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Con: The Toxic Effects of Anesthetics in the Developing Brain: the Clinical Perspective

ties. Exposure to subanesthetic concentrations of anesthetic drugs, such as ketamine, midazolam, propofol, and isoflurane, can cause similar changes as well. Peak vulnerability to apoptogenic action coincides with the period of rapid synaptogenesis (the brain growth spurt period), which occurs in laboratory animals soon after birth, but in humans extends from midgestation to several years after birth. The findings in rodents and nonhuman primates can be relevant to humans because many agents in the environment have NMDA antagonist or GABA-mimetic properties. These include drugs thatmay be abused by pregnant women or those used worldwide for anesthesia in obstetric and pediatric patients. Whether anesthetic drugs induce neuroapoptosis in the developing human brain is the subject of widespread debate and this editorial discusses the available evidence. First, the amount of drug administered and how often it is given must be considered. Some reports indicate that a single dose of ketamine (an NMDA antagonist) does not trigger neuroapoptosis in the infant rat brain and that large doses are needed for prolonged periods of time. In human anesthesia, ketamine is typically used as a 1-time dose that is lower than those found toxic in infant rats. Therefore, ketamine should be safe as a pediatric anesthetic. However, other recent studies suggest that subanesthetic dosing of ketamine induces apoptotic changes in laboratory animals and thus contradict this assertion. Some evidence also indicates that subanesthetic exposure to midazolam or propofol leads to neuroapoptosis in the infant mouse brain, with similar findings reported for sub-MAC doses of isoflurane. On the basis of these studies, the ‘‘huge doses and prolonged exposure argument’’ that some have suggested is required for apoptosis is untenable. It has been argued that anesthesia-induced apoptosis is a species-specific phenomenon. However, studies that reported no neuroapoptosis in infantmice, rabbits, or piglets and near-term fetal sheep did not examine brains soon enough after treatment with the anesthetic to be able to detect relevant changes. To detect neuroapoptotic responses, brain specimens must be examined within 24 hours, which was not the case in these studies. The histologic method (silver staining or activated caspase-3 immunohistochemical staining) used to demonstrate changes may also affect the detection of histologic changes as the activated caspase-3 immunohistochemical process is ideal in detecting acute neurodegenerative processes. Thus, the histologic procedure and posttreatment time interval when detection is attempted are important for accurate determination of neuroapoptosis. For ethical reasons, the issue cannot be studied using the same sensitive methods in humans. Either hypoxia/ischemia or hypoglycemia has been proposed as responsible for the neurodegenerative reaction after exposure to anesthetics. However, evidence does not support this hypothesis. The features of cell death after hypoxia/ischemia are completely different from those shown by apoptosis characteristic of anesthesia-induced neuroapoptosis. Studies in infant rats have shown that when neuroapoptogenic doses of ketamine or an anesthetic combination are administered, oxygenation remain normal although the neurons undergo apoptosis. In studies examining the contribution of hypoglycemia, each exposure condition using isoflurane or a triple anesthetic cocktail of isoflurane, midazolam, and nitrous oxide triggered neuroapoptosis, but blood glucose values remained the same as or higher than control values. Finally, as humans live longer than mice and have a longer synaptogenic period, it has been argued that longer exposure to an anesthetic drug is necessary for a human neuron to be affected by the apoptogenic stimulus. However, in fetal nonhuman primate brains, apoptosis occurs within <8 hours after transplacental exposure to ethanol. Ketamine given by IV infusion in a monkey model triggered neuroapoptosis in the brain within 2 hours of ketamine exposure. Whether anesthesia-induced neuroapoptosis indicates that the neurons are permanently deleted from the brain and not replaced or compensated for requires additional evaluation. This issue can be examined by determining whether the neonatal neuropathologic changes are associated with later neurocognitive deficits. Such an association has been found in rat brains and the deficits persist into rodent adolescence and rodent adulthood. However, some degree of recovery is possible because the disturbances do not involve the entire brain but just certain regions and neighboring neurons may assume some brain functions. In humans, the relevance of these animal studies can be examined by assessing the behavioral changes induced by ethanol damage in human developing brain (eg, the mild hyperactivity disorder and fetal alcohol syndrome). Ethanol shares a neuroapoptosis mechanism similar to other drugs, including most general anesthetics. Exposure to anesthetic drugs does not seem to cause fetal alcohol syndrome. However, the fact that ethanol damaged fetal brains was recognized only about 30 years ago when the association with craniofacial malformations was made. The association was not made on the basis of cognitive dysfunction. Whether exposure to anesthetic drugs creates dysfunction is more difficult as a mother addicted to ethanol exposes her fetus repeatedly during a period of high vulnerability whereas exposure of infants to anesthesia is frequently limited to a single brief episode. In studies of pediatric patients exposed to halogenated ethers for long periods, those with acute neurologic dysfunction recovered within 3 days; however long-term follow-up studies have not been conducted. Therefore, although these impairments resolved in 3 days, the conclusion that the longer-term impact on the brain was benign cannot be substantiated.