1. Patent Ductus Arteriosus in the Preterm Infant (PDA)
Clinical dilemma
Burnard ED. The cardiac murmur in relation to symptoms in the newborn. Br Med J. 1939;1:134
Rudolph AM, Drorbaugh JE, Auld PAM, et al. Studies on the circulation in the neonatal period. Pediatrics. 1961;27: 551–556

3. What is PDA?

4. Fetal DA maintain by PGE2 +NO

5. 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 A
Wu GR et al, pediat res 49,: ; 2001 ,

6. 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

7. 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
With increasing ductal dependency on NO inhibition of prostaglandin production woul;d become less likely to produce ductal constriction
Am J Physiol 287: R652–R660, 2004.

8. INCIDENCE (%) 0-24 hours 24-48 hours 48-72 hours 72-96 hours
GEST
(WEEK)
Healthy
RDS
>40 55
38-40 85 50 5
34-37 96 42 12 4
30-33 87 31 56 13 25 11
< 29 80 88 40 84 20 77 7 65
Reller et al, J pediatr 122: ; 1993

9. Spontaneous permanent closure of the DA in ELBW neonates
Koch, J. et al. Pediatrics 2006;117:

10. The cumulative permanent closure rate of the DA by serial ECHO in 42 ELBW neonates during the first 10 days postnatally
Koch, J. et al. Pediatrics 2006;117:

11. Incidence of PDA in different GA At AFHSR 2006-2007
35/140
29/244
37/1183

12. 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

13. 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

15. Chest X-ray

16. 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.,p ,1995

17. 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

18. How good is clinical examination at detecting a significant patent ductus arteriosus in preterm neonate ?

19. 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

20. Arch. Dis. Child. 2003;88;85-86

21. 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.

22. Do I need to confirm ? No pediatric cardiologist ! What I will do ?
PDA
Do I need to confirm ?
No pediatric cardiologist !
What I will do ?

23. 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

24. 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)

25. Echocardiographic tracing with pulsed Doppler of normal pulmonary artery flow, showing systolic forward flow and minimal turbulence in diastole.

26. NeoReviews Vol.5 No.3 March 2004

27. Echocardiographic tracing with pulsed Doppler of bidirectional shunting that can occur as right-sided pressures of the duct increase (before exceeding systemic pressures).

28. Case 1 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

29. Case 2 Female, Preterm infant 850gm
HMD, Received one dose of surfactant
Extubated To nasal CPAP with FiO 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

30. Do I confirm The diagnosis?
PDA
Do I confirm The diagnosis?
Shall I treat?
Which one I will treat?
How I will treat?

31. 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.

32. Occurrence of patent ductus arteriosus (PDA) in 109
conservatively managed preterm neonates (30 weeks’ gestation, requiring ventilation and surfactant treatment (retrospective analysis).
Arch. Dis. Child. Fetal Neonatal Ed. 2007;92; ;

34. 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.

36. 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

37. Markers may identify preterm with 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 echocardiography 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;

38. Shall I treat?
Yes

39. 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

40. 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

41. 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)

42. Indomethacin Treatment for Symptomatic Patent Ductus Arteriosus in
Effectiveness and Side Effects of an Escalating, Stepwise Approach to
Premature Infants Below 33 Weeks of Gestation Pediatrics 2005;116;

44. Conclusions. High-dose indomethacin after intermediate- dose therapy resulted in an overall closure rate of 98.5%
Pediatrics 2005;116;

47. 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.

48. Timing
Post-natal age
Near term infant PGE2 is not the dominant factor maintain ductus patency CottonBiol Neonate 60: ,1991
Reopening of the duct 23% in <26wks
Early prophylaxis (90% borne <30 wk with NO PDA only 40% will develop significant PDA)

51. 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

52. Ibuprofen
It is emerging rapidly as a potential alternative to indomethacin
Causing less vascular compromise
Mesenteric blood flow
Renal perfusion.
CBF

53. 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: /adc

56. 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.

57. EBM
Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol2003;8:
Thomas RL, Parker GC, Van Overmeire B, et al. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. Eur J Pediatr2005;164:
Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants [Cochrane Review]. In: The Cochrane Library; Issue 2, Oxford: Update Software.
Gournay V, Roze JC, Kuster A, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 2004;364:
Van Overmeire B, Allegaert K, Casaer A, et al.; Multicentre Ibuprofen Prophylaxis Study (MIPS) Investigators. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet2004;364:
Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med2000;343:
Gournay V, Savagner C, Thiriez G, et al. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet2002;359:

58. 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

59. 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

60. 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.

62. AFHSR
17/35
12/35
6/45

63. Complication And Mortality AFHSR 2006-2007

64. Future Directions NO Inhibition PGE2 Receptor Manipulation Vitamin A
Other COX Inhibitors Less effective

65. 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

66. Thanks