Anesthetic-related neurotoxicity in the developing infant: of mice, rats, monkeys and, possibly, humans.

Peter J. Davis, MD† This issue of Anesthesia & Analgesia contains seven varied articles that all relate in some way to the possibility of neuronal toxicity arising from the use of inhaled and certain IV anesthetics in the immature and developing animal. Although there is a fair amount of overlap in the content, the diligent reader should nevertheless be rewarded by a significantly improved understanding of the main aspects of this topic and the controversy that surrounds it. The origins of this debate go back at least as far as 1999 when Dr. John Olney and colleagues reported in Science that N-methyl-d-aspartate (NMDA) antagonists, including MK801 and ketamine, produced evidence of neurotoxicity. Subsequently, his group and others demonstrated that many anesthetics, including nitrous oxide, isoflurane, and ketamine, appear to induce apoptotic changes in neurons, particularly in the brains of infant rodents (detailed in Refs. 1–4). In fact, this debate goes back at least to 1985, when Uemura et al. demonstrated diffuse effects of halothane on synaptic development and subsequent learning behavior in rats. Perhaps, these results are to be expected. Most neurotransmission in the developing brain is primarily due to NMDAand/or -aminobutyric acid-dependent mechanisms, as is the regulation of neuronal developmental and synaptogenesis. There are at least two possible general mechanisms of pro-apoptotic and/or neurotic injury. The first is that receptor blockade by anesthetic drugs decreases “trophic” stimulation at a critical point in time, leading to induction of cell death programs (analogous to the effects of growth factor deprivation in a variety of cell types). The second is that the transient receptor blockade caused by anesthetic drugs results in subsequent receptor upregulation (protein expression and/or receptor activity). When the blocking anesthetic is removed, the affected neuron is subsequently subjected to significantly increased NMDA activity, resulting in increased excitatory amino acid neurotoxicity. The mechanisms remain largely unsolved, although the available evidence weakly suggests the second. Regardless of the exact mechanisms, the available data raise the specter that standard clinical anesthesia practice could promote brain injury in the human fetus, infant, and young child. These reports taken together led the United States Food and Drug Administration (FDA) to convene an Advisory Committee Meeting in April of 2007 (meeting transcript available at http://www.fda.gov/ohrms/docets/ac/07/transcripts/2007/ 4285t1.pdf). The purpose of the FDA meeting was to evaluate the potential neurodegenerative effects of anesthetics in infant and juvenile animals. The FDA panel focused on the data presented in a nearly contemporaneous comprehensive review. We personally believe that the evidence demonstrating the potential for different types of anesthetics to stimulate proapoptotic and neurotoxic events in infant rats and other species appears to be reasonably good. However, as the reader will also see, the extrapolation of the animal data to humans, and human infants in particular, is very tenuous. In the From the *Division of Cardiac Anesthesia, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; and †Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Accepted for publication March 10, 2008. Reprints will not be available from the author. Address correspondence to Francis X. McGowan, Jr., MD, Chief, Division of Cardiac Anesthesia, Children’s Hospital of Boston, 300 Longwood Avenue, Boston, MA 02115. Address e-mail to francis.mcgowan@ childrens.harvard. edu. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e31817330cf