Theophylline Affects Sleep-Wake State Development in Premature Infants*

Abstract

This study investigated the prolonged effects on state behavior of theophylline administered to infants for apnea of prematurity. There were three groups: Four premature infants who had received theophylline in the preterm period, five premature infants who had not received theophylline, and twenty-eight normal fullterm infants. The Theophylline infants had been off the drug for at least one month prior to the beginning of the study. Sleep-wake states were observed in the home for seven-hour periods when all infants were the same corrected ages: two, three, four and five weeks post-term. Data from the portion of the day that the infants were alone were analysed for this study. The state organization of the Theophylline group differed significantly from those of the other groups. They exhibited more non-alert waking activity, more alert, more drowse or transition, and less active sleep than did the Non-Theophylline and Fullterm infants. The state distributions of the latter two groups did not differ. On the basis of similarities between the results of this study and of a previous animal study, it was concluded that theophylline altered the normal development of state organization in premature infants. These effects persisted long after the drug had cleared the body.

Effect of Doxapram on Episodes of Apnoea, Bradycardia and Hypoxaemia in Preterm Infants

“…These findings are again in line with those on piglets, where doxapram had less effect on sleep structure than, for example, theophylline [21]. The latter substance inhibits active sleep also in human neonates [23]. Jitteriness and seizures, side effects reported by other investigators at doses of 2-2.5 mg/kg/h and another indicator that doxapram has an effect on the central nervous system [20], were not observed in our study, possibly because we used slightly lower doses.…”

Apneic preterms and methylxanthines: arousal deficits, sleep fragmentation and suppressed spontaneous movements

“…12,24 The potential long-term effects of neonatal methylxanthine treatment on CNS processes controlling sleep and arousal organization require further study.…”

“…In neonatal rabbits, one dose (10 mg kg À1 ) of theophylline on postnatal day 1 led to 3 weeks of increased waking, decreased active sleep and delay of quiet sleep development. 26 Similarly, Thoman et al 12 reported that infants previously treated with theophylline, but not currently treated, showed higher rates of wake and drowse/transitional states when examined in the home.…”

“…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. [9][10][11][12] Although two laboratories have failed to find effects of methylxanthines on sleep states in the premature, 13,14 behavioral indices of waking and temporal properties of movement were not studied. Thoman et al 12 found increased wake and decreased active sleep 8 weeks after cessation of theophylline treatment in preterm infants.…”

The development of potentially better practices to support the neurodevelopment of infants in the NICU

“…The theophylline infants had decreased AS as well as alterations in state organization. 132 Nonsteroidal anti-inflammatory agents such as indomethacin and ibuprofen disrupt the sleep cycle, possibly due to the inhibition of prostaglandin synthetase. 133,134 Newborn exposure to alcohol through breast milk caused a general decrease in sleep time and a marked decrease in AS.…”