Caffeine Therapy for Apnea of Prematurity: Single-Center Study on Dosing Practices and Perceived Effectiveness

Abstract

Introduction: Caffeine is the registered pharmacologic treatment for apnea of prematurity and is extensively used in the neonatal intensive care units (NICUs) based on evidence from randomized controlled trials. This study aimed to describe the clinical use of caffeine based on real-world data, hypothesizing a divergence from the registered dosing regimen.

Methods: A retrospective analysis included infants born before 30 weeks of gestation, admitted to the NICU of the Erasmus MC Rotterdam from 2018 to 2021. Exclusion criteria comprised infants admitted after postnatal day 2, those not receiving caffeine during admission, patients admitted for less than 24 h, those who spent less than 24 h on non-invasive support, and cases lacking medication data. The primary outcome was the proportion of patients receiving an average caffeine dose higher than registered on the label.

Results: A total of 451 patients with a median gestational age of 28+0 weeks (IQR 26+2-29+0) and birthweight of 1,015 g (IQR 800-1,218) were included. Of these, 402 infants (89%) received an average daily caffeine dosage exceeding the registered dose range. The median caffeine maintenance dose per patient was 5.3 mg/kg/day (IQR 5.0-5.8), with additional therapy (mini-load, doxapram, or intubation) needed in 318 patients (71%).

Conclusion: This study highlights the frequent use of higher caffeine dosages in clinical practice than registered and recommended based on long-term safety data. Despite these high dosages and frequent mini-loads, 28% of patients still required additional treatment with doxapram and/or invasive mechanical ventilation, indicating the need for individualized dosing strategies or alternative therapies.

Keywords: Apnea of prematurity; Caffeine; Neonatal intensive care unit; Pharmacotherapy; Premature infants.

Fig. 1.

Flowchart of patient selection.

Fig. 2.

Prescribed caffeine maintenance dosages in the first four weeks of life. # is considered a medication error.

Fig. 3.

Time to insufficient dosing. a Kaplan-Meier curve of the entire cohort for the time to insufficient dosing. The dashed line reveals the median time to insufficient dosing, indicating the point on the curve where the probability of insufficient dosing is 0.5. b Kaplan-Meier survival curve of the entire cohort for the time to insufficient dosing for the different weeks of GA. The dashed lines reveal the median time to insufficient dosing, indicating the point on the curves where the probability of insufficient dosing is 0.5 for that specific GA group. The table in the upper-right corner reveals the p values of the pairwise comparisons.

Fig. 4.

Time to treatment failure. a Kaplan-Meier curve of the entire cohort for the time to treatment failure. b Kaplan-Meier survival curve of the entire cohort for the time to treatment failure for the different weeks of GA. The dashed lines reveal the median time to treatment failure, indicating the point on the curves, where the probability of treatment failure is 0.5 for that specific GA group. The table in the upper-right corner reveals the p values of the pairwise comparisons.