We used standard, extensive Cochrane search methods. The latest search date was March 2023.
SELECTION CRITERIA: We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied
doxapram for treatment of
apnea in preterm infants. Three studied
doxapram to prevent reintubation in preterm infants. None studied
doxapram in preventing
apnea in preterm infants. All studies administered
doxapram intravenously as continuous infusions. Two studies used
doxapram as an adjunct to
aminophylline compared to
aminophylline alone and one study as an adjunct to
caffeine compared to
caffeine alone. When used to treat
apnea, compared to no treatment,
doxapram may result in a slight reduction in failed
apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of
doxapram on need for
positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence).
Doxapram may result in little to no difference in side effects causing cessation of
therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of
doxapram on failed
apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of
doxapram on need for
positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2).
Doxapram may result in little to no difference in side effects causing cessation of
therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct
therapy to
methylxanthine, the evidence is very uncertain about the effect of
doxapram on failed
apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical
apnea, chronic
lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for
positive pressure ventilation and side effects when used as adjunct
therapy to
methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of
doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct
therapy to
methylxanthine,
doxapram may result in a slight reduction in 'clinical
apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence).
Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of
doxapram on side effects causing cessation of
therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for
positive pressure ventilation, chronic
lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical
apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium.
AUTHORS' CONCLUSIONS: In treating
apnea of prematurity,
doxapram may slightly reduce failure in
apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for
positive pressure ventilation when compared to no treatment or alternative treatment and about failed
apnea reduction when used as alternative or adjunct
therapy to
methylxanthine. For use to prevent reintubation,
doxapram may reduce
apnea episodes when administered in adjunct to
methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about
doxapram's effect on death when used as adjunct
therapy to
methylxanthine and about failed extubation when used as alternative or adjunct
therapy to
methylxanthine. There is a knowledge gap about the use of
doxapram as a
therapy to prevent
apnea. More studies are needed to clarify the role of
doxapram in the treatment of
apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.