Doxapram Treatment for Apnea of Prematurity: A Systematic Review

Abstract

Background: Apnea of prematurity (AOP) is a common complication of preterm birth, for which caffeine is the first treatment of choice. In case of persistent AOP, doxapram has been advocated as an additional therapy. Objective: To identify and appraise all existing evidence regarding efficacy and safety of doxapram use for AOP in infants born before 34 weeks of gestational age. Methods: All studies reporting on doxapram use for AOP were identified by searching electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research. Two reviewers independently assessed study eligibility and quality, and extracted data on study design, patient characteristics, efficacy and safety outcomes. Results: The randomized controlled trials showed less apnea during doxapram treatment when compared to placebo, but no difference in treatment effect when compared to theophylline. No serious adverse effects were reported. We identified 28 observational studies consisting mainly of cohort studies and case series (n = 1,994). There was considerable heterogeneity in study design and quality. Most studies reported a positive effect of doxapram on apnea rate. A few studies reported on long-term outcomes with conflicting results. A range of possible doxapram-related short-term adverse effects were reported, sometimes associated with the use of higher doses. Conclusion: Based on the limited number of studies and level of evidence, no firm conclusions on the efficacy and safety of doxapram in preterm infants can be drawn. For this reason, routine use cannot be recommended. A large multicenter randomized controlled trial is urgently needed to provide more conclusive evidence.

Doxapram Treatment and Diaphragmatic Activity in Preterm Infants

“…Previous studies have shown that doxapram reduces apnea frequency and the need for invasive mechanical ventilation [4]. However, a recent systematic review, based on a small number of studies with mainly low quality of evidence, indicated that no firm conclusions can be drawn on the efficacy and safety of doxapram [7]. Furthermore, its working mechanism is still poorly understood.…”

“…Furthermore, some small physiological studies have shown an increase in minute ventilation and tidal volume after infusion of doxapram, but only if dosed > 1 mg/kg/h [5, 6]. However, due to concerns about the effect of doxapram on long-term outcomes of preterm infants it is used as a rescue in infants with imminent respiratory failure due to severe AOP [7]. …”

Retrospective study shows that doxapram therapy avoided the need for endotracheal intubation in most premature neonates

“…Nevertheless, doxapram is only licensed for use in children over 12 and the efficacy of doxapram for the treatment of AOP has rarely been studied . This might be due to the fact that in the UK and USA, doxapram is only available in a solvent containing the toxic excipient benzyl alcohol, which raises concerns about toxicity, although these have not been confirmed yet .…”

“…Doxapram is off‐label for use in children and neonates, and evidence about efficacy and safety has been limited to a few small studies that have reported successful control of AOP cases that were unresponsive to methylxanthines. Other reports on doxapram therapy suggest adverse side effects, such as gastrointestinal disturbances, increased agitation, excessive crying, jitteriness, irritability , hypokalaemia , hypertension , atrioventricular heart block , higher percentages of continuous activity, more electrographic seizure activity and less sleep–wake cycling than in control groups .…”

High versus standard dose caffeine for apnoea: a systematic review

“…In addition, the quality of evidence was also assessed for the main outcome measures using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach16 by two independent reviewers (RV and MM), as previously described 17. The following (clinical relevant) outcomes were assessed: combined outcome death or BPD, BPD, tachycardia, necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH) ≥grade 2, death or disability at 1-year CA.…”