Abstract
Evidence of anesthetic neurotoxicity is unequivocal when studied in animal models. These findings have translated poorly to the clinical domain when equated to postoperative delirium (POD) in adults and postoperative cognitive dysfunction (POCD) in either children or the elderly. In this perspective, we examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of POD and POCD and make suggestions as to potential directions for ongoing research. We hypothesize that the animal anesthetic neurotoxicity models are limited, in part, due to failed scaling correction of physiological time. We posit that important insights into POCD in children and adults may be gleaned from studies in adults examining alterations in perioperative management designed to limit POD. In this way, POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition. We argue that it is time to move beyond animal models of neurotoxicity to directly examine these problems in well-conducted clinical trials with comprehensive preoperative neuropsychometric and psychiatric testing, high fidelity intraoperative monitoring of physiological parameters during the anesthetic course and postoperative assessment of subthreshold and full classification of POD. In this manner, we can “model ourselves” to better understand these important and poorly understood conditions.
Highlights
Reviewed by: Corinne Lasmezas, The Scripps Research Institute, United States John Weiss, University of California, Irvine, United States
We examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) and make suggestions as to potential directions for ongoing research
POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition
Summary
The animal models used to investigate anesthetic neurotoxicity were based on an understanding of the critical role that NMDAand GABA-mediated pathways play in normal neurodevelopment, coupled with the possibility that anesthetics with NMDA receptor antagonism might mimic the known detrimental effects of long-term ethanol and anticonvulsant exposure on these receptor subtypes [14]. The animal models are maximized to assure measurable biomarkers to assess neuronal injury in exposed versus unexposed animals. In this regard, anesthetic agent exposure is often prolonged and administered in large and often outmoded dosage, such as high inspired concentrations of nitrous oxide, to establish a quantifiable lesion. Maximal synaptogenesis occurs from the third trimester of pregnancy up to the first 2–3 years of life [17]. Important are issues raised by Hovens et al [18] as to the differences between measurable lesions felt to represent markers of cognitive decline in experimental animals and the considerably more complicated modeling seen in humans
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