Methylxanthine therapy in premature infants: Sound practice, disaster, or fruitless byway?,☆☆

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“Neonatal Apnea, Bradycardia, or Desaturation: Does It Matter?”

Martin and Fanaroff4 chose this provocative title for a recent editorial in The Journal. These authors concluded that “the clinical significance and long-term consequences of persistent apnea, bradycardia, or desaturation remain a subject of considerable debate.”4 Although it is reasonable to be concerned about episodes that cause prolonged anoxia and acidosis, such events are unlikely to occur as a result of apnea of prematurity in the closely monitored environment of modern neonatal intensive

Randomized Controlled Trials of Methylxanthine Therapy in Preterm Infants: Small Numbers and Short Duration of Follow-up

The efficacy of methylxanthine treatment for apnea in preterm infants has been the subject of 4 recent systematic reviews of randomized clinical trials for the international Cochrane Collaboration. Infants in the control groups of those trials were randomized to the following alternatives: (1) placebo or no treatment,18 (2) doxapram,19 (3) continuous positive airway pressure,20 and (4) kinesthetic stimulation.21 Two additional Cochrane review groups examined prophylactic methylxanthine for

Should We Be Concerned About the Safety of Methylxanthine Therapy in Premature Infants?

Methylxanthines are antagonists of adenosine A1 and A2a receptors at “therapeutic” plasma concentrations.26, 27 Adenosine is neuroprotective during ischemia; acute administration of a methylxanthine exacerbates ischemic brain damage.28

Over the past 20 years, several investigators have warned of the potential for deleterious effects of methylxanthines during acute neonatal hypoxemia and ischemia.29, 30, 31 The experiments by Thurston et al29 are especially of concern: 3- to 9-day-old mice were

Acknowledgements

I am grateful to Drs Edmund Hey, William Silverman, and John C. Sinclair for their encouragement and advice.

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  • Cited by (59)

    • When to start and stop caffeine and why respiratory status matters

      2020, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      It is important to note that the CAP trial was initially conceived as a trial of safety of a drug class that was already in widespread use [5]. Although there was evidence of efficacy in terms of an ability to reduce the frequency of apnea, only 222 preterm infants had been treated with methylxanthines in the context a of randomized trial [5]. Both the number of patients treated and the duration of follow-up provided no reassurance of either short or long-term safety.

    • History of caffeine use in neonatal medicine and the role of the CAP trial

      2020, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      Despite that clearly insufficient evidence for safety and potentially deleterious long-term effects on neurological development and childhood behavior, caffeine was very widely used in neonatal care. Few people criticized that common practice but the group around Barbara Schmidt planned a large randomized controlled trial to contribute data on safety and long-term effects of caffeine use in preterm infants [8,9]. The CAP (“Caffeine for Apnea of Prematurity”) trial was a large international, multicenter, randomized placebo-controlled trial, designed and conducted by Schmidt and colleagues in order to clarify possible risks and benefits of methylxanthine treatment.

    • Apnea of Prematurity

      2012, Principles and Practice of Pediatric Sleep Medicine: Second Edition
    • An inflammatory pathway to apnea and autonomic dysregulation

      2011, Respiratory Physiology and Neurobiology
      Citation Excerpt :

      This is encouraging, since deleterious effects have been described in several animal models (Thurston et al., 1978). Nonetheless there are still lingering concerns about manipulating adenosinergic and related neurotransmitter function during early life (Martin and Wilson, 2009; Schmidt, 1999). Animal studies indicate that long-term effects of caffeine during pregnancy and postnatal life may alter behavior including respiratory control in the offspring.

    View all citing articles on Scopus

    J Pediatr 1999;135:526-8.

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