Key messages
– Due to a lack of robust evidence, the benefits and risks of doxapram (a medication used in cases when stimulation of breathing is necessary) in preventing or treating breathing pauses in premature babies are unclear. We found no data on long-term effects of the treatments.
– Doxapram might be slightly better than no treatment in reducing breath-holding episodes with little or no difference in unwanted effects. Doxapram may be of little or no help in having the babies breathing on their own without machine support.
– The studies that we found were written more than 20 years ago. However, there are two studies in progress on this topic that could add information on the use of doxapram.
What is apnea of prematurity?
Apnea of prematurity is a common problem in premature infants. Very small babies sometimes 'forget' to breathe and, when they hold their breath for 20 seconds or more, or when these episodes lead to alterations in their heart beat and oxygen values, it is called apnea. Apnea episodes can have a negative effect on the babies' development during their lives.
How is it usually treated in premature babies?
Doctors usually treat breath-holding episodes with medicines that stimulate the babies' brains to result in breathing. These medicines are called methylxanthines and the most well-known is caffeine.
What did we want to find out?
We wanted to know if doxapram, a stimulating medicine that is different from methylxanthine, could help to treat or prevent breath-holding episodes. We also wanted to find out if doxapram was associated with any unwanted effects.
What did we do?
We searched for studies that compared doxapram, alone or with methylxanthine, to no treatment or alternative treatment in treating or preventing breath-holding episodes or in helping babies to breathe on their own without a machine support.
We compared and summarized their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found eight studies that involved 248 premature babies, from 25 to 32 weeks of gestational age (from the first day of the woman's last period to birth). The biggest study was in 56 babies and the smallest study was in 10 babies. Doxapram and the other medicines were given through infusion in a vein. None of the studies was about prevention of breath-holding events. Three studies focused on medicines used to help babies breathing on their own without machine support, while five were on treatment of breath-holding events.
Doxapram might work slightly better than no treatment in reducing episodes when babies stop breathing for some seconds with little or no difference in unwanted effects when compared to no treatment or to other medicines used for the same purpose. We do not know if doxapram has an effect on the occurrence of breath-holding events when compared to other treatments, or on the need for breathing support by a machine.
When trying to shift ventilated babies to breathing on their own, doxapram may help other commonly used medicines to reduce breath-holding episodes, and it may shorten the duration of oxygen support, even if it might be of little or no help in stopping machine support. The effect of doxapram on unwanted events in this situation is unclear.
What are the limitations of the evidence?
We have little confidence in the evidence because not all the studies provided data about everything of interest. Available data are on few infants with a very low number of events of interest.
How up to date is this evidence?
The evidence is up to date to March 2023.
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.
Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment.
To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants.
We used standard, extensive Cochrane search methods. The latest search date was March 2023.
We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route.
We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome.
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.