Caffeine Therapy for Apnea of Prematurity

Caffeine is one of the most commonly prescribed drugs among premature infants, with the aim to reduce the incidence of episodes of apnea associated with an immature central nervous system and to facilitate weaning from mechanical ventilation. Drug exposure may last for a long time. Despite the widespread use of caffeine for these indications, the evidence to support its use is based on a few small and short-term studies. Moreover, it is uncertain if methylxanthines have short- and long-term risks in infants with very low birth weight. The potential for harm exists because caffeine is an inhibitor of adenosine receptors; adenosine protects brain cells during experimental hypoxia and ischemia in animal models and preserve their ATP level. Moreover, caffeine increases oxygen consumption in preterm infants and may therefore diminish growth.
On these basis, the Caffeine for Apnea of Prematurity Trial Group has recently published on the New England Journal of Medicine (NEJM) ad-interim preliminary results of a placebo- controlled, multicentre trial to study the short- and long-term efficacy and safety of caffeine therapy in infants with very low birth weight.
Infants with birth weights of 500 to 1250 g during the first 10 days of life were randomized to receive either caffeine (20 mg/Kg for the first administration and then 5 mg/Kg/day) or placebo, until drug therapy was no longer needed. While data on the primary outcome of the trial — a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 to 21 months — are not yet available, short-term outcomes were evaluated before the first discharge home and are reported in NEJM.
Of 963 infants assigned to caffeine group and still alive at a postmenstrual age of 36 weeks, 36% developed bronchopulmonary dysplasia, defined as the need for supplemental oxygen at a corrected postmenstrual age of 36 weeks, versus 47% in the placebo group (P<0.001). Positive airway pressure was discontinued earlier in the caffeine than in the placebo group (31 vs 32 weeks; P<0.001). Caffeine reduced weight gain temporarily: the mean difference in weight gain between the two groups was greatest after two weeks (−23 g; P<0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not vary significantly between the two groups.
The results of this study suggest that caffeine therapy for apnea of prematurity may reduce the incidence of bronchopulmonary dysplasia, at least in infants not requiring prolonged intubation. Except for a temporary reduction in weight gain, caffeine has no apparent short term risks and at the dosis used in this trial, drug-induced toxicity is low. The recognition that bronchopulmonary dysplasia is an important risk factor for neurosensory impairment in early childhood may suggest the potential for long-term benefits of caffeine therapy in infants with very low birth weights. However, information on short-term outcomes is insufficient to assess the overall efficacy and risk of neonatal interventions. Follow-up of study cohort to the corrected ages of 18 to 21 months and 5 years is needed before the use of methylxanthine therapy for apnea of prematurity can be recommended.

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