Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation

Doxapram has not been shown to improve outcomes for babies being weaned off mechanical breathing support.When preterm babies have been on mechanical breathing support in neonatal intensive care, it can be hard to wean them off the machine (tracheal extubation). Using drugs called methylxanthines, or breathing support via the nose (nasal CPAP - continuous positive airways pressure) can help. Doxapram stimulates breathing, and is another drug that is sometimes used around extubation. However, the review of trials found no evidence that doxapram can reduce problems for babies around extubation, and it may cause some adverse effects. Further research is needed.

Authors' conclusions: 

The evidence does not support the routine use of doxapram to assist endotracheal extubation in preterm infants who are eligible for methylxanthine and/or CPAP. The results should be interpreted with caution because the small number of infants studied does not allow reliable assessment of the benefits and harms of doxapram. Further trials are required to evaluate the benefits and harms of doxapram compared with no treatment or with other treatments, such as methylxanthines or CPAP, to evaluate whether it is more effective in infants not responding to these other treatments, and to assess whether the drug is effective when given orally.

Read the full abstract...

When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory effort and tendency to develop hypoventilation and apnea, particularly in very preterm infants. Doxapram stimulates breathing and appears to act via stimulation of both the peripheral chemoreceptors and the central nervous system. This effect might increase the chance of successful tracheal extubation.


To determine the effect of doxapram on the use of intubation and IPPV and morbidity in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned. In this regard, how does doxapram compare with standard treatment or with an alternative treatment such as methylxanthine or CPAP? Subgroup analyses were prespecified according to birth weight and/or gestational age, use of co-interventions (methylxanthines or nasal CPAP), and route of administration (intravenous or oral).

Search strategy: 

The standard search strategy of the Neonatal Review Group as outlined in The Cochrane Library was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Oxford Database of Perinatal Trials, MEDLINE, EMBASE and CINAHL up to May 2009.

Selection criteria: 

Eligible studies included published trials utilising random or quasi-random patient allocation in which preterm or low birth weight infants being weaned from IPPV were given doxapram compared with standard care or other treatments, to facilitate weaning from IPPV and endotracheal extubation. Trials were independently assessed by the review authors before inclusion.

Data collection and analysis: 

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each review author extracted data separately. The results were compared and any differences resolved. The data were synthesized using the standard method of Neonatal Review Group with use of relative risk and risk difference.

Main results: 

Two trials involving a total of 85 infants compared doxapram and placebo. In both the individual trials and the meta-analyses there were no significant differences between the doxapram and placebo groups in any of the outcomes (failed extubation, death before discharge, respiratory failure, duration of IPPV, side effects, oxygen at 28 days or oxygen at discharge). There was a trend towards an increase in side effects (hypertension or irritability leading to cessation of treatment) in the doxapram group [summary RR 3.21 (0.53, 19.43). In one of these two trials (Huon 1998) an 'alarming rise in blood pressure' occurred in five infants in the doxapram group and none of the controls, although in only one was treatment withdrawn. One additional trial involving only eight infants compared doxapram with aminophylline, but there were insufficient data for meaningful analysis.