Doxapram in Preterm Infants: From Respiratory Stimulation to Individualized Therapy-A Narrative Review

Background: Apnea of prematurity (AOP) remains one of the most common complications of preterm birth, and despite the established role of caffeine as first-line therapy, a proportion of extremely preterm infants continue to experience clinically significant apnea. Doxapram, a respiratory stimulant first investigated in preterm infants in the 1980s, has remained a potential second-line pharmacological option for more than four decades, yet its place in neonatal practice remains uncertain, with marked variability in use across countries and institutions. Methods: Previous reviews have primarily focused on summarizing the efficacy and safety evidence for doxapram. This narrative review instead examines how knowledge of doxapram's efficacy, safety, pharmacokinetics, and clinical use has evolved over time, situating this evidence within the broader historical transformation of neonatal intensive care. Results: We found that the persistent uncertainty surrounding doxapram reflects not only well-recognized methodological limitations of the available studies, but also the fact that the clinical questions considered relevant have changed more rapidly than the evidence generated to answer them. Conclusions: Doxapram has a relatively consistent short-term respiratory stimulant effect, but evidence that it improves clinically important outcomes remains limited and of low certainty. It should not be regarded as an established therapy for routine use; rather, it may represent a rescue or adjunctive option for selected preterm infants with persistent clinically significant apnea despite optimized caffeine therapy and non-invasive respiratory support. Further adequately powered trials are needed to define its clinical role.