Developmental Effects of Neonatal Isoflurane and Sevoflurane Exposure in Rats

Abstract

Abstract Background: The general anesthetics, isoflurane and sevoflurane, cause developmental abnormalities in neonatal animal models via incompletely understood mechanisms. Despite many common molecular targets, isoflurane and sevoflurane exhibit substantial differences in their actions. The authors sought to determine whether these differences can also be detected at the level of neurodevelopmental effects. Methods: Postnatal rats, 4–6 days old, were exposed to 1.2% isoflurane or 2.1% sevoflurane for 1–6 h and studied for immediate and delayed effects. Results: Isoflurane exposure was associated with weaker seizure-like electroencephalogram patterns than sevoflurane exposure. Confronted with a new environment at a juvenile age, the sevoflurane-exposed rats spent significantly more time in an “immobile” state than unexposed rats. Electroencephalographic (mean ± SE, 55.5 ± 12.80 s vs. 14.86 ± 7.03 s; P = 0.014; n = 6–7) and spontaneous behavior (F(2,39) = 4.43; P = 0.018) effects of sevoflurane were significantly diminished by pretreatment with the Na+–K+–2Cl– cotransporter inhibitor bumetanide, whereas those of isoflurane were not. Pretreatment with bumetanide, however, diminished isoflurane-induced activation of caspase-3 in the cerebral cortex (F(2,8) = 22.869; P = 0.002) and prevented impairment in sensorimotor gating function (F(2,36) = 5.978; P = 0.006). Conclusions: These findings in combination with results previously reported by the authors suggest that isoflurane and sevoflurane produce developmental effects acting via similar mechanisms that involve an anesthetic-induced increase in neuronal activity. At the same time, differences in their effects suggest differences in the mediating mechanisms and in their relative safety profile for neonatal anesthesia.