D J Henderson-Smart1, P G Davis. 1. NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Institute for Mothers and Infants, Building DO2, University of Sydney, Sydney, NSW, Australia, 2006. dhs@mail.usyd.edu.au
Abstract
BACKGROUND: 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. OBJECTIVES: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with doxapram reduce the use of intubation and IPPV, or reduce other morbidity, without clinically important side effects? 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 Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE and EMBASE. 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 authors before inclusion. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each 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. REVIEWER'S 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.
BACKGROUND: 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. OBJECTIVES: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with doxapram reduce the use of intubation and IPPV, or reduce other morbidity, without clinically important side effects? 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 Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE and EMBASE. 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 authors before inclusion. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each 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. REVIEWER'S 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.