Caffeine treatment for apnea in infants and children: protocol for a systematic review and meta-analysis

Caffeine citrate is recommended to treat apnea of prematurity in premature neonates based on high-quality evidence demonstrating improved outcomes. In contrast, the prescription of caffeine for mature neonates and infants hospitalized with apnea is based on a paucity of evidence. We present here our protocol for a systematic review to synthesize existing data on the safety and effectiveness of caffeine treatment for apnea in hospitalized pediatric patients, with findings expected to focus on mature neonates and infants.

We developed this systematic review protocol in accordance with the PRISMA guidelines and PRISMA-P checklist. The search strategy was developed with the assistance of an information specialist. Information sources will include MEDLINE, Embase, CINAHL, and CENTRAL databases, as well as unpublished literature sources. Eligible studies will include randomized controlled trials, non-randomized trials, and observational studies investigating caffeine (of any formulation, administered by any route, of any duration) versus placebo, usual care, or non-methylxanthine comparator. The population of interest is children aged 0-17 years with apnea presenting to emergency, critical care, or in-patient settings; studies of premature babies receiving treatment for apnea of prematurity will be excluded. Critical outcomes include total duration of respiratory support, ventilator-free days, duration of invasive mechanical ventilation, duration of non-invasive respiratory support, time to apnea cessation, and serious adverse events. Two authors will independently screen identified studies against prespecified eligibility criteria. Data from included studies will be abstracted in duplicate and entered into our data abstraction form. Risk of bias for each included study will be independently assessed by two reviewers using the appropriate risk of bias tool. If appropriate, we will perform a meta-analysis. The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, with results presented in a summary of findings table.

We will undertake the first rigorous evidence synthesis examining the safety and efficacy of caffeine treatment for apnea in hospitalized pediatric patients, where studies of premature babies with apnea of prematurity will be specifically excluded. We aim to fill the identified knowledge gap with this systematic review.

PROSPERO CRD420251146484.