N CAFFEINE X NICU

 N

Here is a concise bullet-point gist of the review:

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BULLET GIST

Rationale

• Caffeine is widely used in preterm infants to support breathing.

• Optimal timing and indications for starting caffeine remain uncertain.

Objectives

• Compare benefits and harms of different strategies for initiating caffeine in preterm infants.

Methods

• Searched major databases and trial registries to April 2025.

• Included RCTs (including cluster and quasi-RCTs) comparing different initiation timings/indications.

• Outcomes: mortality, chronic lung disease (CLD), adverse events, respiratory and neurodevelopmental outcomes.

• Risk of bias: Cochrane RoB 2.0.

• Analysis: fixed-effect meta-analysis; GRADE certainty assessment.

Included Studies

• 11 RCTs; 774 infants; GA 23–34 weeks; published 2014–2023.

• Comparisons:

  • Caffeine within 2 hours vs 2–24 hours (3 RCTs)

  • Caffeine within 72 hours vs after 72 hours (3 RCTs)

  • Prophylactic caffeine (≤72 h, asymptomatic) vs treating symptomatic apnea (2 RCTs)

  • During mechanical ventilation vs at extubation (3 RCTs)

• No trials compared minimal-symptom vs moderate-to-severe apnea initiation.

• Seven ongoing studies.

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Synthesis of Key Results

1. Caffeine ≤2 h vs 2–24 h

• CLD: Very uncertain effect.

• Duration of ventilation (DMV): Very uncertain.

• Mortality & adverse events: Not reported.

• Hospital stay & apnea: Not reported.

2. Caffeine ≤72 h vs after 72 h

• Mortality: Very uncertain.

• CLD: Likely reduced (moderate certainty).

• Apnea: Likely reduced (moderate certainty).

• DMV & hospital stay: Very uncertain.

• Adverse events: Not reported.

3. Prophylactic ≤72 h vs treating only symptomatic infants

• Mortality: Little to no difference (low certainty).

• CLD: Likely reduced (moderate certainty).

• Adverse events leading to cessation: Little/no difference (low certainty).

• DMV, hospital stay: Very uncertain.

• Apnea: Not reported.

4. Starting caffeine during mechanical ventilation vs at extubation

• CLD: May be reduced (low certainty).

• DMV: May be substantially reduced (low certainty).

• Mortality: Very uncertain.

• Adverse events, apnea, hospital stay: Not reported.

No studies reported intermittent hypoxemia.

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Conclusions

• Evidence for starting caffeine within the first 2 hours or first 72 hours is very uncertain for many major outcomes.

• Starting ≤72 h may reduce CLD and apnea compared with starting after 72 h.

• Prophylactic ≤72 h vs symptomatic treatment:

  • Similar mortality and adverse events.

  • Probably reduces CLD.

• Initiating during mechanical ventilation may reduce CLD and shorten ventilation time, but mortality effects remain uncertain.

• Ongoing trials may significantly influence future conclusions.