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J Pediatr. 2008 Oct;153(4):513-8. doi: 10.1016/j.jpeds.2008.04.025. Epub 2008 Jun 4.

A randomized controlled trial of theophylline versus CO2 inhalation for treating apnea of prematurity.

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  • 1Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.



To determine whether inhalation of 0.8% CO(2) in preterm infants decreases the duration and rate of apnea as effectively as or better than theophylline with fewer adverse side effects.


A prospective, randomized, control study of 42 preterm infants of gestational age 27 to 32 weeks assigned to receive inhaled CO(2) (n = 21) or theophylline (n = 21). The study group had a mean (+/- standard error of the mean) birth weight of 1437 +/- 57 g, gestational age of 29.4 +/- 0.3 weeks, and postnatal age of 43 +/- 4 days. After a control period, 0.8% CO(2) or theophylline was given for 2 hours, followed by a recovery period.


In the CO(2) group, apneic time and rate decreased significantly, from 9.4 +/- 1.6 seconds/minute and 94 +/- 15 apneic episodes/hour to 3.0 +/- 0.5 seconds/minute and 34 +/- 5 apneic episodes/hour. In the theophylline group, apneic time and rate decreased significantly, from 8 +/- 1 seconds/minute and 80 +/- 8 apneic episodes/hour to 2.5 +/- 0.4 seconds/minute and 28 +/- 3 apneic episodes/hour. Cerebral blood flow velocity (CBFV) decreased only during theophylline administration.


Our findings suggest that inhaled low (0.8%) CO(2) concentrations in preterm infants is at least as effective as theophylline in decreasing the duration and number of apneic episodes, has fewer side effects, and causes no changes in CBFV. We speculate that CO(2) may be a better treatment for apnea of prematurity than methylxanthines.

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