1. Patent Ductus Arteriosus in the Preterm Infant Dr Sam Thompson Tuesday Club 15/3/16

2. Quiz 1.What is the normal location of the DA? 2.What is the normal ‘pattern’ of smooth muscle in the DA? 3.In a normal term infant how long after birth, approximately, has ‘functional’ closure of the duct taken place? 4.What factors in the preterm infant are associated with persistence of DA after birth? 5.Approximately what % in PDAs will close spontaneously in 24-27 week neonates? 6.How might a symptomatic PDA present via: (a) respiratory system (b) CVS (c) blood biochemistry? 7.What level of fluid restriction is reasonable when managing a symptomatic PDA? 8.What other supportive measures are recommended? 9.Why should a loop diuretic, such as Furosemide, be used with caution in the management of a symptomatic PDA? 10.How do indomethacin & ibuprofen cause constriction of PDA? 11.What % of infants may respond to a second course of COX inhibitor?

3. PDA in the Preterm Infant Physiology of normal fetal circulation Mechanism of natural closure of DA Factors affecting DA patency in preterm infant Effects, associations & clinical presentations of PDA in the preterm infant Clinical diagnosis When should intervention to close PDA be considered? How should PDA be treated?: Treatment options & current evidence Summary Quiz References

4. Physiology of Fetal Circulation RV typically 60% of IU CO High pulmonary vascular resistance & low systemic Typically DA arises from region just distal to left subclavian artery & connects to junction of main/left pulmonary arteries DA diameter = descending Ao Histologically different from both Ao & PA- thicker intima & more smooth muscle (characteristic spiral arrangement) Patency maintained by low PaO 2 & circulating PGE2 (partly produced by placenta)

5. Mechanism of Normal DA Closure Rise in systemic vascular resistance Decreased circulating PGE2 (reduced production due to placental ‘removal’ & increased clearance by circulating prostaglandin dehydrogenase) Rise in PaO 2 (oxygen sensitive potassium channel mediates DA constriction) Closure begins at PA end Incidence of isolated PDA in term infants 0.03- 0.08% (cf. 30% of infants <1500g) Functional closure in 90% term infant by 48hours; in preterm >30wks may take until 4 th day of life

6. Factors affecting DA patency in the preterm infant Maternal corticosteroids facilitate ductal constriction (possibly by reducing sensitivity to PGE2) Higher circulating PGE2 associated with respiratory distress Immature DA less sensitive to constricting effect of oxygen; more sensitive to circulating PGE2 & NO Pathological changes within DA after constriction are much slower in preterm therefore more readily reopens

7. Effects, Associations & Clinical Presentations of PDA- A Spectrum Mostly asymptomatic Pulmonary oedema (L→R shunt)- increased WOB, increased oxygen requirement, reduced lung compliance, ventilator dependence, CHF Pulmonary haemorrhage- ‘pink’ pulmonary oedema or frank bleeding Systemic hypo-perfusion (ductal ‘steal’)- hypotension (incl. wide pulse pressure), metabolic acidosis, renal impairment, IVH, NEC Chronic oxygen dependency & CLD Apnoea

8. Clinical diagnosis Murmur: in newborn typically short ejection systolic rather than classical long ‘machinery’; often throughout praecordium (may be localised to upper LSE) ‘active praecordium’ (prominent left ventricular impulse) ‘bounding pulse’: wide pulse pressure (>25mmHg) Signs of CHF (tachypnoea, tachycardia, hepatomegaly)

9. When should intervention to close PDA be considered? Ideally decision should be made on combination of clinical grounds (symptomatic PDA) & EchoCG evidence of moderate-large PDA Ventilated infants Infants with persistent signs of CHF Pulmonary congestion/oedema Renal impairment Pulmonary haemorrhage (as part of comprehensive management approach)

10. How should (symptomatic) PDA be treated?....First pause for thought! Neither individual trials nor meta-analyses have demonstrated long-term benefits from measures to close PDA- “there is substantial evidence for an absence of benefit” 1 No benefit from early intervention (“prophylaxis”) PDA spontaneously closes in almost 75% of 24-27 week neonates 2 Interventions (medical or surgical) themselves are not benign! Look for & treat any conditions likely to be contributing to persistent ductal patency, e.g. anaemia, hypoxia, acidosis, sepsis Conservative/supportive management is reasonable option in non-ventilated infants

11. How should (symptomatic) PDA be treated?....Conservative/supportive management appropriate for all infants Neutral thermal environment and adequate oxygenation that minimize demands on LV function The use of positive end-expiratory pressure (PEEP) to improve gas exchange in infants with respiratory compromise. In a study in preterm lambs, PEEP decreased left-to-right ductal flow and increased systemic blood flow Maintenance of the PCV at 0.35-0.40 may increase pulmonary vascular resistance and reduce left-to-right shunting

12. How should (symptomatic) PDA be treated?.... options & current evidence (1) Diuretics: loop diuretics (incl. Furosemide) stimulate renal synthesis of PGE2 & should be used with caution; consider chlorthiazide as alternative Fluid restriction: widely used but lacking in evidence although fluids over 170mls/kg/d are assoc. with increased incidence of PDA; moderate restriction (110-130mls/kg/day) is appropriate Cyclo-oxygenase (COX, prostaglandin synthetase) inhibitors: both Indomethacin & Iburofen equally effective 3 ; Ibup. has increased risk of CLD but lower risk of NEC & transient renal insufficiency [N.B. increased interest in paracetamol- peroxidase inhibitor 5 ] Duration of course of COX inhibitor: Ibup. 10/5/5mg/kg at 24hour intervals, Indo. 0.1- 0.2mg/kg every (12-)24hrs (x3) ; some limited evidence that single dose (0.1mg/kg) Indo. may be effective; no evidence for benefit from prolonged course Repeated courses of COX inhibitors: failure to respond associated with greater immaturity, lack of antenatal corticosteroid therapy, increased severity of respiratory distress, IU inflammation; ~40% infants may respond to subsequent course but further courses unlikely to be beneficial Feeding during COX treatment: no evidence that continuing enteral feeding increases risk of GI adverse effects

13. How should (symptomatic) PDA be treated?.... options & current evidence (2) Surgical ligation- only recommended if remains symptomatic after COX inhibitor treatment or if this is contraindicated; significant potential adverse effects (blood pressure fluctuations, respiratory compromise, infection, IVH, chylothorax, recurrent laryngeal nerve paralysis, CLD & death) especially there is a significant risk of post-operative impaired left ventricular function & hypo-perfusion (decreased LV preload & increased systemic vascular resistance)

14. How should (symptomatic) PDA be treated? How should (symptomatic) PDA be treated? 4 All infants: Fluid restriction 110-130mls/kg/day Maintain PCV >0.35 Consider chlorthiazide if diuretic indicated Ventilated infants: Permissive hypercapnia, low PaO 2 targets & PEEP to facilitate weaning & extubation Consider inotropes Cyclo-oxygenase inhibitor if ventilator-dependent (use of EchoCG to monitor effects) Surgical ligation if failed medical therapy & continued high ventilation requirement

15. Summary Maternal corticosteroids reduce risk of PDA by reducing severity of RDS & ductal sensitivity to PGE2 PDA is associated with a range of potential respiratory, cardiovascular, CNS & renal complications All infants with a PDA should have careful supportive care incl. appropriate fluids, monitoring of oxygen requirement, correction of any contributing factors, e.g. anaemia, acidosis, sepsis Neither individual trials nor meta-analyses have demonstrated long-term benefits from measures to close PDA Use loop diuretics with caution Conservative/supportive management is appropriate in non-ventilated infants

16. Quiz What is the normal location of the DA? What is the normal ‘pattern’ of smooth muscle in the DA? In a normal term infant how long after birth, approximately, has ‘functional’ closure of the duct taken place? What factors in the preterm infant are associated with persistence of DA after birth? Approximately what % of PDAs will close spontaneously in 24-27 week neonates? How might a symptomatic PDA present via: (a) respiratory system (b) CVS (c) blood biochemistry? What level of fluid restriction is reasonable when managing a symptomatic PDA? What other supportive measures are recommended? Why should a loop diuretic, such as Furosemide, be used with caution in the management of a symptomatic PDA? How do indomethacin & ibuprofen cause constriction of PDA? What % of infants may respond to a second course of COX inhibitor? Distal to L Carotid Spiral pattern 48hrs Lack of A/N CS, resp. distress (↑PGE2), immature DA response, slow closure 75% 110-130mls/kg/d NTE, PEEP, PCV 0.35-0.4 Stimulates renal PGE2 Cyclo-oxygenase (PS) inhibitors 40%

17. References 1. Patent ductus arteriosus: to treat or not to treat? William E Benitz Arch Dis Child Fetal Neonatal Ed 2012;97:2 F80-F82 Published Online First: 15 December 2011 doi:10.1136/archdischild-2011-300381 2. Natural evolution of patent ductus arteriosus in the extremely preterm infant. Rolland A, et al. Arch Dis Child Fetal Neonatal Ed 2015; 100:F55-F58 3. Network meta-analysis of indomethacin versus iburofen versus placebo for PDA in preterm infants. Jones LJ et al Arch Dis Child Neonatal Edition 2011; 96:F45 4. Pathophysiology, clinical manifestations and diagnosis of patent ductus arteriosus in premature infants. UpToDate: Literature review current Feb 2016. Last updated Dec1, 2015 5. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Terrin G et al. Arch Dis Child Fetal Neonatal Ed 2016; 101:F127-F136