Caffeine Therapy for Premature Infants Improves Survival?
Caffeine Therapy for Premature Infants Improves Survival?
Schmidt B, Roberts RS, Davis P, et al for the Caffeine for Apnea of Prematurity Trial Group
N Engl J Med. 2007;357:1893-1902.
This report represents an 18- to 21-month follow-up of a multicenter randomized controlled trial of caffeine given to premature infants. A previous report from this trial demonstrated that infants receiving caffeine had lower rates of bronchopulmonary dysplasia (BPD) than those who did not; however, potential neurodevelopmental adverse outcomes from use of methylxanthines in the developing brain necessitated longer-term developmental follow-up.
The subjects were originally enrolled if they weighed between 500 and 1250 g and were considered in need of methylxanthine therapy before they were 11 days old (n = 2006). When enrolled, the infants received a loading dose of 20 mg/kg of caffeine followed by 5 mg/kg daily (increased to 10 mg/kg if the 5-mg dose was not clinically sufficient).
For this study, the authors were primarily interested in rates of death or other developmental outcome at 18 months. Other adverse outcomes of interest were cerebral palsy, hearing loss, cognitive deficit, or bilateral blindness.
For each of the developmental outcomes, a standard and validated measurement was used to determine level of function. For example, cognitive delay was defined as performance 1 standard deviation below the mean on the Bayley Scales of Infant Development III.
While the goal was to test infants at 18 months, the authors allowed testing up until 21 months. Of the original cohort, 1869 children (93%) had data for outcomes of this study. The combined outcome of "death or neurodevelopmental disability" occurred more commonly in infants in the placebo group at 46.2% compared to 40.2% of the infants receiving caffeine. This resulted in a number-needed-to-treat of 16 infants to prevent 1 case of death or disability.
When looking at specific outcomes, the differences in rates of death (6.4% for caffeine and 6.5% for placebo), hearing loss (1.9% vs 2.4%), and blindness (0.7% vs 0.9%), and cognitive delay between the 2 groups did not reach statistical significance. The rate of cognitive delay was marginally higher in the placebo group at 38.2% vs 33.8% of treated infants, but this did not reach statistical significance after full adjustment for center and patient characteristics (adjusted odds ratio [OR] 0.83, 95% confidence interval [CI] 0.67-1.02). However, the rate of cerebral palsy was higher in placebo infants at 7.3% vs 4.4%, and this difference remained significant after full adjustment (adjusted OR 0.59, 95% CI 0.39-0.89).
The authors examined clinical outcome variables to determine which short-term benefit of caffeine correlated with long-term benefit of the composite outcome of "death or disability." In short, reduction in time of requiring any positive airway pressure correlated most strongly with reduction in the primary outcome.
The authors conclude that the use of caffeine in premature infants improves survival without neurodevelopmental disability or death.
The authors mention that longer-term outcomes will also be evaluated in this cohort of patients, so stay tuned. It certainly stands to reason that because caffeine reduced morbidity in the first few months after birth (less respiratory and oxygen support), those benefits might extend to better outcomes later. The authors note that the detail of data collected did not allow them to determine if the placebo infants suffered more apneas or desaturations in the newborn period, but it certainly raises an interesting hypothesis of how caffeine might provide the beneficial effects.
Abstract
Schmidt B, Roberts RS, Davis P, et al for the Caffeine for Apnea of Prematurity Trial Group
N Engl J Med. 2007;357:1893-1902.
This report represents an 18- to 21-month follow-up of a multicenter randomized controlled trial of caffeine given to premature infants. A previous report from this trial demonstrated that infants receiving caffeine had lower rates of bronchopulmonary dysplasia (BPD) than those who did not; however, potential neurodevelopmental adverse outcomes from use of methylxanthines in the developing brain necessitated longer-term developmental follow-up.
The subjects were originally enrolled if they weighed between 500 and 1250 g and were considered in need of methylxanthine therapy before they were 11 days old (n = 2006). When enrolled, the infants received a loading dose of 20 mg/kg of caffeine followed by 5 mg/kg daily (increased to 10 mg/kg if the 5-mg dose was not clinically sufficient).
For this study, the authors were primarily interested in rates of death or other developmental outcome at 18 months. Other adverse outcomes of interest were cerebral palsy, hearing loss, cognitive deficit, or bilateral blindness.
For each of the developmental outcomes, a standard and validated measurement was used to determine level of function. For example, cognitive delay was defined as performance 1 standard deviation below the mean on the Bayley Scales of Infant Development III.
While the goal was to test infants at 18 months, the authors allowed testing up until 21 months. Of the original cohort, 1869 children (93%) had data for outcomes of this study. The combined outcome of "death or neurodevelopmental disability" occurred more commonly in infants in the placebo group at 46.2% compared to 40.2% of the infants receiving caffeine. This resulted in a number-needed-to-treat of 16 infants to prevent 1 case of death or disability.
When looking at specific outcomes, the differences in rates of death (6.4% for caffeine and 6.5% for placebo), hearing loss (1.9% vs 2.4%), and blindness (0.7% vs 0.9%), and cognitive delay between the 2 groups did not reach statistical significance. The rate of cognitive delay was marginally higher in the placebo group at 38.2% vs 33.8% of treated infants, but this did not reach statistical significance after full adjustment for center and patient characteristics (adjusted odds ratio [OR] 0.83, 95% confidence interval [CI] 0.67-1.02). However, the rate of cerebral palsy was higher in placebo infants at 7.3% vs 4.4%, and this difference remained significant after full adjustment (adjusted OR 0.59, 95% CI 0.39-0.89).
The authors examined clinical outcome variables to determine which short-term benefit of caffeine correlated with long-term benefit of the composite outcome of "death or disability." In short, reduction in time of requiring any positive airway pressure correlated most strongly with reduction in the primary outcome.
The authors conclude that the use of caffeine in premature infants improves survival without neurodevelopmental disability or death.
The authors mention that longer-term outcomes will also be evaluated in this cohort of patients, so stay tuned. It certainly stands to reason that because caffeine reduced morbidity in the first few months after birth (less respiratory and oxygen support), those benefits might extend to better outcomes later. The authors note that the detail of data collected did not allow them to determine if the placebo infants suffered more apneas or desaturations in the newborn period, but it certainly raises an interesting hypothesis of how caffeine might provide the beneficial effects.
Abstract
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