Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys

Abstract

Previously our laboratory has shown that ketamine exposure (24 hours of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24 hrs and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier [47] beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-hr episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits.

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

“…2010; Paule et al. 2011). This is a 4‐ to 24‐fold increase in treatment duration compared to pediatric ambulatory surgeries and is not a realistic prediction for children among the single‐episode exposure group.…”

“…2010; Paule et al. 2011). As a comparison, children undergoing routine surgeries are typically exposed to only 1 MAC (minimum alveolar concentration) of iso or sevo for <1 h (Rabbitts et al.…”

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Reports also show that exposure of the developing brain to a clinically relevant cocktail of anesthetics that has both NMDA antagonist and GABA mimetic properties results in an extensive pattern of neuroapoptosis, and subsequent cognitive deficits (Olney et al, 2002b). Several reports have illustrated that ketamine can induce neuronal apoptosis when administered in high doses and/or for prolonged durations during susceptible periods of development in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007a;Wang et al, 2006) and these effects can manifest on later disruptions in cognitive function (Paule et al, 2011). To minimize risks to children exposed to anesthesia, it is paramount to understand how anesthetic drugs affect the developing nervous system and whether those effects can be ameliorated or prevented.…”

MicroPET/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity

“…Recent data from monkeys demonstrate cognitive deficits lasting years after a single prolonged exposure to the NMDA receptor antagonist ketamine [43]. The use of nonhuman primate models continues to garner considerable interest among anesthesiologists, pharmacologists, and toxicologists with growing recognition to be anticipated from surgeons and neonatologists.…”