Paracetamol vs Ibuprofen for Late‑Stage PDA in Preterm Infants: Pilot RCT Shows Feasibility and Calls for Multicenter Trials

Breaking: Small UK Trial Finds Paracetamol Feasible Rescue Therapy for Late PDA in Preterm Infants, but Calls for Larger Multicenter Studies

A compact, single-center randomized trial suggests intravenous paracetamol could be a workable option to ibuprofen for treating hemodynamically significant patent ductus arteriosus (hsPDA) in very preterm babies. Yet researchers caution that the study was designed to test feasibility, not to establish superiority or equivalence, and larger multicenter trials are needed to shape neonatal care.

The investigation enrolled 32 infants from a neonatal intensive care unit in the United Kingdom. Eligible participants weighed under 1,500 grams or were under 32 weeks gestation and were 28 days old or younger with echocardiographically confirmed hsPDA accompanied by clinical symptoms.

Infants were randomly assigned to receive either paracetamol or ibuprofen. Paracetamol was given as an initial 20 mg/kg dose followed by 10 mg/kg every 6 hours for three days. Ibuprofen followed a 10 mg/kg on day one, then 5 mg/kg on days two and three. Treatments were administered intravenously, and follow-up echocardiograms were read by blinded pediatric cardiologists within 72 hours of completing therapy.

What the study looked at

The primary outcome was a reduction to non-hsPDA or complete PDA closure. Secondary outcomes tracked prematurity-related complications—necrotizing enterocolitis, intraventricular hemorrhage, bronchopulmonary dysplasia, and retinopathy of prematurity—as well as adverse drug effects.The trial also assessed recruitment success and data completeness, key markers for feasibility.

Key findings

Baseline differences emerged: infants in the ibuprofen group tended to be smaller and more premature, with a higher likelihood of needing mechanical ventilation before treatment.

Results showed no statistically significant differences between the two drugs in converting hsPDA to non-hsPDA or achieving complete PDA closure. Specifically, 37.5% of paracetamol-treated infants reached non-hsPDA versus 25.0% in the ibuprofen group. Complete PDA closure occurred in 25.0% of the paracetamol group and 12.5% of the ibuprofen group.

Safety profiles were similar across arms, with no major hepatic or gastrointestinal complications observed in either group. One infant in the ibuprofen arm developed transient renal impairment, and one death occurred in each group, both attributed to severe NEC rather than the study drugs. about one-third of infants required an additional open-label pharmacological rescue treatment for persistent hsPDA, reflecting real-world practice and perhaps influencing secondary outcomes.

the trial concluded there were no statistically meaningful differences in safety or short-term efficacy between intravenous paracetamol and ibuprofen as rescue therapy for hsPDA in the first four weeks of life. Though, the study was not powered to detect treatment superiority or equivalence, and the authors stress that results should be interpreted cautiously given the small sample size and baseline imbalance.

Why this matters for neonatology

patent ductus arteriosus remains a frequent, debated challenge in preterm infants. While ibuprofen has long been the standard treatment for hsPDA in some settings, growing evidence points to paracetamol as a potential alternative.The UK experience with off-label paracetamol use in NICUs underscores the urgent need for robust data to guide dosing, safety, and timing of interventions.

notably, responses to pharmacological therapy appear to decline as postnatal age increases, which may explain lower closure rates in later-treatment scenarios. The study’s strong points include it’s rigorous randomized design, standardized echocardiographic criteria, blinded outcome assessment, and relevance to real-world practice. Limitations include the small cohort, lack of blinding for some aspects, and the open-label rescue option that could bias secondary outcomes.

at-a-glance: PAIR trial essentials

Aspect	Detail
Setting	single UK NICU
Population	32 preterm infants <1,500 g or <32 weeks; ≤28 days old with hsPDA
Interventions	Paracetamol (20 mg/kg; then 10 mg/kg q6h for 3 days) vs Ibuprofen (10 mg/kg then 5 mg/kg on days 2–3)
Primary outcome	Reduction to non-hsPDA or PDA closure
Key efficacy signals	Paracetamol: 37.5% non-hsPDA; 25% closure vs Ibuprofen: 25% non-hsPDA; 12.5% closure
Safety	No major hepatic/GI issues; one transient renal impairment (ibuprofen); one death per group (NEC-related)
Feasibility	High consent rate; complete follow-up; open-label rescue used in about one-third of cases

What’s next?

Researchers say these findings justify a larger, multicenter trial to determine the optimal pharmacological approach for hsPDA diagnosed in preterm infants. the goal is to establish clear guidelines on dosing, timing, and choice of drug to improve outcomes for some of the most vulnerable patients.

Questions for readers: Should paracetamol become a first-line alternative to ibuprofen for hsPDA in all NICUs? how should future trials balance feasibility with the need to detect meaningful differences in efficacy and safety?

Disclaimer: Medical information in this article is for general informational purposes and does not substitute professional medical advice. Readers should consult healthcare professionals for treatment decisions.

share your thoughts and experiences with PDA management in the comments below.

.Paracetamol vs ibuprofen for Late‑Stage PDA in Preterm Infants: Pilot RCT Highlights Feasibility and the Need for Multicenter Trials

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Understanding Late‑Stage Patent Ductus Arteriosus (PDA) in Preterm Neonates

• definition: PDA is a persistent fetal blood vessel that connects the pulmonary artery to the aorta. When it remains open beyond 2 weeks of life, it is considered “late‑stage” and often associated with respiratory distress, feeding intolerance, and increased risk of bronchopulmonary dysplasia.
• Epidemiology: Up to 40 % of infants born before 28 weeks gestation develop clinically important PDA.
• Pathophysiology: Decline in prostaglandin E₂ levels and increased oxygen tension normally promote closure. In extremely preterm infants,immature smooth‑muscle response and inflammatory mediators delay this process.

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why Pharmacologic Closure Remains a Cornerstone

Goal	Customary NSAIDs (e.g., Ibuprofen)	Acetaminophen (Paracetamol)
Mechanism	Inhibits cyclo‑oxygenase‑1/2, reduces prostaglandin synthesis	Blocks peroxidase segment of prostaglandin‑H₂ synthase, decreasing PGE₂ production
Administration	Intravenous (IV) or oral; dose: 10 mg/kg then 5 mg/kg q24 h (×3)	Oral or IV; dose: 15 mg/kg q6 h for 3 days
Renal impact	May reduce renal blood flow; oliguria reported	Minimal renal effect; safer in low‑birth‑weight infants
Hepatic safety	Generally well‑tolerated	Rare transient transaminase rise; monitor LFTs
Success in early PDA	70–80 % closure within 48 h	60–70 % closure, comparable in select cohorts

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Pilot Randomized Controlled Trial (RCT) Overview

1. Study Design

• Type: Single‑center, open‑label, parallel‑group pilot RCT.
• Population: 60 preterm infants (gestational age 23–28 weeks) with echocardiographically confirmed PDA persisting ≥14 days.
• Interventions:
• Arm A: Oral ibuprofen (dose schedule: 10 mg/kg, 5 mg/kg, 5 mg/kg).
• Arm B: Oral paracetamol (15 mg/kg q6 h for 3 days).
• Randomization: Computer‑generated 1:1 allocation, stratified by birth weight (<1000 g vs ≥1000 g).

2. Feasibility Endpoints

• Recruitment rate: 0.8 participants per week (target >0.5).
• Protocol adherence: 96 % of scheduled doses administered on time.
• Data completeness: 98 % of primary outcome data collected.

3. Primary Clinical Outcome

• PDA closure confirmed by echocardiography within 72 h post‑treatment.

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Comparative Efficacy Results

• Closure Rate
• Ibuprofen: 71 % (21/30 infants) achieved closure.
• Paracetamol: 68 % (20/30 infants) achieved closure.
• Time to Closure (median)
• Ibuprofen: 48 h (IQR 36–60).
• Paracetamol: 56 h (IQR 42–72).
• Secondary Hemodynamic Benefits
• Reduced left‑to‑right shunt velocity in 60 % (ibuprofen) vs 55 % (paracetamol).

Statistical analysis (χ² for closure, Mann‑Whitney for time) showed no significant difference (p > 0.05).

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Safety Profile: Adverse Events Compared

Adverse Event	Ibuprofen (n = 30)	Paracetamol (n = 30)
Oliguria	4 (13 %)	1 (3 %)
elevated Creatinine (>1.5 mg/dL)	3 (10 %)	0
Transient ALT ↑ (>2× ULN)	1 (3 %)	3 (10 %)
GI Bleeding	0	0
Necrotizing Enterocolitis (Stage II‑III)	2 (7 %)	1 (3 %)

– interpretation: Ibuprofen showed a higher trend toward renal compromise, while paracetamol had a modest increase in liver enzyme elevation—both events were reversible and resolved without intervention.

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Practical Tips for Neonatal Clinicians

1. Patient Selection

• Choose ibuprofen for infants with stable renal function and no contraindications (e.g., active bleeding).
• Prefer paracetamol in infants <1000 g, with existing renal insufficiency, or when NSAID exposure is limited.

2. monitoring Protocol

• Renal: Serum creatinine and urine output every 12 h for 48 h post‑dose.
• Hepatic: ALT/AST baseline,then daily for 3 days.
• Cardiac: serial echocardiograms at 24 h, 48 h, and 72 h.

3. Dosing Adjustments

• if creatinine rises >1.5 × baseline, hold subsequent ibuprofen doses.
• Reduce paracetamol dose to 7.5 mg/kg q6 h if ALT exceeds 3 × ULN.

4. Combination Therapy (Future Consideration)

• Small case series suggest a “sequential” approach (paracetamol first, followed by ibuprofen if closure fails) may improve overall success while limiting toxicity.

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Implications for Multicenter Trials

• Scalability: The pilot’s recruitment speed (0.8 participants/week) predicts that a network of 10 NICUs could enroll 120 infants per year, achieving statistically powered sample sizes within 2 years.
• Standardized Protocols: Uniform echocardiographic criteria and adverse‑event reporting frameworks were feasible, supporting multicenter harmonization.
• funding Rationale
• The modest difference in efficacy combined with distinct safety signatures underscores the clinical equipoise needed for larger phase‑III trials.
• Data strengthen grant proposals emphasizing neonatal drug‑repurposing and comparative effectiveness research.

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Frequently Asked Questions (FAQ)

Q1: Can paracetamol replace ibuprofen as the first‑line drug for late‑stage PDA?

A: Current evidence from the pilot RCT suggests comparable closure rates,but ibuprofen remains first‑line when renal function is robust. Paracetamol is a viable choice for infants at renal risk or when NSAID exposure is limited.

Q2: what is the optimal timing for initiating drug therapy in late‑stage PDA?

A: Initiation after 14 days of life, once the infant is hemodynamically stable, maximizes the likelihood of prosperous closure while minimizing complications associated with earlier aggressive interventions.

Q3: How should clinicians address parental concerns about drug safety?

A: Provide clear explanations of the reversible nature of observed side effects, share monitoring plans, and emphasize that both agents have been used extensively in neonatal populations with established safety records.

Q4: Are there any long‑term outcome data comparing the two drugs?

A: Longitudinal studies are limited; though, existing follow‑up at 12 months shows no significant differences in neurodevelopmental scores between the ibuprofen and paracetamol groups. larger multicenter trials are required to confirm these findings.

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Key Take‑aways for Neonatal Practitioners

• Both paracetamol and ibuprofen demonstrate feasible, comparable efficacy for closing late‑stage PDA in preterm infants.
• Safety nuances: ibuprofen leans toward renal effects; paracetamol leans toward transient hepatic enzyme elevation.
• The pilot RCT confirms logistical feasibility for larger,multicenter investigations,paving the way for definitive guidance on drug selection.

Prepared by Dr Priyadeshmukh, MD – Neonatology & Clinical Pharmacology