The Evolution of Caffeine in Neonatal Intensive Care
Caffeine citrate has long been recognized as a cornerstone of neonatal pharmacology. Since the landmark Caffeine for Apnea of Prematurity (CAP) trial in 2006, methylxanthines—specifically caffeine—have transitioned from being a targeted treatment for apnea to a foundational therapy for improving respiratory outcomes in very low birth weight infants. Despite its widespread use, the neonatal community continues to grapple with the “when” and “why” of caffeine initiation. The 2025 Cochrane systematic review by Borys and colleagues provides a timely and rigorous evaluation of the relative benefits and harms associated with different timings and clinical indications for starting this essential medication.
Highlights
1. Caffeine initiation within the first 48 to 72 hours of life is increasingly associated with a reduction in the incidence of chronic lung disease (CLD) and successful extubation.
2. While early prophylactic use is common, the evidence distinguishing between initiation within two hours of birth versus later in the first day remains a critical area of investigation.
3. The therapeutic window for caffeine extends beyond simple respiratory stimulation, potentially offering neuroprotective and renal protective effects in the fragile preterm population.
Background: The Burden of Respiratory Failure in Preterm Infants
Preterm infants, particularly those born before 32 weeks of gestation, face significant risks of respiratory distress syndrome (RDS) and apnea of prematurity (AOP). These conditions often necessitate mechanical ventilation, which, while life-saving, contributes to the development of bronchopulmonary dysplasia (BPD) or chronic lung disease (CLD). CLD remains a primary driver of long-term morbidity, including developmental delay and persistent pulmonary hypertension.
Caffeine serves as a potent adenosine receptor antagonist. By blocking A1 and A2A receptors, caffeine increases the sensitivity of the medullary respiratory center to carbon dioxide, stimulates diaphragmatic contractility, and improves minute ventilation. However, the optimal timing for starting this therapy—whether as a prophylactic measure immediately after birth or as a rescue treatment when symptoms appear—remains a subject of intense clinical debate.
Study Design and Methodological Rigor
The 2025 Cochrane review (Borys et al.) employed a comprehensive search strategy across MEDLINE, Embase, and CENTRAL, including trial registries up to April 2025. The researchers focused on randomized controlled trials (RCTs), including cluster-RCTs and quasi-RCTs, to ensure the highest level of evidence. The primary objective was to evaluate the relative benefits and harms of various initiation strategies.
Clinical Comparisons Evaluated
The review categorized caffeine initiation into five distinct comparative frameworks:
1. Ultra-early initiation (within 2 hours of life) versus initiation between 2 and 24 hours.
2. Early initiation (within 72 hours of life) versus late initiation (after 72 hours).
3. Prophylactic initiation (within 72 hours) versus treatment only once the infant becomes symptomatic.
4. Initiation while the infant is still on mechanical ventilation versus initiation only at the time of extubation.
5. Initiation at the onset of minimal symptoms versus waiting for moderate-to-severe apnea.
Defining Success: Outcome Measures
The researchers identified all-cause mortality, chronic lung disease (CLD), and severe adverse events as critical outcomes. Important secondary outcomes included the duration of mechanical ventilation (DMV), duration of hospital stay (DHS), incidence of acute kidney injury (AKI), and long-term neurodevelopmental markers such as cerebral palsy, developmental delay, and sensory impairments (blindness or deafness).
Key Findings: Timing Matters
The synthesis of current evidence suggests that the timing of caffeine initiation is not merely a matter of administrative convenience but a physiological intervention that can alter the trajectory of neonatal lung injury.
Early vs. Late Initiation
Data consistently indicate that initiating caffeine within the first 72 hours of life is associated with a reduced risk of CLD compared to later initiation. This “early” window appears to facilitate the transition from invasive ventilation to non-invasive support. By increasing respiratory drive and reducing the inflammatory response in the lungs, early caffeine may mitigate the barotrauma and volutrauma associated with prolonged intubation.
Mechanical Ventilation and Extubation
A significant finding in the review pertains to infants on mechanical ventilation. Initiating caffeine while the infant is still intubated, rather than waiting for the moment of extubation, appears to increase the success rate of the first extubation attempt. This is clinically significant as failed extubations and subsequent re-intubations are known risk factors for both BPD and intraventricular hemorrhage (IVH).
Safety and Adverse Events
Caffeine is generally well-tolerated in the neonatal population. The Cochrane review monitored for adverse events such as tachycardia, gastric intolerance, and seizures. While higher doses or very early administration can sometimes lead to transient increases in heart rate, the overall safety profile remains robust. Interestingly, some data suggest a protective effect against acute kidney injury, likely due to caffeine’s influence on renal blood flow and adenosine-mediated vasoconstriction.
Expert Commentary: Translating Evidence to the Bedside
The shift toward earlier caffeine initiation reflects a broader trend in neonatology: moving from reactive rescue to proactive prevention. Experts suggest that for the most vulnerable infants—those under 28 weeks’ gestation—the benefits of starting caffeine in the delivery room or within the first few hours of life likely outweigh the risks.
However, clinicians must remain mindful of the “caffeine paradox.” While caffeine reduces BPD, we must ensure that it does not mask underlying pathologies or lead to the premature withdrawal of necessary respiratory support. Furthermore, the long-term neurodevelopmental data, largely derived from the CAP trial, show that caffeine is safe and perhaps even beneficial for neuroregeneration, though the specific impact of “ultra-early” (<2 hours) dosing on the developing brain requires more longitudinal study.
Conclusion and Future Directions
The 2025 Cochrane review reaffirms caffeine’s role as a vital tool in the NICU. The evidence leans heavily toward earlier initiation—specifically within the first 72 hours—to reduce the duration of mechanical ventilation and the incidence of chronic lung disease. Future research should focus on refining the dosage for ultra-early administration and exploring the potential synergistic effects of caffeine when combined with other therapies like surfactant or non-invasive neurally adjusted ventilatory assist (NAVA).
For now, the message for clinicians is clear: timing is a critical variable. Delaying caffeine until apnea becomes severe may miss a vital window for pulmonary protection and successful respiratory transition.