CON: The toxic effects of anesthetics in the developing brain: the clinical perspective.

Sulpicio G. Soriano, MD, FAAP‡ “All models are wrong, some models are useful” This quote by the statistician George E. P. Box seems to have relevance for the current preeminent controversy in pediatric anesthesiology, namely, developmental neuroapoptotic cell death after an anesthetic exposure in the immature brain. Worldwide, general anesthetics and sedatives are used in hundreds of thousands of neonates and infants every year during surgical operations, invasive procedures, and imaging studies. The possibility of anesthesiainduced neuronal cell loss, as suggested by animal models, during an otherwise uneventful procedure has sparked vigorous discussions among anesthesiologists about the safety of anesthesia in human newborns and infants. These concerns were recently addressed at the March 29, 2007, public hearing of the Anesthesia and Life Support Drugs Advisory Committee of the Food and Drug Administration (transcript available at http://www. fda.gov/ohrms/dockets/ac/07/transcripts/2007-4285t1.pdf). Although the exact mechanism of general anesthesia is not entirely understood, alterations of synaptic transmission involving !-aminobutyric acid type A (GABAA) and N-methyl-d-aspartate (NMDA) glutamate receptors, to varying degrees, seem to play an important role. Because GABA and NMDA-mediated neuronal activity is essential for normal mammalian brain development, exposure to anesthetics could potentially interfere with brain maturation, learning, and neurocognitive function. Concerns about the effects of general anesthetics on neuronal structure and neurocognitive function were first raised more than two decades ago. In a series of studies, chronic subanesthetic exposure of pregnant rats to halothane led to delayed synaptogenesis and behavioral abnormalities in their pups. More recently, the potential for ketamine to cause increased neuronal cell death was documented in rat pups. However, although ketamine is rarely used for pediatric anesthesia, general anesthetics routinely used in pediatric practice have subsequently also been implicated not only in producing widespread neuronal cell death, but also in leading to long-term cognitive impairment in adult animals exposed to neonatal anesthesia. A 6-h exposure to a combination of isoflurane, nitrous oxide, and midazolam led to widespread apoptotic brain cell death in 7-day-old rats. When animals were examined in adulthood, many tests of behavior and attention remained normal. However, several tests of spatial learning and memory demonstrated impairment in adult animals that were exposed to the anesthetic cocktail as neonates, compared with their unanesthetized littermates. Several groups of investigators have now confirmed the neurotoxic effects of various anesthetics in a variety of in vivo and in vitro developing animal models. From the *Departments of Anesthesia and Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine; and †Institute of Pediatric Anesthesia, Cincinnati Children’s Research Foundation, Cincinnati, Ohio; and ‡Department of Anaesthesia, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts. Accepted for publication March 5, 2008. Address correspondence and reprint requests to Dr. Andreas Loepke, Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, ML2001, 3333 Burnet Ave., Cincinnati, OH 45229. Address e-mail to [email protected]. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e3181733ef8