Sleep and arousal dysregulation in apneic preterms treated with methylxanthines

Apnea of prematurity is a common problem in preterm infants. Standard treatment is with high-dose methylxanthines, theophylline or caffeine, for several days or weeks and mechanical ventilation. These agents, and especially caffeine, decrease CO2 levels, increase O2 consumption and improve respiratory drive. However, they produce autonomic side effects in the neonate, such as tachycardia, as well as renal and CNS toxicity, neutrophil compromise and several other adverse effects at higher doses. In particular, it is postulated that chronic methylxanthine exposure may affect sleep, arousal and motor activation in premature infants following extubation. Both theophylline and caffeine have important effects on sleep-wake organization in adults. Prematurity, and specifically the 30 to 40 weeks post-menstrual age (PMA), is a critical developmental window for sleep-wake state organization, and the emergence of sustained arousal capacity. Thereafter, the longer half-life and neurotoxicity risk of methylxanthines in neonates compared to adults, support the hypothesis that developing sleep and arousal systems may be adversely affected by high dose, chronic treatment. On these bases, an American group conducted a study to examine the hypothesis that apneic preterms exposed to chronic methylxanthines may express sleep and arousal dysregulation, and structural disruption of spontaneous movements measured with an actigraphic piezoelectric mattress. Activational effects of chronic methylxanthine are supposed to be cumulative, i.e. exposure effects would increment over days. Moreover, sleep-deprived infants are supposed to show a decrease in sleep-related body movements on the day of testing. To verify these hypotheses, states of sleep, wake and brief arousals, and the temporal properties of actigraphically derived movement and quiescence periods were compared in methylxanthine-treated and matched -untreated neonates. Sleep, wake, arousal and actigraphic movements were monitored for 5 hours in extubated clinically stable premature infants (N = 37). Neonates were free of other medications for >72 h and were grouped based on methylxanthine exposure: >5 days with caffeine (n = 14), >5 days theophylline (n = 13) or no prior exposure (n = 10). Results show that duration of methylxanthine treatment increased arousals, wakefulness and actigraphic movements, and decreased active sleep. During the recording from 12.00 to 05.00 hours, methylxanthine-treated groups showed reductions in all arousal parameters, including waking state, number of wake epochs, brief arousals and composite arousal index, and shorter fast-burst, sleep-related motility than untreated controls. The findings of the study, published in the Journal of Perinatology, suggest that the standard regimens of caffeine and theophylline, even when carefully titrated to achieve therapeutic levels, are associated with cumulative activational effects. Future work is needed to determine the parameters of methylxanthine exposure duration that may indicate a risk for potentially deleterious effects on the premature. Moreover, the potential long-term outcomes of neonatal methylxanthine treatment on CNS processes controlling sleep and arousal organization require further study.

Top