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Caffeine Helps Premature Infants' Breathing

May 29, 2006

Caffeine therapy may benefit premature infants in at least two ways. In a new study, premature infants who received caffeine therapy for apnea needed less continuous positive airway pressure and mechanical ventilation, and were less likely to develop bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is a major risk factor for neurosensory impairment in early childhood, according to the researchers.

The findings were published in The New England Journal of Medicine (NEJM) and reported by MedPage Today on May 18.

The results are secondary, short-term findings from the Caffeine for Apnea of Prematurity Trial Group. This international, randomized, placebo-controlled trial is gathering data on the long-term (18-21 months) safety and effectiveness of treating very-low-birth-weight infants with methylxanthine therapy.

Methylxanthines, such as caffeine, are derived from a group of chemicals called xanthines. Their various effects in the body include dilation of the bronchial tubes.

The early results about caffeine's apparent benefits in these infants were reported because of their clinical relevance, according to Barbara Schmidt, MD, at McMaster University, and colleagues.

Clinical Trial

The NEJM report included 2,006 infants weighing 500-1250 g considered eligible to receive methylxanthines for the prevention or treatment of apnea, or to facilitate extubation, during the first 10 days of life.

Each infant was randomized to receive either caffeine citrate (Cafcit) or placebo, until drug therapy for apnea of prematurity was no longer required.

Each infant received its first dose of Cafcit or placebo at median postmenstrual age 28 weeks and were weaned off the drug before median postmenstrual age 35 weeks. An IV loading dose of Cafcit 20 mg/k was followed by a daily dose of 5 mg/k, adjusted up to 10 mg/k depending on individual requirements. Oral drug administration was possible once an infant adjusted to oral feeding.

Researchers evaluated the short-term results before the infants were first discharged home. (Long-term follow-up continues.)

In total, 963 infants who received caffeine and who were alive at a postmenstrual age of 36 weeks, 350 (36%) received supplemental oxygen, compared with 447 (47%) of 954 infants who received placebo.

In addition, infants receiving caffeine had their positive airway pressure discontinued one week earlier than infants receiving placebo.

While caffeine appeared substantially to reduce the frequency of bronchopulmonary dysplasia, it also had the potentially adverse effect of reducing infants' weight gain for three weeks of therapy. Importantly, no significant differences in weight gain occurred 4-6 weeks after randomization.

Caffeine intake did not significantly affect the death-rate before the first discharge home, the ultrasonographic signs of brain injury, or necrotizing enterocolitis. Caffeine also appeared to reduce the frequency of patent ductus arteriosus that was judged to require closure with drug therapy or surgery. However, this unexpected finding should be interpreted with caution, said Dr Schmidt.

The researchers noted that information about caffeine's short-term benefits is insufficient, and that long-term follow-up must be undertaken to confirm advisability of caffeine therapy as standard treatment for apnea of prematurity.

The study's long-term primary outcome is a composite of death, cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18-21 months.

Accompanying Editorial

An accompanying editorial in the NEJM, by Eduardo Bancalari, MD, of the University of Miami, regretted that the study's authors did not include apnea or episodes of hypoxemia among the study's endpoints.

Consequently, Dr Bancalari said, they missed an opportunity to evaluate the efficacy of the therapy in reducing the frequency of apnea, the main indication for which caffeine is prescribed:

"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 respiratory stimulants are generally not prescribed until an infant is approaching extubation. Therefore, the relatively early entry criteria used in this study (within 10 days of birth), effectively excluded many of the smallest infants, who remain on mechanical ventilation longer - "[y]et these are the infants who are the most vulnerable to the development of long-term neurologic and pulmonary complications," wrote Dr Bancalari.

He added, "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."

However, he also warned that neonatologists should 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."

"Assessment of the long-term effects of caffeine is needed before this therapy can be routinely recommended to prevent bronchopulmonary dysplasia," he concluded.

Sources: Caffeine Therapy for Apnea of Prematurity. Barbara Schmidt, et al, New England Journal of Medicine, volume 354, pages 2112-2121, 2006.

Caffeine for Apnea of Prematurity. Eduardo Bancalari, New England Journal of Medicine, volume 354, pages 2179-2181, 2006.

Posted: May 2006