Patent ductus arteriosus in preterm infants — formative SAQs

SAQ 1 — A weaning preterm who stops weaning (10 marks)

A 26-week gestation, 780 g infant is day 5 of life, ventilated for respiratory distress syndrome and weaning on volume-targeted ventilation. Over 36 hours the oxygen requirement has risen from 28% to 42%, the team note bounding pulses and a hyperdynamic precordium, the blood pressure is 52/24 (mean 34), the urine output has fallen to 0.8 mL/kg/h, and there is a soft systolic murmur at the upper left sternal border. The functional echocardiogram shows a 2.1 mm duct with left-to-right flow, a left atrial-to-aortic root ratio of 1.7, and diastolic flow reversal in the descending aorta. [13]

a) What makes this ductus arteriosus haemodynamically significant? Give the bedside and echocardiographic evidence. (3 marks) [13]

This is a haemodynamically significant PDA. The bedside evidence is the large left-to-right shunt signature — bounding pulses, a hyperdynamic precordium and a widened pulse pressure with a characteristically low diastolic (52/24) — combined with end-organ compromise in the form of oliguria (0.8 mL/kg/h) and a rising oxygen requirement. The echocardiographic evidence is the constellation of a duct diameter above 1.5 mm (2.1 mm), a left atrial-to-aortic root ratio above 1.5 (1.7), and diastolic flow reversal in the descending aorta, which is the direct fingerprint of the systemic steal. [13]

b) Explain in mechanistic terms why the preterm ductus fails to close and why the shunt becomes left-to-right. (3 marks) [13]

The preterm ductus fails for three reasons: its smooth muscle is immature (a thinner medial layer with a weak contractile response to oxygen), it is abnormally sensitive to the relaxing prostaglandins that fall only slowly after birth because clearance is poor, and its intimal cushions are underdeveloped, so the substrate for anatomic closure is deficient. The shunt becomes left-to-right because the pulmonary vascular resistance falls over the first week of life, reversing the pressure gradient across the duct so blood flows from the aorta into the pulmonary circulation in systole and diastole. [13]

c) Outline your immediate management, including the conservative measures you would institute before reaching for a drug. (2 marks) [13]

The immediate management begins with expectant, supportive care: correct hypoxia and acidosis (both relax the ductal smooth muscle), treat anaemia to preserve oxygen delivery, review the ventilation toward lung-protective settings with permissive hypercapnia, and avoid fluid overload while modestly restricting intake. Support the circulation with a vasoconstrictor if hypotension persists (volume boluses rarely help the steal-driven hypotension and may worsen the shunt), and reduce or pause feeds to protect the gut. The end-organ signs are charted serially, because the decision to escalate is made on trajectory. [13]

d) State the two landmark trials that anchor the expectant-first paradigm and what they showed, and the first-line drug with its dose if escalation is needed. (2 marks) [1]

The BeNeDuct trial (NEJM 2023) showed that early ibuprofen did not improve death or bronchopulmonary dysplasia compared with expectant management, and the PDA-TOLERATE trial showed that treating a moderate-to-large duct at one week did not reduce death or bronchopulmonary dysplasia either. If this infant's end-organ compromise progresses despite supportive care, the first-line drug is ibuprofen 10 mg/kg then 5 mg/kg at 24 and 48 hours. [1] [6]

SAQ 2 — The drug, the dose and the ligation debate (10 marks)

A 24-week, 540 g infant has a haemodynamically significant PDA with progressive oliguria (creatinine risen from 78 to 132 µmol/L), a falling diastolic blood pressure, and an escalating oxygen requirement. The team agree that pharmacological closure is now indicated. [13]

a) Give the doses of the three pharmacological agents used to close a preterm PDA, and state which is favoured when renal function is impaired. (3 marks) [2]

The three agents are: ibuprofen — 10 mg/kg loading dose then 5 mg/kg at 24 and 48 hours (a three-day course); paracetamol (acetaminophen) — 15 mg/kg orally or intravenously every six hours for two to three days; and indomethacin — 0.2 mg/kg intravenously every 12 to 24 hours for three doses. When renal function is impaired, as in this infant, paracetamol is favoured, because the cyclo-oxygenase inhibitors (ibuprofen and indomethacin) reduce renal blood flow and worsen oliguria, whereas paracetamol has a more favourable renal profile. [2] [4]

b) Summarise the comparative effectiveness and safety evidence from the Mitra network meta-analysis. (2 marks) [2]

The Mitra JAMA 2018 network meta-analysis showed that ibuprofen, indomethacin and paracetamol were each more effective than placebo for ductal closure, and that ibuprofen and paracetamol were generally favoured over indomethacin because of fewer renal and gastrointestinal adverse effects (less oliguria and fewer feeding issues). This is the evidence base for paracetamol's emergence as an effective, better-tolerated agent. [2]

c) This infant has rising creatinine. Why is a cyclo-oxygenase inhibitor relatively contraindicated here, and what is your chosen agent and your rationale? (2 marks) [4]

A cyclo-oxygenase inhibitor is relatively contraindicated because both ibuprofen and indomethacin reduce renal and mesenteric blood flow, which would deepen this infant's oliguria and risk intestinal ischaemia. The chosen agent is paracetamol, which closes the duct through prostaglandin-related pathways in the ductal wall without the renal vasoconstriction, making it the safer option in established renal dysfunction. [4]

d) Suppose the duct fails two courses of pharmacotherapy. Before recommending surgical ligation, explain the causality-or-bias debate and how it should temper the decision. (3 marks) [10]

The well-documented observational association of ligation with bronchopulmonary dysplasia, intraventricular haemorrhage and neurodevelopmental impairment is heavily confounded by indication — the sickest infants with the largest ducts are the ones selected for ligation, so the harms may reflect the underlying illness rather than the operation itself. This is the causality-or-bias argument of Weisz and McNamara. The decision should therefore be weighed on haemodynamic merits — is the duct the clear limiting factor preventing weaning, and is the infant failing all pharmacological options — rather than driven by an over-read of the association as causation. The modern lean is toward continued expectant and supportive care, reserving ligation for the infant who cannot be weaned from the ventilator and in whom the duct is the demonstrable cause. [10] [13]