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Anesthetic Neurotoxicity: The Collision between Laboratory Neuroscience and Clinical Medicine

Todd, Michael M. M.D.

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ON October 10, 2003, at the 31st Annual Meeting of the Society of Neurosurgical Anesthesia and Critical Care, San Francisco, California, John Olney, M.D., Professor, Department of Psychiatry and Neuropathology, Washington University School of Medicine, St. Louis, Missouri, presented a lecture entitled “Anesthetic Neurotoxicity in Young and Aged Animals.” In 1989, Dr. Olney reported in Science that N-methyl-d-aspartate antagonists such as MK801 (a well studied neuroprotectant) could produce histopathologic changes suggestive of toxicity in the brains of normal adult rats.1 Subsequent studies have extended and refined this work to show that many anesthetics (including N2O) can produce what appear to be apoptotic changes, particularly the brains of very young rodents. This has raised the possibility, albeit one that is still very speculative, that even a routine anesthetic using the most routine drugs might pose a risk of neurotoxicity to the fetus, the neonate, or even the young child.
Given the obvious anxiety that such laboratory findings have produced in the minds of clinical anesthesiologists, it was not surprising that Dr. Olney’s presentation was followed by an active discussion and debate. Sol Soriano, M.D., Associate Professor, Department of Anesthesia, Boston Children’s Hospital, Boston, Massachusetts, was an active participant in that debate and, some months later, submitted a manuscript coauthored by K.J.S. Anand, M.B.B.S., D.Phil., Chair, Department of Critical Care Medicine, University of Arkansas, Little Rock, Arkansas, discussing and critiquing the work by Dr. Olney et al. In particular, Drs. Anand and Soriano asked whether or not Dr. Olney’s findings are attributable to the direct effects of anesthetics or, alternatively, were the result of factors unlikely to be encountered clinically (e.g., high doses given over long periods, acid-based disturbances, hypoxia, starvation). In essence, what they are also asking is whether or not the published findings in rats can really be extrapolated to humans. Given the importance of the subject, the reviewers recommended that the article be published and I strongly agreed. However, I also felt that the other side of the issue needed to be heard, and hence I invited Dr. Olney and his coworkers to write the following editorial comment (although some might view it as being more akin to a “point-counterpoint” exchange between the different authors).
I personally believe that the evidence documenting the “neurotoxic”/proapoptotic effects of many anesthetics in infant rats is reasonably good. However, whether or not this can be extrapolated to humans (particularly the very young) is unknown. It would also be entirely inappropriate for anyone to suggest that anesthesiologists should change their practice based on such work, both because we don’t know if the findings apply to humans and because we have no idea what kind of change would be appropriate. In fact, neither Dr. Olney nor Drs. Anand and Soriano have made such a suggestion. The question is, however, of real importance and both Olney and coworkers and Anand and Soriano agree that much more work is needed, both in the laboratory and (hopefully) in the clinic and operating room. This is a topic that should attract the interest of far more anesthesiologists/neuroscientists. I hope that the exchange in this issue of Anesthesiology will serve to encourage such work.
Michael M. Todd, M.D.
Editor-in-Chief, Anesthesiology, Department of Anesthesia, The University of Iowa, Iowa City, Iowa.
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1.Olney JW, Labruyere J, Price MT: Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989; 244:1360–2

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