patent ductus arteriosus in the preterm infant (pda) clinical dilemma rudolph am, drorbaugh je, auld...

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