Isoflurane Anesthesia Has Long-term Consequences on Motor and Behavioral Development in Infant Rhesus Macaques

Abstract

Background Experimental evidence correlates anesthetic exposure during early development with neuronal and glial injury and death, as well as behavioral and cognitive impairments, in young animals. Several, although not all, retrospective human studies of neurocognitive and behavioral disorders after childhood exposure to anesthesia suggest a similar association. Few studies have specifically investigated the effects of infant anesthesia exposure on subsequent neurobehavioral development. Using a highly translational nonhuman primate model, the authors investigated the potential dose-dependent effects of anesthesia across the first year of development. Methods The authors examined the effects of single or multiple early postnatal isoflurane exposures on subsequent behavioral development in 24 socially reared rhesus macaques. Infants were exposed to 5 h of isoflurane anesthesia once, three times (ISO-3), or not at all (control). The authors assessed reflex development and anxiety using standardized tests. At approximately 1 yr, infants (n = 23) were weaned and housed indoors with 5 to 6 other subjects. The authors recorded their response to this move and reassessed anxiety. Results Compared to controls, animals exposed to repeated isoflurane (ISO-3) presented with motor reflex deficits at 1 month (median [range]: ISO-3 = 2 [1 to 5] vs. control = 5 [3 to 7]; P < 0.005) and responded to their new social environment with increased anxiety (median [range]: ISO-3 = 0.4 bouts/min [0.2 to 0.6]; control = 0.25 bouts/min [0.1 to 0.3]; P = 0.05) and affiliative/appeasement behavior (median [range]: ISO-3 = 0.1 [0 to 0.2]; control = 0 bouts/min [0 to 0.1]; P < 0.01) at 12 months. There were no statistically significant behavioral alterations after single isoflurane exposure. Conclusions Neonatal exposure to isoflurane, particularly when repeated, has long-term behavioral consequences affecting both motor and socioemotional aspects of behavior.

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“…Studies in nonhuman primates found that general anesthesia exposure of >5 hours resulted in negative functional and behavioral outcomes. 21,22 Additionally, a recent review reported that more than 80% of animal studies investigating neurotoxicity of general anesthesia found a negative effect after exposure of 3 hours or longer. 23 However, there remains limited information from human studies on the effect of long general anesthesia duration and results have been inconsistent.…”

An open label pilot study of a dexmedetomidine‐remifentanil‐caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study

“…1 Some studies have also demonstrated long-term behavioral and functional changes in the neurodevelopment of animals exposed to prolonged anesthesia in infancy. 2 There is, however, controversy over whether these animal data are relevant in the care of children undergoing general anesthesia. [3][4][5] The changes seen in preclinical studies are greatest with exposure to gamma-aminobutyric acid (GABA) agonists and N-methyl-Daspartate (NMDA) antagonists such as volatile anesthetics (eg, sevoflurane), propofol, midazolam, ketamine, and nitrous oxide.…”

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

“…However, recent data in non-human primates have provided definitive evidence that early postnatal GA exposure can have lasting effects on cognition, including deficits in socioemotional and learning function [16][17][18][19].…”