Neurotoxic effects of anesthetics on the developing brain
- Richard J Levy, MD, FAAP
Richard J Levy, MD, FAAP
- Vice Chair for Pediatric Laboratory Research
- Department of Anesthesiology
- Columbia University Medical Center
- Caleb Ing, MD, MS
Caleb Ing, MD, MS
- Assistant Professor of Anesthesiology and Epidemiology
- Columbia University Medical Center
- Section Editors
- Lena S Sun, MD
Lena S Sun, MD
- Editor-in-Chief — Anesthesiology
- Section Editor — Pediatric/Neonatal Anesthesia
- Professor of Anesthesiology and Pediatrics
- Columbia University Medical Center
- Andrew Davidson, MD
Andrew Davidson, MD
- Section Editor — Pediatric/Neonatal Anesthesia
- Associate Professor, Department of Pediatrics
- The University of Melbourne
The possibility that anesthetic and sedative drugs may be neurotoxic to the developing brain is of widespread importance to patients, parents, and the clinicians who care for them. This topic will discuss the neuronal damage and neurodevelopmental changes that have been reported after exposure of the developing brain to anesthetics in animal and human studies, the proposed mechanisms for these effects, and the limitations of existing literature.
Studies in animals have shown that anesthetic and sedative drugs can cause neuronal damage to the developing brain, and can cause lasting behavioral and cognitive deficits. Some human studies suggest an association between exposure of young children to anesthesia and subsequent neurodevelopmental deficits, though causation has not been established, and the specific anesthetic and patient factors that may affect risk are unknown. While concerns have also been raised regarding anesthetic exposure of the developing brain in utero, there is currently little to no evidence in humans to support these concerns.
Any degree of neurotoxicity of anesthetic and sedative drugs in humans may have widespread implications. In the United States, there are over 1.3 million children under the age of five years who undergo surgical procedures each year [1,2]. Most of these children need and receive general anesthesia, and most of these procedures cannot be delayed without adding substantial risk. In addition, an increasing number of young children receive sedatives or general anesthesia for neuroimaging studies , and many more require procedural sedation in the emergency department.
Much of the research on the mechanisms of anesthetic neurotoxicity has focused on apoptosis, though it is now evident that other mechanisms may be involved.
●Oxidative stress associated apoptosis — Anesthetic agents cause neuronal oxidative stress by inducing reactive oxygen species (ROS) formation within mitochondria during exposure [4,5]. ROS produced in this setting permit cytochrome c mobilization from the inner mitochondrial membrane [6,7]. Simultaneously, the outer mitochondrial membrane becomes permeable following anesthetic-mediated gamma-aminobutyric acidA (GABAA) receptor stimulation and N-methyl-D-aspartate (NMDA) receptor antagonism . The combination of these events allows cytochrome c to be released into the cytosol and sets in motion a cascade of cellular events that ultimately leads to apoptotic neuronal cell death.
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- THE ISSUE
- PROPOSED MECHANISMS
- NEUROTOXICOLOGIC EFFECTS IN ANIMAL STUDIES
- LACK OF DEFINITIVE EVIDENCE IN HUMAN STUDIES
- Limitations of the literature
- Prospective, randomized trial
- Observational studies
- VULNERABLE AGE PERIODS
- POTENTIALLY TOXIC EXPOSURE DOSES
- THE FDA WARNING
- WHAT WE TELL PARENTS AND PATIENTS
- SUMMARY AND RECOMMENDATIONS