Anesthesia and the Developing Brain

Abstract

A fundamental premise of general anesthesia is that anesthetics produce a reversible state of unconsciousness and unresponsiveness. Implicit in this premise is that the brain is neurophysiologically the same before and after anesthesia. Recent experimental data have questioned the complete reversibility of anesthesia. In certain circumstances, anesthetic exposure in neonatal animals leads to neuronal death. Although the relevance of these findings to humans is a subject of heated debate, the unequivocal demonstration of neuronal death in animals exposed to clinically relevant concentrations of anesthetics has provoked significant concern among anesthesia care providers and patients. The mechanisms by which anesthetics produce neuronal death are under intense investigation. Many of the agents that produce neurodegeneration are antagonists of the NMDA receptor, which include ketamine and nitrous oxide. It is well established that glutamate signaling via the NMDA receptor plays a crucial role in synaptic development and neuronal survival. During the critical period of synaptogenesis, inhibition of NMDA receptor signaling is detrimental to brain development. Indeed, other NMDA antagonists also produce a pattern of neurodegeneration that is similar to that produced by ketamine.Volatile anesthetics, propofol, barbiturates, and benzodiazepines are GABAA agonists, and each of these is associated with neuronal toxicity. Numerous animal studies in rodents indicate that NMDA receptor antagonists, including ketamine induce neurodegeneration in the developing brain. The effects of ketamine are dose dependent. The data suggest that limiting exposure limits the potential for neurodegeneration. There is also evidence that other general anesthetics, such as isoflurane, can induce neurodegeneration in rodent models, which may be exacerbated by concurrent administration of midazolam or nitrous oxide. There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models. However, the studies that have been reported suggest subtle, but prolonged, behavioral changes in rodents. Although the doses and durations of ketamine exposure that resulted in neurodegeneration were slightly larger than those used in the clinical setting. There are insufficient human data to either support or refute the clinical applicability of these findings. Ultimately, what still remains is the question of the relevance of anesthetic neurotoxicity in animal models to human pediatric anesthesia. Although two retrospective studies herein suggest that a correlation between anesthetic exposure early in life is associated with learning and behavioral abnormalities later in life, the data cannot be considered to be evidence of the existence of anesthetic neurotoxicity in humans. The absence of rigorously conducted prospective randomized trials precludes recommendations on clinical practice. Nevertheless, the findings from the two clinical studies highlight the urgent need for the conduct of one or more large-scale human studies, with well defined outcome measures and an appropriate follow-up period that specifically examine the effects of anesthesia and surgery on cognitive development in pediatric patients. It is therefore encouraging that the United States Food and Drug Administration recently launched the first phase of the SAFEKIDS (Safety of Key Inhaled and Intravenous Drugs in Pediatrics) initiative to provide some seed funding for several clinical projects. The ultimate goal of this initiative is to construct a private-public partnership that would support clinical investigations that would provide sufficient data so that clinicians and parents can make informed decisions with respect to the safety of anesthesia in children.