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Apnea of prematurity, bronchopulmonary dysplasia.


The objective of this care path is to summarize current evidence and provide guidance on the use of caffeine in preterm infants as it relates to the management of apnea of prematurity.


Apnea of prematurity, defined as a cessation of breathing for 20 seconds or longer, or a shorter pause accompanied by bradycardia, cyanosis, or pallor, is one of the most common diagnoses in the neonatal intensive care unit. Apnea is traditionally classified into three categories: central, obstructive, and mixed, with the majority of apneic episodes in preterm infants being mixed events. The incidence of apnea increases with decreasing gestational age, occurring in nearly all infants born at or before 28 weeks’ gestation and 85% of infants who are born at 30 weeks’ gestation. The frequency of hypoxemic episodes, which can be related to apnea, are associated with a higher risk of death or disability at 18 months corrected age. Methylxanthines, including aminophylline, theophylline, or caffeine, have been the mainstay of pharmacologic therapy to treat and prevent apnea of prematurity for more than 30 years. Caffeine is currently the preferred and most commonly used methylxanthine because of its wide therapeutic index, longer half-life, and lack of need for drug-level monitoring.



Treatment with caffeine in the first 10 days after birth in a large, multicenter, multinational, placebo-controlled, and blinded randomized trial was demonstrated to reduce the risk of bronchopulmonary dysplasia (BPD) (adjusted odds ratio 0.63; 95% CI 0.52–0.76) and decrease the risk of death or disability at 18–21 months (adjusted odds ratio 0.77; 95% CI 0.64–0.93) without any significant short- or long-term safety concerns. Further, a systematic review and meta-analysis of five studies enrolling 192 preterm infants demonstrated methylxanthine treatment effectively reduces apnea 2 to 7 days after treatment (pooled relative risk 0.44; 95% CI 0.32–0.60; I2 10%).

  • Recommendation: In patients weighing 500 to 1250 g at birth, caffeine citrate should be initiated at a loading dose of 20 mg/kg followed by 5 mg/kg daily to either treat apnea, prevent apnea, or to facilitate extubation. Strong recommendation, high quality evidence.

  • GRADE assessment: No significant downgrades to the quality of evidence were identified, based on the cumulative evidence from a systematic review and meta-analysis of five trials evaluating the effect of methylxanthines on apnea as well as a single, large, multicenter randomized trial evaluating the effect of caffeine on short- and long-term outcomes. In addition, future randomized, placebo-controlled trials of caffeine are unlikely to be conducted given the efficacy and safety of caffeine demonstrated in studies to date.

Practice Option #1: Should Caffeine be Used to Increase the Success of Extubation?

Several randomized ...

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