Healthy RDS
>40 55 0 0 0
38-40 85 50 5 0
34-37 96 42 12 4
30-33 87 87 31 56 13 25 0 11
< 29 80 88 40 84 20 77 7 65
0-24 hours 24-48 hours 48-72 hours 72-96 hours
Reller et al, J pediatr 122:559-562; 1993
Koch, J. et al. Pediatrics 2006;117:1113-1121
Spontaneous permanent closure of the DA in ELBW neonates
Koch, J. et al. Pediatrics 2006;117:1113-1121
The cumulative permanent closure rate of the DA by serial ECHO in 42 ELBW neonates during the first 10 days postnatally
Incidence of PDA in different GA At AFHSR 2006-2007
PDA Sp Closure0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<=28wk29-32>=33wk
35/140
29/244
37/1183
The usual story
PRETERM MALE INFANT WITH HMD Treated with mechanical ventilation, and
SURFACTANT Improved, with lower inspired oxygen
requirements and ventilation support Aminophyline started in preparing for extubation 2-3 days, when discussions ensued about
EXTUBATION FiO2 requirement and pressure support increased
Hemodynamic alteration
Magnitude of L R shunt ( >50% COP) Increase pulmonary venous pressure and
Pulmonary congestion Increaser HR and stroke volume Blood flow rearrangement lead to organ
hypoperfusion Pulmonary hemorrhage
Pediatr Res 35:331A, 1994
Chest X-ray
Course Left-to-right shunting through the ductus. Increased pulmonary blood flow &
pulmonary congestion Hemorrhagic pulmonary Edema Worsening respiratory status with ventilation
difficulties surfactant dysfunction Reduced organ perfusion Metabolic Acidosis PDA affects key outcome variables of early
preterm life.
Lung Biology in health and Disease vol84.,p531-545,1995
Clinical Diagnosis
Failure to wean ventilator pressures and O2
Systolic murmur at the left upper sternal edge radiating to the back
Increased precardial impulses Widened pulse pressure Prominent or bounding peripheral pulses
J Paediatr Child Health. 1994;30:406–411
How good is clinical examination at detecting a significant patent ductus
arteriosus in preterm neonate ?
Is It diagnostic ?
Homodynamic significance PDA Very low sensitivity for diagnosis Most significant PDA did not produce
clinical signs.
Davis P . Arch Pediatr Adolesc Med. 1995;149:1136–1141
Arch. Dis. Child. 2003;88;85-86
CLINICAL BOTTOM LINE
Clinical evaluation of PDA, either by auscultation or by palpation of pulses, is of limited value
Reliance on clinical signs results in a delayed diagnosis of PDA.
Doppler flow echocardiography is required to confidently rule in or rule out the diagnosis of PDA.
J Perinat Med. 2005;33(2):161-4.
PDA
Do I need to confirm ? No pediatric cardiologist !
What I will do ?
Echocardiographic Diagnosis
The consequence is accurate but rarely timely diagnosis
Availability of Pediatric cardiologist & ECHO Does this baby have a structurally normal
heart? Requires neonatologists to develop the
skills to perform the imaging.
NeoReviews Vol.5 No.3 March 2004
ECHO
Anatomy of the Great Vessels Is the Ductus Arteriosus Patent? Direct Imaging OF DA TURBULENCE IN THE MPA Is the Ductal Shunting Hemodynamically
Significant? VOLUME OF DUCTAL SHUNTING (Qp:Qs)
Echocardiographic tracing with pulsed Doppler of normal pulmonary artery flow, showing systolic forward flow and minimal turbulence in diastole.
NeoReviews Vol.5 No.3 March 2004
Echocardiographic tracing with pulsed Doppler of bidirectional shunting that can occur as right-sided pressures of the duct increase (before exceeding systemic pressures).
Case 2 Female, Preterm infant 850gm HMD, Received one dose of surfactant Extubated To nasal CPAP with FiO2 0.21
after aminophylin loading and maintained N. Gastric Feeding initiated Third day a loud systolic murmur heard with
widing pulse pressure ABG Norma, maintain normal hemodynamic
status
Do I confirm The diagnosis?
Shall I treat?Which one I will treat?
How I will treat?
PDA
Conservative treatment for patent ductus arteriosus in the preterm
It is important to make distinguish between a clinically significant and non-significant PDA
Fluid restriction (maximum 130 ml/kg a day beyond day 3
Adjustment of ventilation by lowering inspiratory time to as low as 0.35 s, and giving higher PEEP
Arch Dis Child Fetal Neonatal Ed 2007;92:F244–F247.
Arch. Dis. Child. Fetal Neonatal Ed. 2007;92;244-247;
Occurrence of patent ductus arteriosus (PDA) in 109conservatively managed preterm neonates (30 weeks’ gestation, requiring ventilation and surfactant treatment
(retrospective analysis).
Conclusion: The managed care plan resulted in an overall ductal closure rate of 100%. These results suggest that conservative treatment of PDA is a worthy alternative to medical treatment.
Impact of patent ductus arteriosus cerebral oxygenation in preterm infants. A hemodynamically significant patent ductus
arteriosus has a negative effect on cerebral oxygenation in the premature infant.
Subsequent and adequate treatment of a PDA may prevent diminished cerebral perfusion and reduces the change of damage to the vulnerable immature brain.
PEDIATRICS Vol. 121 No. 1 January 2008, pp. 142-147
Markers may identify pretermwith PDA at high risk
It is difficult to predict which infants with a PDA go on to develop major complications
Conventional echocardiographic markers applied at 48 hours of life do not predict outcome
Serum cardiac Troponin T (cTnT) B-type natriuretic peptide (BNP) NTpBNP and cTnT in conjunction with echocardio
graphy may provide a basis for trials of targeted medical treatment in infants with a PDA.
Arch. Dis. Child. Fetal Neonatal Ed. published online 19 Feb 2008;
Shall I treat?
Yes
Treatment
PGE2 appears to be the most important factor regulating ductal patency
Inhibition of PG synthesis by inhibition of the enzyme cyclooxygenase (COX) produces constriction of the DA
Indomethacin
Over the years, therapy with indomethacin has been accepted as effective in mediating ductal closure in preterm neonates.
Little consensus regarding proper dosage, treatment duration, and optimal timing of treatment.
NeoReviews Vol.4 No.8 August 2003 e215
Indomethacin Dose & Timing
The response of the ductus to indomethacin depends on the size of the dose and the number of doses administered.
3 doses regimen Vs 5-6 doses (at 0 hours, 12 hours, 24 hours, 48 hours, and 72 hours).
Continuous infusion (17 mcg/kg per hour over 36 h)
Indomethacin Treatment for Symptomatic Patent Ductus Arteriosus inEffectiveness and Side Effects of an Escalating, Stepwise Approach toPremature Infants Below 33 Weeks of Gestation Pediatrics 2005;116;1361-1366
Conclusions. High-dose indomethacin after
intermediate-dose therapy resulted in an overall
closure rate of98.5%
Pediatrics 2005;116;1361-1366
Authors’ conclusions
Prolonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality.
The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course.
Timing
Post-natal age Near term infant PGE2 is not the dominant
factor maintain ductus patency CottonBiol Neonate 60:273-282,1991
Reopening of the duct 23% in <26wks Early prophylaxis (90% borne <30 wk with NO PDA
only 40% will develop significant PDA)
Complications of Indomethacin
Decrease in glomerular filtration rate Inhibits platelets and prolongs the bleeding
time Frank renal or gastrointestinal bleeding are
contraindications to the use of indomethacin.
Isolated cases of localized intestinal perforation & NEC
? Sepsis NeoReviews Vol.4 No.8 August 2003
Ibuprofen
It is emerging rapidly as a potential alternative to indomethacin
Causing less vascular compromise Mesenteric blood flow Renal perfusion. CBF
Safety and efficacy of ibuprofen
Ibuprofen is as effective as indometacin for PDA treatment in extremely premature infants
No increasing in the incidence of complications NEC, CLD
Fewer doses of drugs were needed to achieve acceptable closing rates.
Arch Dis Child Fetal Neonatal Ed 2008;93:F94–F99. doi:10.1136/adc.2007.120584
Conclusion
No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA.
Ibuprofen reduces the risk of oliguria. ibuprofen may increase the risk for CLD,
and pulmonary hypertension Indomethacin should remain the drug of
choice for the treatment of a PDA.
The Cochrane Collaboration 2007.
Undesirable adverse effect
Increased vascular resistant Increase the free fraction of bilirubin by a
factor of four & the risk of bilirubin encephalopathy
BPD and PPHN
Speziale MV, Allen RG, Henderson CR, Barrington KJ, Finer NN. Effects of ibuprofen and indomethacin on the regional circulation in newborn piglets. Biol Neonate. 1999;76:242–252
Concurrent Use of Furosemide
It increases PG production It could decrease ductal response to
indomethacin. Consequently, furosemide may have conflicting
physiologic effects in the preterm infant who has PDA
Used only with signs of congestive HF and pulmonary congestion
not with fluid restriction and indomethacin or Ibu.
Cochrane review 2004
Surgical Closure
It is usually reserved for PDA refractory to medical management
Proposed as a primary treatment of PDA and the treatment of PDA that responds poorly to indometacin
Little DC, Pratt TC, Blalock SE, et al. Patent ductus arteriosus in micropreemies and full-term infants: the relative merits of surgical ligation versus indometacin treatment. J Pediatr Surg 2003;38:492–6.
AFHSR 2006-2007
Conser INDO IBU Surg
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<=28 29-32
>=33
12/3517/35
6/45
Complication And Mortality AFHSR 2006-2007
PDA MR IVH NEC PHE0.000%
5.000%
10.000%
15.000%
20.000%
25.000%
30.000%
<=28 wk
29-32
>=33
P 0.001
Future Directions
NO Inhibition PGE2 Receptor Manipulation Vitamin A Other COX Inhibitors Less effective
Summary
PDA is a common complication of very low-birthweight infants who is recovering from RDS
Early diagnosis (ECHO)and treatment of homodynamic significant duct prevent major morbidity
Conservative treatment is visible Either indo. Or IBU you need the duct
closed with out the hand of surgeons