Doxapram versus methylxanthine for apnea in preterm infants

Doxapram and methylxanthine stimulate breathing in infants with apnea. Infant apnea is a pause in breathing of greater than 20 seconds. This can be harmful to the developing brain and cause dysfunction of the gastrointestinal tract or other organs. Drugs such as doxapram and methylxanthine are thought to stimulate breathing and are given to reduce apnea. The review of four small trials found that there was no large difference between the drugs in the short term. There is not enough evidence to exclude a small difference in benefit, long term effects or a difference in less common adverse effects. More research is needed into the long term and adverse effects of these drugs.

Authors' conclusions: 

Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Long term outcome of infants treated in these trials has not been reported. Further studies would require a large number of infants to clarify whether there might be differences in responses or adverse effects with these two drugs at different ages.

Read the full abstract...

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram and methylxanthine drugs have been used to stimulate breathing and thereby prevent apnea and its consequences.


To assess the effects of doxapram compared with methylxanthine in preterm infants with recurrent apnea.

Search strategy: 

The Cochrane Collaboration Clinical Trials Register, MEDLINE, EMBASE and CINAHL, reference lists of relevant articles and conference proceedings. Search updated in February 2010.

Selection criteria: 

Randomised and quasi-randomised trials of doxapram compared with methylxanthine (e.g. theophylline, aminophylline or caffeine) for the treatment of apnea in preterm infants.

Data collection and analysis: 

The methodological quality of each trial was reviewed by the two reviewer trial authors. Additional information was requested from authors. Each reviewer extracted the data separately, then they were compared and differences resolved. Meta-analysis was carried out with use of relative risk and risk difference.

Main results: 

Four trials involving 91 infants were included. No difference was detected between intravenous doxapram or methylxanthine in the incidence of failed treatment within 48 hours [typical relative risk 0.91, 95% confidence interval (95% CI) 0.45, 1.85] . Only one trial reported results at 7 days and there was no difference in results. No infants were reported to have been given mechanical ventilation on either treatment. No adverse effects were reported.