Caffeine reduces the rate of bronchopulmonary dysplasia in very low birth weight infants

Article Outline

• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-21
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Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-21 

Question Among infants with very low birth weight, do methylxanthines, such as caffeine, improve respiratory function and other outcomes?

Design Randomized, controlled trial.

Setting Multiple centers, world-wide.

Participants 2006 infants with birth weights of 500 to 1250 g.

Intervention Infants were assigned during the first 10 days of life to receive either caffeine (20 mg/kg loading dose, then 5 mg/kg/d) or placebo, until drug therapy for apnea of prematurity was no longer needed.

Outcomes The primary outcome is a composite of death, cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18 to 21 months. Secondary outcomes include bronchopulmonary dysplasia, ultrasonographic signs of brain injury, necrotizing enterocolitis, retinopathy of prematurity, and growth.

Main Results Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36%) received supplemental oxygen, as did 447 of the 954 infants (47%) assigned to placebo (adjusted odds ratio, 0.63; number needed to treat [NNT] = 10). Positive airway pressure was discontinued 1 week earlier in the infants assigned to caffeine compared with placebo (median postmenstrual age, 31.0 weeks vs 32.0 weeks; P < .001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after 2 weeks (mean difference, −23 g; 95 percent confidence interval, −32 to −13; P < .001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the 2 groups.

Conclusions Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight.

Commentary Schmidt et al performed a multicenter trial to evaluate the effects of caffeine on long-term neurological outcome. These results are not yet available, but the short-term outcomes are now available. Caffeine-treated infants had a shorter duration of respiratory support and were less likely to have BPD. There were no differences in mortality, ROP, NEC, or signs of brain injury. The early entry criterion used in this study (first 10 days) excluded the smallest, sickest infants, who are not candidates for caffeine therapy until much later. Yet, these infants are the most vulnerable to development of neurologic and pulmonary complications. It is not clear whether the reduction in the need for respiratory support in the caffeine treated infants was due to a reduction in lung damage, enhanced respiratory drive, or a combination of both. Caffeine facilitates weaning from mechanical ventilation, and therefore the shorter duration of ventilation is not surprising. Enhanced respiratory drive may also shorten the need for supplemental oxygen that in many instances is used to treat hypoxemic episodes associated with apnea. Caffeine may also directly improve lung mechanics and gas exchange in the immature injured lung. Caffeine-treated infants also had a decreased need for PDA closure, and this could also contribute to the lower incidence of BPD. Assessment of the primary long-term outcomes of this trial is essential before caffeine may be considered in the prevention of BPD.