High versus standard dose caffeine in prevention of apnea of prematurity: an assessor-blinded randomized controlled trial (HI-CAF trial).

High-dose caffeine may improve respiratory outcomes in preterm neonates, but evidence remains uncertain in the era of routine early caffeine use and non-invasive ventilation. We compared high-dose (HDC) versus standard-dose caffeine (SDC) in preterm neonates at risk of or having apnea of prematurity. This single-center, assessor-blinded, randomized controlled trial enrolled preterm neonates born at < 32 weeks' gestation. Neonates were randomized to receive either HDC (loading dose 40 mg/kg, maintenance 10 mg/kg/day) or SDC (loading dose 20 mg/kg, maintenance 5 mg/kg/day). The primary outcome was the need for escalation to non-invasive positive pressure ventilation (NIPPV) for apnea. Secondary outcomes included duration of respiratory support before successful weaning, extubation failure, duration and utilization of respiratory support, feeding outcomes, adverse effects, neonatal morbidities and mortality. A total of 140 neonates were randomized, with 70 assigned to each group. Baseline maternal and neonatal characteristics were comparable. Requiring escalation to NIPPV for apnea in HDC was 30 (42.9%), and in SDC, 38 (54.3%) (RR 0.79; 95% confidence interval (CI) 0.56, 1.11; p = 0.176). The median (IQR) duration of respiratory support before successful weaning was 11.5 (5.0-25.0) days in the HDC and 8.5 (5.0-17.3) days in the SDC group (median difference 1 day; 95% CI - 2.0, 5.0; p = 0.385). Competing-risk analysis accounting for death before successful weaning showed no difference between groups (sub-distribution hazard ratio: 0.89; 95% CI 0.61, 1.30; p = 0.570). Extubation failure, respiratory support utilization, neonatal morbidities, adverse effects, and mortality were similar between groups.

conclusionAmong preterm neonates born at < 32 weeks' gestation, high-dose caffeine did not demonstrate a statistically significant difference in escalation to NIPPV for apnea. Adequately powered multicentre trials are required to evaluate the additional benefit of HDC alongside the use of NIPPV.

trial registrationCTRI/2024/03/063926. Registration date: 11/03/2024. WHAT IS KNOWN: • Caffeine, at standard pharmacological doses, facilitates extubation in preterm infants and reduces the rates of bronchopulmonary dysplasia. • Previous studies have suggested that higher caffeine doses may reduce extubation failure and bronchopulmonary dysplasia. WHAT IS KNOWN: • In preterm neonates born at < 32 weeks' gestation, high-dose caffeine did not significantly reduce the need for escalation to non-invasive positive pressure ventilation for apnea compared with standard-dose caffeine. • High-dose caffeine did not improve duration of respiratory support, extubation failure, neonatal morbidities, or mortality.