Elsevier

The Journal of Pediatrics

Volume 156, Issue 3, March 2010, Pages 382-387.e3
The Journal of Pediatrics

Original Article
Caffeine for Apnea of Prematurity Trial: Benefits May Vary in Subgroups

https://doi.org/10.1016/j.jpeds.2009.09.069Get rights and content

Objective

To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial.

Study design

Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (≤3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions.

Results

There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (–0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03).

Conclusions

There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

Section snippets

Methods

The trial design and the short- and long-term outcomes of the CAP trial have been reported previously.1, 2 The research ethics boards of all participating centers approved the trial. Written parental consent was obtained prior to study entry. In summary, infants with a birth weight between 500 and 1250 g were randomized to receive either caffeine citrate (n = 1006) or normal saline placebo (n = 1000). A computer-generated randomization scheme with variable block sizes was used, and a designated

Results

Adequate data for an analysis of the primary composite outcome were available for 1869 (93.2%) of the infants who were enrolled in the study. The characteristics of these 1869 children were similar in the 2 groups at birth (Table I; available at www.jpeds.com). There were no important differences in these characteristics between the subgroups (Table II).

The number of infants in each subgroup with an adverse outcome (n), the total number in each group (N), the odds ratios, and their 95% CIs are

Discussion

The CAP study showed that caffeine significantly improved survival without neurodevelopmental disability at a corrected age of 18 to 21 months.2 Caffeine also reduced the incidence of bronchopulmonary dysplasia and shortened the duration of supplemental oxygen therapy and assisted ventilation.1 The eligibility criteria were broad and pragmatic. Infants with birth weights from 500 to 1250 g could be randomized in the first 10 days of life when their caregivers considered them to be candidates

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Funded by the Canadian Institute of Health Research and the National Health and Medical Research Council of Australia. The authors declare no conflicts of interest.

Additional members of the Caffeine for Apnea of Prematurity Trial Group are available at www.jpeds.com (Appendix).

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