Evidence-Based Methylxanthine Use in the NICU

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Methylxanthine treatment of apnea: historical aspects

Apnea remains the primary absolute indication for the institution of positive pressure ventilation in the NICU. Infants who fail to breathe must have their ventilation supported, especially primary apnea during resuscitation in the course of early life. Most problems with apnea clinically, however, occur when an infant is either being weaned from positive pressure support or has been removed from the common forms of ventilatory support. The infant continues to demonstrate immaturity of

Treatment of AOP

The most common indication for initiation of methylxanthine use in the NICU is AOP. This indication has been reviewed on a recurring basis by the Cochrane Collaboration, which since 1993 has provided systematic reviews of a variety of aspects of neonatal care. The Cochrane relies on randomized controlled trials to evaluate medical practice that is based on the highest quality of available evidence. In their most recent evaluation of methylxanthine therapy, Henderson-Smart and DePaoli23 found

Treatment

Methylxanthines, especially caffeine, seem to be highly effective and safe for the treatment of AOP. Caffeine also seems to be helpful when used prophylactically for the management of endotracheal tube extubation. The standard dose for caffeine is a loading dose of caffeine citrate of 20 to 25 mg/kg (equivalent to 10–12.5 mg/kg of caffeine base) intravenously or by mouth, followed by a maintenance dose of 5 to 10 mg/kg/d. Therapeutic serum levels should be checked after approximately 48 hours

Summary

The risk of recurrence for apnea or bradycardia differs depending on the gestational age of the infant and the postmenstrual age of the last apnea or bradycardia event. The following options are suggested for any infant treated with caffeine for AOP (Fig. 2). If the child is otherwise stable and ready for NICU discharge but caffeine has not yet been stopped, the infant should be sent home on caffeine and provided with a home cardiorespiratory monitor for at least the duration of time that it

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      In descending order of their metabolic concentrations, these are paraxanthine, theobromine, and theophylline, all of them with high polar characteristics and low log Kow values (Fig. 1). Caffeine is also used in the treatment of apnea of prematurity in neonates to stimulate breathing efforts [7]. It has advantages to other treatments due to its long half-life and wide therapeutic range [8].

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      Respiratory stimulant drugs are essential tools of neonatal medicine, and for more than 40 years, xanthine molecules (caffeine, theophylline, aminophylline or theobromine) have been used as a treatment against apnea of prematurity. However, while the long-term safety of this treatment has been well established in young infants (18–21 months) and up to 11 years of age (Murner-Lavanchy et al., 2018; Schmidt et al., 2017, Schmidt et al., 2007), a non-negligible fraction of patients present persistent apneas (Spitzer, 2012), and it has been emphasized that new therapy should be developed (Finer et al., 2006). A further reason to develop new pharmacological treatments for apnea of prematurity is that theophylline and caffeine in preterm infants promote sleep fragmentation and induce a sleep-debt (Hayes et al., 2007).

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