Comparison of Outcomes of High-Dose Versus Low-Dose Caffeine Citrate in the Treatment of Apnea of Prematurity: A Randomized Clinical Trial

Apnea of prematurity (AOP) is common in preterm neonates, and the optimal caffeine citrate dose remains uncertain. Objective: To compare outcomes of high-dose versus low-dose caffeine citrate for AOP. Methods: This open-label randomized clinical trial (NCT06905496) was conducted at Nishtar Hospital, Multan, from January to October 2025 after approval (7028) and written consent. Preterm neonates 32 to less than 37 weeks’ gestation with AOP were randomized 1:1. High-dose caffeine citrate comprised a 40 mg/kg loading dose followed by 20 mg/kg/day for 7 days; low-dose comprised 20 mg/kg then 10 mg/kg/day for 7 days. The primary outcome was extubation failure within 48 hours; secondary outcomes were apnea episode frequency, need and duration of mechanical ventilation, duration of oxygen therapy, and in-hospital mortality. Statistical Package for the Social Sciences version 26.0 was used with a probability value (p) < 0.05. Results: One hundred fourteen neonates were allocated (57 per group). Baseline characteristics were similar except for sex distribution (p=0.036). Apnea episodes were lower with high-dose therapy (10.74 ± 2.91 vs 12.89 ± 2.20), mean difference −2.16 (95% confidence interval −3.12 to −1.20; p<0.001). Mechanical ventilation requirement was similar (38.6% vs 43.9%; p=0.568). In ventilated neonates (47), extubation failure was reduced (27.3% vs 56.0%; p=0.047) and ventilation duration was shorter (median 2 vs 4 days; p=0.027). Oxygen therapy duration (median 10 vs 11 days; p=0.555) and mortality (5.3% vs 8.8%; p=0.463) did not differ. Conclusion: In conclusion, high-dose caffeine reduced apnea burden and improved extubation outcomes without differences in oxygen days or in-hospital mortality.