seminar PDA

seminar PDA

1. Welcome to Seminar Dr. Shimul Mandal (Year 3) Dr. Md. Sazzadul Alam (year 4) Resident Department of Neonatology BSMMU

2. Case summary S/O Jannatul Preterm(29 weeks) LBW(1600 gm) AGA , baby developed repeated apnea, desaturation from 75 hours of age on CPAP then put on mechanical ventilation. At day 7 there was systolic murmur in left upper chest with high pulse volume & normal blood pressure, other parameter was normal on MV support. What may be possibilities behind these scenario?

3. PATENT DUCTUS ARTERIOS (PDA)

4. Contents History Definition Embryology Fetal circulation New adaptation after birth Incidence Classification Risk factor Pathophysiology Diagnosis Management Literature Prognosis

5. History In the early first century(181 AD) Galen initially described the ductus arteriosus Harvey undertook further physiologic study in fetal circulation In 1888 Munro conducted the dissection & ligation of the ductus arteriosus in an infant cadaver In 1938 Robert E. Gross successfully ligated a PDA in a 7 years old child Catheter based closure first performed in 1971 In 1998 Amplatzer duct occluder (ADO) was introduced Amplatzer duct occluder II additional size(ADO II AS) are currently being used.

6. INTRODUCTION The ductus arteriosus is a large vessel that connects the main pulmonary trunk (or proximal left pulmonary artery) with the descending aorta, some 5–10 mm distal to the origin of the left subclavian artery. Patent ductus arteriosus (PDA ) refers to the failure of the closure process and continued patency of this fetal channel . Tricia Lacy Gomella 7 th edition

7. Embryology In normal cardiovascular development the distal portion of the left sixth aortic arch persists as the ductus arteriosus , connecting the left pulmonary artery with the left dorsal aorta. This transformation is complete by 8 weeks of fetal life.

8. Fetal circulation PDA : R-L shunting Pulmonary vascular resistance : High Systemic vascular resistance : Low

9. Major changes in infant circulation occurs following birth: Pulmonary Circulation: Lungs expand, Pulmonary Vasodilation, Drop in pulmonary vascular resistance Systemic Circulation: ↑resistance with placental removal PDA: Flow reverses to L→R shunting, Begins to functionally close due to ↑PaO2 and ↓PGE2 levels

10. PATENT DUCTUS ARTERIOSUS The ductus arteriosus is patent in all newborns at the time of delivery . In full-term healthy newborns, functional closure of the ductus occurs in almost half of full-term infants by 24 hours of age, in 90% by 48 hours after birth . A ductus open beyond 72 h can be considered to be a persistently patent ductus arteriosus . Rennie & Roberton’s Text book of Neonatology 5 th edition Tricia Lacy Gomella 7 th edition

11. Physiology of closure of DA Functional closure(10-15 hrs after birth): Within few hours of birth increased PaO2 & decreased circulating prostaglandins Constriction of inner smooth muscle of the DA Anatomical closure(by 2-3 weeks): DA become ischaemic & hypoxic Formation of vascular endothelial growth factor & other growth factors Transforming the DA into a non-contractile ligament ( Ligamentum arteriosum ) Rennie & Roberton’s Text book of Neonatology 5 th edition A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

12. Incidence In term neonate: 1/2000 live birth(5% to 10% of all CHD) In preterm neonate: 8/1000 live birth(20-42%) In preterm neonates PDA is inversely related to gestational age & maturity. In preterm neonates weighing less than 1000gm: 80% F>M (2:1) A PDA is seen in 10% of patients with other congenital heart lesions . A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

13. Title: Patent Ductus Arteriosus : An Overview James E. Dice , PharmD  and  Jatinder Bhatia , MBBS Source: J Pediatr Pharmacol Ther . 2007 Jul-Sep; 12(3): 138–146 They reported incidence of PDA in term neonates is only 1 in 2,000 births, accounting for 5%–10% of all congenital heart disease. The incidence of PDA in preterm neonates is far greater, with reports ranging from 20%–60% (depending on population and diagnostic criteria ). Gestational age and weight are intimately linked to PDA in preterm neonates. Specifically, PDA is present in 80% of infants weighing less than 1,200 g at birth, compared to 40% of infants weighing less than 2,000 g at birth . Furthermore , symptomatic PDA is present in 48% of infants with a birth weight of less than 1,000 g .

14. Classification of PDA A. Depending on the size (size of the internal ductal diameter in the lateral angiographic view ): Silent : ˂ 1 mm Very small : ≤ 1.5 mm Small : 1.5-3 mm Moderate : 3-5 mm Large : >5 mm A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

15. Type A - conical duct with well defined aortic ampulla and constriction near the pulmonary artery end . Type B - window like structure which is very short in length. B . According to Shape A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

16. Type C - tubular duct without any constriction. Type D - complex duct with multiple constrictions. Type E - elongated duct with constriction remote from the edge of the trachea (as viewed on lateral angiography). A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

17. Risk Factors Factors associated with increased incidence of PDA 1. Prematurity: The incidence is inversely related to gestational age. PDA is found in ~45% of infants <1750 g & 80% in infants weighing <1000 g 2. Respiratory distress syndrome (RDS) 3. Fluid administration 4. Asphyxia 5. Congenital syndromes: PDA is present in 60–70% of infants with congenital rubella syndrome. Trisomy 13, trisomy 18. 6. High altitude 7. Congenital heart disease: A PDA may occur as part of a congenital heart disease Tricia Lacy Gomella 7 th edition

18. Factors associated with decreased incidence of PDA: 1. Antenatal steroid administration 2. Intrauterine growth restriction 3. Prolonged rupture of membranes Tricia Lacy Gomella 7 th edition

19. Pathophysiology Left-to-Right Shunting: The magnitude of shunt depends on : The diameter and length of the ductus arteriosus . The pressure difference between the aorta and the pulmonary artery The systemic and pulmonary vascular resistances. Tricia Lacy Gomella 7 th edition

20. Cont … Left-to-right shunt through the ductus arteriosus results in pulmonary over-circulation and left heart volume overload. If the PDA is small, pressures within the pulmonary artery, the right ventricle and the right atrium are normal. In Moderate or large PDA pulmonary artery pressure may be elevated to systemic levels during both systole and diastole, causes decreased lung compliance, which results in increased work of breathing.

21. Cont … Neuroendocrine adaptations also occur, with increased sympathetic activity and circulating catecholamines that result in increased contractility and heart rate. Long-standing left-to-right shunt causes increased pulmonary vascular resistance. When this resistance approaches and exceeds systemic vascular resistance, leads to reversal of the shunt and develops Eisenmenger’s syndrome.

22. What makes the PDA hemodynamically significant? Pulmonary Overcirculation : Oxygenation failure Increased ventilation requirements Pulmonary Edema Cardiomegaly Systemic Hypoperfusion : Systemic Hypotension End-Organ Hypoperfusion Renal Insufficiency NEC IVH Acidosis(Metabolic, Lactic)

23. Congenital malformation of cardiovascular system in BSMMU from 01/07/18 to 30/06/19 Birth Defect type Male Female Total ASD 19 10 29 VSD 6 8 14 PDA 5 4 9 Double inlet ventricle 2 2 Common atrium 1 2 3 Atrioventricular septal defect 1 1 2 Patent/persistent foramen ovale 1 1 Sinus venosus defect 1 1 Congenital pulmonary valve stenosis 1 1 Ebstein’s anomaly 1 1 Hypoplastic left heart syndrome 1 1 Congenital mitral stenosis 2 2 Dextrocardia 2 2 Other cong. Malformation of heart 2 1 3 Total 42 29 71

24. Diagnosis & Management

25. History Risk factor Prematurity Respiratory distress with surfactant Fluid administration Asphyxia Sex Congenital syndromes Genetic factor No Antenatal steroid Frusemide Tricia Lacy Gomella 7 th edition Mildred T et al

26. Clinical Presentation Usually 1-4 days of age, may at birth Respiratory deterioration Apnea Tachypnea Tricia Lacy Gomella 7 th edition

27. Clinical complication Metabolic Acidosis Intracranial haemorrhage NEC Pulmonary oedema Haemorrhage Rennie & Roberton’s Text book of Neonatology 5 th edition

28. Hypotension Crackles Hepatomegaly

29. Investigation Echocardiography : Gold standard Direct visualization Shunt: Size Shape Direction of flow Secondary effect Contractility Tricia Lacy Gomella 7 th edition

30. Shape of PDA A comprehensive approach to congenital heart diseases: IB Vijayalaksmi

31. CXR

32. Biomarker Natriuretic peptide ANP BNP N –terminal pro BNP Care of the Newborn Revised 8 th edition:Maharban singh

33. Predict the development of symptom Birth wt <1500 gm & <10 days of age, PDA 1.5 mm Left atrial : aortic root > 1.5 after 1 st day Doppler wave form(Closing pattern) Pulsatile pattern Rennie & Roberton’s Text book of Neonatology 5 th edition

34. Indications for treatment(Preterm) hsPDA with one of the following Features of CHF Prolong respiratory support Unexplained/↑ O 2 requirement Recurrent apnea requiring respiratory support(CPAP/MV) attributed to PDA. AIIMS Protocol: 1 st edition 2015

35. Treatment 1 st line : Respiratory support O 2 Support Ventilator support Fluid restriction ↑ Hematocrit Diuretic therapy Rennie & Roberton’s Text book of Neonatology 5 th edition

36. Drug therapy Duct closure therapy by drug Usually tried 1 st unless contraindication Contraindication: GIT/Renal anomaly Suspected CHD Suspected/Active necrotising endocarditis Active bleeding/PLT <50000/ cmm U/O <0.6ml/kg/ hr S.Creatinine ↑ Active infection Rennie & Roberton’s Text book of Neonatology 5 th edition

37. Drug therapy Indomethacin Ibuprofen Acetaminophen(Not approved by FDA)

38. Indomethacin Prophylactic Criteria All infants <1250 gm with surfactant for RDS (Before any clinical sign) Dose: 0.1 mg/kg Route : I/V Duration: Daily f or day 6(From 1 st day) Tricia Lacy Gomella 7 th edition

39. Indomethacin Early symptomatic Dose: I/V O hrs : 0.2 mg/kg 12 hrs : 0.1 mg/kg 36 hrs : 0.1 mg/kg BW >1250 gm or PNA >7 days 2 nd & 3 rd dose 0.2 mg/kg BW <1250 gm PNA <7 days Tricia Lacy Gomella 7 th edition

40. Indomethacin Late symptomatic Dose :0.25 mg/kg When sign of congestive cardiac failure Usually 7-10 days Tricia Lacy Gomella 7 th edition

41. Indomethacin Complication: Renal effect GIT bleeding Thrombocytopenia Tricia Lacy Gomella 7 th edition

42. Ibuprofen Within 1 st wk Dose : hrs : 10 mg/kg 24 hrs : 5 mg/kg 48 hrs : 5 mg/kg At 2 nd wk Dose : hrs : 18mg/kg 24 hrs :9 mg/kg 48 hrs :9 mg/kg Advantage comparision with indomethacin Not ↓ Mesenteric blood flow Not ↓ Renal blood flow ↑Urine ourput ↓ S.Creatinine Tricia Lacy Gomella 7 th edition

43. Surgery Surgery: Significant PDA Contraindication of indomethacin Indomethacin ineffective Relapse after 2nd short course Failure of medical therapy Intractable congenital heart failure with progressive cardiomegaly & deteriorating pulmonary compliance Rennie & Roberton’s Text book of Neonatology 5 th edition Care of the Newborn Revised 8 th edition:Maharban singh

44. PDA in Term Baby Term neonates with PDA should not be treated with indomethacin/ ibuprofen and should have a detailed echo to rule out an underlying congenital heart defect. They would require surgery for closure of an isolated patent ductus arteriosus. AIIMS- NICU protocols 2007

45. Literature Review

46. Cont … Selection criteria Randomised or quasi- randomised controlled trials of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral ) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies,576 infants) The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants)

47. Cont … Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants;

48. Cont … C onclusions Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency . Therefore, of these two drugs, ibuprofen appears to be the drug of choice .

49. The Role of Paracetamol for Closing Patent Ductus Arteriosus. A Challenging Alternative for Ductal Closure ?

50. Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial Source :The journal of paediatrics Published :2016 From the PEDEGO Research Center, and MRC Oulu, University of Oulu, and the Department of Children and Adolescents , Oulu University Hospital , Oulu, Finland Study design : In a controlled, double-blind , phase I-II trial, very low gestational age (<32 weeks) infants requiring intensive care were randomly assigned to intravenous paracetamol or placebo (0.45% NaCl ). A loading dose of 20 mg/kg was given within 24 hours of birth, followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound examinations of ductal calibers were performed before the first dose, and until 1 day after the last dose. The main outcome was a decrease in the ductal caliber without side effects

51. Cont … Results Of 63 screened infants, 48 were randomized: 23 were assigned to paracetamo l and 25 to placebo . Before the intervention, their ductal calibers were similar. During the intervention, the ductus closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours (31.1-324) for the paracetamol -treated vs 338 hours (118-557) for controls ( P = .045 ). Paracetamol serum levels were within the therapeutic range, and no adverse effects were evident. Conclusions Prophylactic paracetamol induced early closure of the ductus arteriosus without detectable side effects . Further trials are required to determine whether intravenous paracetamol may safely prevent symptomatic patent ductus arteriosus .

52. Comparative study of the efficacy and safety of paracetamol , ibuprofen , and indomethacin in closure of patent ductus arteriosus in preterm neonates Source: Eur J Pediatr Published : 12 December 2016 Pediatric Department, Tanta University Hospital, Elgeish street, Tanta , Egypt Inclusion criteria :Preterm neonates with gestational age less than 28 weeks or birth weight less than 1500 g in the first 2 weeks of life with hs -PDA diagnosed with echocardiography and clinical examination

53. Cont … Study design :This prospective study , we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA ( hs -PDA ) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I ( paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days . Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses.

54. Cont … There was no significant difference between all groups regarding efficacy of PDA closure (P = 0.868 ). There was a s ignificant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups (P < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups (P < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group (P = 0.003). No significant difference of hemoglobin (HB ) level or liver enzymes in all groups (P > 0.05).

55. Cont … Conclusion : Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding

56. Cont … Results: They included eight studies that reported on 916 infants . One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants . Therewas no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group .

57. Cont … Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group.

58. Cont … Conclusions: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen ; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA.

59. Oral Paracetamol versus Intravenous Paracetamol in the Closure of Patent Ductus Arteriosus : A Proportion Meta‑ Analysis Source: Journal of clinical neonatology Published: 2 nd august 2018 Author: Jesmin Hossain, Mohammad Kamrul Hassan Shabuj Study: They included 14 studies with 454 premature infants having PDA. Conclusion: Events of closure of hsPDA in premature infants with oral and IV paracetamol were comparable in pooled proportion , and any route of administration can be used

60. Prognosis Isolated PDA : Excellent PT <30 wk : Spontaneous closure 72% Conservative treatment with medication closure rate 94% Tricia Lacy Gomella 7 th edition

61. Thank You