The possibility of anesthetic neurotoxicity was first suggested more than 15 years ago with findings of apoptosis in the brains of rodents after ethanol exposure during critical periods of neurodevelopment. A similar neuroapoptotic effect was soon identified in anesthetic agents and linked to long-term functional consequences. Since then, nearly all commonly used N-methyl-D-aspartate (NMDA) antagonists and γ-amino butyric acid (GABA) agonists have been evaluated and were found to result in neurotoxic effects in a variety of animal species, including non-human primates. Hundreds of preclinical studies have now been published demonstrating effects with anesthetic doses relevant to humans and using monitoring standards similar to those used for clinical care in children. Despite the presence of this robust body of preclinical data, however, the clinical evidence is much sparser.

Published clinical studies are composed of two main branches: observational studies...

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