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Caffeine for Apnea of Prematurity
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     Caffeine is one of the most commonly prescribed drugs among premature infants. It is a potent respiratory stimulant indicated primarily to reduce the incidence of episodes of apnea associated with an immature central nervous system. It is also used frequently in these infants to facilitate weaning from mechanical ventilation. Despite the widespread use of caffeine for these indications, the evidence to support its use is based on the results of a few relatively small and short-term studies.1 Information is lacking on possible long-term effects of prolonged administration of caffeine on the development of the brain and other organs.

    In this issue of the Journal, Schmidt et al. report short-term results of a large, international, randomized, placebo-controlled trial of caffeine administration in preterm infants.2 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. The study included 2006 infants with birth weights of 500 to 1250 g who were considered by their clinicians to be candidates to receive respiratory stimulants for apnea or to facilitate extubation during the first 10 days after birth.

    Important findings in the current report were that infants in the caffeine group had a shorter duration of continuous positive airway pressure and mechanical ventilation than those in the placebo group and were less likely to have bronchopulmonary dysplasia, defined as the need for supplemental oxygen at a corrected postmenstrual age of 36 weeks. There were no differences in the incidence of retinopathy of prematurity, necrotizing enterocolitis, or ultrasonographic signs of brain injury, but during the three weeks after randomization, weight gain was slower in the caffeine group than in the placebo group.

    Although the authors mention that one of the aims of the study was to evaluate the efficacy of caffeine therapy, they did not include apnea or episodes of hypoxemia among the end points of the study. As a result, an opportunity was missed to evaluate the efficacy of this therapy in reducing the frequency of apnea, the main indication for which caffeine is prescribed. Another concern is that because respiratory stimulants are generally not prescribed until an infant is considered to be approaching extubation, the relatively early entry criterion used in this study (i.e., within the first 10 days after birth) effectively excluded many of the smallest infants, who remain on mechanical ventilation for longer periods of time. Yet these are the infants who are the most vulnerable to the development of long-term neurologic and pulmonary complications. This aspect of study design probably explains the relatively high mean gestational age and birth weight of the study population.

    A key question is whether the reported reduction in the need for respiratory support reflects a real reduction in lung damage, enhanced central respiratory drive, or a combination of both. The reduced need for mechanical ventilation with caffeine therapy is not surprising, since respiratory stimulants have previously been shown to improve the chances of successful weaning from mechanical ventilation in preterm infants.3 This finding has been attributed to the increased respiratory drive4 and possibly to the improved diaphragmatic contractility that has been reported in humans and animals in association with the administration of caffeine.5,6

    These effects, however, do not explain the reduced requirement for supplemental oxygen observed among the infants who were treated with caffeine; this observation suggests that the lungs of infants in the caffeine group sustained less damage than was the case in the placebo group. How might this occur? Animal models and data on preterm infants suggest that caffeine may improve lung mechanics and gas exchange in the immature injured lung. For example, mechanically ventilated preterm baboons treated with caffeine had lower pulmonary resistance, higher lung compliance, and better gas exchange than control animals.7 Similarly, in ventilator-dependent preterm infants, caffeine has been shown to reduce pulmonary resistance and increase lung compliance, with a concomitant reduction in the requirement for inspired oxygen.8,9 Conceivably, a shorter duration of mechanical ventilation resulting from enhanced respiratory center activity may actually reduce ventilator-induced lung damage. In addition, caffeine has a diuretic effect that may reduce lung fluid and improve lung mechanics and gas exchange. It is also possible (though unproven) that caffeine has an antiinflammatory action in the immature lung, given the well-documented antiinflammatory properties associated with methylxanthines in patients with asthma.10

    One intriguing possibility is that the lung-protective effect of caffeine reported by Schmidt et al. may relate to their finding that infants treated with caffeine had a decreased need for pharmacologic and surgical closure of the ductus arteriosus. There is evidence that the prolonged patency of the ductus arteriosus in preterm infants is associated with deterioration in lung function and an increased risk of bronchopulmonary dysplasia,11,12 and it is conceivable, therefore, that earlier closure may reduce this risk. However, as the authors point out, the observations regarding closure of a patent ductus arteriosus, which were not among the prespecified hypotheses, must be interpreted cautiously and require confirmation in other studies.

    In contrast to this trial, in which caffeine therapy was initiated as soon as possible after random assignment, which took place during the first 10 days after birth, most infants in whom bronchopulmonary dysplasia develops today are extremely premature and remain on mechanical ventilation for extended periods of time, frequently until long after severe lung damage has developed. When caffeine is used for apnea in these infants, it is prescribed at a much later age, shortly before and after they are extubated and, therefore, after most of the lung damage has occurred. It is unknown whether caffeine would protect against lung injury in this clinical setting, but it seems unlikely.

    After almost 40 years of searching unsuccessfully for effective strategies to prevent bronchopulmonary dysplasia, it would be a welcome surprise if a simple pharmacologic intervention proved to reduce its incidence. The findings of Schmidt et al. suggest the possibility that caffeine may have this effect, at least in infants who do not require prolonged intubation. However, neonatologists must not repeat the same mishap that occurred with the use of corticosteroids in preterm infants to prevent bronchopulmonary dysplasia, which resulted in worse long-term neurologic outcomes. The primary outcomes of the caffeine trial (i.e., long-term outcomes) are still pending. Assessment of the long-term effects of caffeine is needed before this therapy can be routinely recommended to prevent bronchopulmonary dysplasia.

    Dr. Bancalari reports having received grant support from Mead Johnson Nutritionals for a neonatal conference. No other potential conflict of interest relevant to this article was reported.

    Source Information

    From the Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami.

    References

    Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev 2001;3:CD000140-CD000140.

    Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-2121.

    Steer P, Flenady V, Shearman A. High dose caffeine citrate for extubation of preterm infants: a randomized controlled trial. Arch Dis Child Fetal Neonatal Ed 2004;89:F499-F503.

    Aranda JV, Turmen T, Davis J, et al. Effect of caffeine on control of breathing in infantile apnea. J Pediatr 1983;103:975-978.

    Supinski GS, Deal EC Jr, Kelsen SG. The effects of caffeine and theophylline on diaphragm contractility. Am Rev Respir Dis 1984;130:429-433.

    G?lgeli A, ?zesmi C, ?zesmi M. The effects of theophylline and caffeine on the isolated rat diaphragm. Acta Physiol Pharmacol Ther Latinoam 1995;45:105-113.

    Yoder B, Thomson M, Coalson J. Lung function in immature baboons with respiratory distress syndrome receiving early caffeine therapy: a pilot study. Acta Paediatr 2005;94:92-98.

    Davis JM, Bhutani VK, Stefano JL, Fox WW, Spitzer AR. Changes in pulmonary mechanics following caffeine administration in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 1989;6:49-52.

    Laubscher B, Greenough A, Dimitriou G. Comparative effects of theophylline and caffeine on respiratory function of prematurely born infants. Early Hum Dev 1998;50:185-192.

    Page CP. Recent advances in our understanding of the use of theophylline in the treatment of asthma. J Clin Pharmacol 1999;39:237-240.

    Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126:605-610.

    Gonzalez A, Sosenko IR, Chandar J, Hummler H, Claure N, Bancalari E. Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr 1996;128:470-478.(Eduardo Bancalari, M.D.)