Long-Term Neurodevelopmental Outcome after Doxapram for Apnea of Prematurity

Abstract

Background: Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP). Objective: To evaluate the effect of doxapram on long-term neurodevelopmental outcome in preterm infants as its safety still needs to be established. Methods: From a retrospective cohort of preterm infants with a gestational age (GA) <30 weeks and/or a birth weight <1,250 g, born between 2000 and 2010, infants treated with doxapram (n = 142) and a nontreated control group were selected (n = 284). Patient characteristics and clinical and neurodevelopmental outcome data at 24 months' corrected age were collected. Neurodevelopmental delay (ND) was defined as having a Mental or Psychomotor Developmental Index (MDI/PDI) <-1 standard deviation (SD), cerebral palsy, or a hearing or visual impairment. Odds ratios (OR) were calculated using multiple logistic regression analyses adjusting for potential confounders. Results: Infants treated with doxapram had a lower GA compared to controls. The number of infants with a MDI or PDI <-1 SD was not different between the groups. The risk of the combined outcome death or ND was significantly lower in the doxapram group after adjusting for confounding factors (OR = 0.54, 95% CI: 0.37, 0.78). Doxapram-treated infants had a higher risk of bronchopulmonary dysplasia and patent ductus arteriosus, but a lower risk of spontaneous intestinal perforation. All other morbidities were not different between the groups. Conclusions: This study suggests that doxapram is not associated with an increased risk of ND. These findings need to be confirmed or refuted by a large, well-designed, placebo-controlled randomized trial.

Severity of Bronchopulmonary Dysplasia and Neurodevelopmental Outcome at 2 and 5 Years Corrected Age

“…Furthermore, the generalizability of this study might be hampered by the use of doxapram in our center, which is not globally accepted therapy given the paucity of long term outcome data (40). Although we cannot rule out any modifying effect, a cohort study did not show an increased risk of death or NDI in favor of doxapram treatment (41). Finally, the currently used and still international accepted BPD definition from 2001 is under Although alternative criteria have been proposed (42,43), to our knowledge no large external validation study has been performed and therefore no formal and definite change in the criteria has yet been recommended.…”

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 .…”

“…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 . Because doxapram may affect brain haemodynamics, concerns have been raised about the possible long‐term effects on mental development , although such effects were not confirmed in a cohort study .…”

Apnea of Prematurity: An Update

“…In summary, it appears that doxapram therapy is beneficial in infants with persistent AOP despite caffeine and optimal care, but randomized controlled trials are lacking, and the late outcomes of premature infants treated with doxapram for AOP are unclear. 77,[79][80][81]…”