Indications and timings for caffeine initiation in preterm infants

Area of Science:

• Neonatal Medicine
• Pharmacology
• Respiratory Physiology

Background:

• Caffeine is widely used to enhance respiratory function in preterm infants.
• Optimal strategies for initiating caffeine therapy, including timing and indications, are not well-defined.
• This review addresses the need for evidence-based guidelines on caffeine administration in this vulnerable population.

Purpose of the Study:

• To systematically evaluate the comparative benefits and harms of different caffeine initiation strategies in preterm infants.
• To assess the impact of timing (e.g., within 2 hours, within 72 hours) and indications (e.g., mechanical ventilation vs. extubation) on critical and important outcomes.

Main Methods:

• A comprehensive search of major databases (MEDLINE, Embase, CENTRAL) and trial registries was conducted up to April 2025.
• Included were randomized controlled trials (RCTs), cluster-RCTs, and quasi-RCTs comparing various caffeine initiation protocols.
• Meta-analyses were performed using fixed-effect models, with evidence certainty assessed using GRADE methods.

Main Results:

• Evidence is very uncertain regarding the effects of early caffeine initiation (within 2 hours or 72 hours) on chronic lung disease (CLD) and duration of mechanical ventilation (DMV).
• Caffeine initiated within 72 hours (C72H) likely reduces CLD and apnea, with moderate certainty evidence.
• Initiating caffeine during mechanical ventilation may reduce CLD and DMV, but evidence for mortality is very uncertain.

Conclusions:

• The optimal timing and indications for caffeine initiation in preterm infants require further investigation due to very uncertain evidence for many comparisons.
• Caffeine initiated within 72 hours appears beneficial for reducing CLD and apnea, though more research is needed.
• Ongoing studies are expected to provide more definitive evidence, potentially altering current conclusions.