Through the years, care of millions of premature infants and young children has resulted in numerous exposures to a variety of anesthetic and sedative agents. These agents, designed to achieve the substantial depth of neuronal inhibition required for complete loss of consciousness and insensitivity to pain, are often a necessary component of successful treatment. However, data collected in animal models over the past decade suggest that general anesthetics damage developing neurons. Emerging animal and human data also suggest an association between early exposure to general anesthesia and long-term impairment of cognitive development. Consequently, the prudence of administering anesthesia to this population is now being scrutinized. Because general anesthesia cannot often be avoided when young children are diagnosed with conditions requiring surgery, or undergo time in intensive care units, the scientific community is focused on gaining a thorough understanding of the mechanisms of action so that we may take full advantage of the beneficial effects of anesthetics and sedatives without potentially devastating neurotoxic outcomes.
A distinctive panel of speakers convened during SmartTots: Pediatric Anesthesia Neurotoxicity, a session at the 2011 International Anesthesia Research Society Annual Meeting, to provide an overview of 2 important lines of research. One focused on improving our knowledge of the cellular mechanisms operational in anesthetic-induced developmental neurotoxicity, and another focused on advancing our understanding of anesthesia-related neurobehavioral sequelae in mammalian species exposed to anesthesia during critical stages of brain development.
Laszlo Vutskits, MD, PhD, University Hospitals of Geneva and Head, Neuroscience-oriented Anesthesia Research Group, University of Geneva, Switzerland, offered insight into recent experimental work demonstrating that general anesthetics have a major impact on the formation and elimination of synaptic contacts between neurons. The purpose of this presentation, “Beyond Toxicity: General Anesthetics and Synaptogenesis,” was to address (1) major neurodevelopmental events taking place during the brain growth spurt with a special emphasis on synaptogenesis, (2) the role of neural activity during neural network formation, and (3) how general anesthetics, being powerful modulators of neural activity, influence physiological patterns of synaptogenesis in a developmental stage–dependent manner.
Vutskits reviewed basic neurobiological doctrines related to the brain growth spurt and recent observations suggesting that general anesthetics might stand as powerful regulators of synaptogenesis and thereby neural plasticity. Vutskits provided the following conclusions: (1) neural activity has a fundamental role during the assembly of the central nervous system; (2) functional properties of developing neural networks are fundamentally different between the early and late stage of the growth spurt, thus emphasizing the need for probing multiple time points; and (3) general anesthetics can rapidly induce developmental stage–dependent, persistent changes in synapse densities. Functional implications and significance of these conclusions remain unclear.
Greg Stratmann, MD, PhD, Associate Professor of Clinical Anesthesia and Perioperative Care at the University of California, San Francisco, presented his research investigating whether anesthesia-induced cognitive decline is treatable. During his presentation, Stratmann discussed a conceptual framework of the neurocognitive deficit that may be caused by anesthesia in infancy, the concepts of prevention and treatment of anesthesia-induced neurocognitive decline, and the efficacy of an intervention designed to treat anesthesia-induced neurocognitive decline in rats.
Stratmann reviewed his model for environmental enrichment and discussed his findings that the ill effects of anesthesia on brain function, which are apparent later in life, can be overcome when environmental enrichment is instituted up to 3 weeks after exposure to sevoflurane. These findings support the concept that harnessing the brain's natural ability to adapt to functional demands can modify the course of anesthesia-induced cognitive decline in rats. He emphasized the need to understand if, and how, anesthesia changes brain function both in animals and in humans. Stratmann cautioned that clinical practice should not be changed until we are certain that a change is necessary, and we know exactly what changes will result in a better outcome.
Studies in nonhuman primates, including rhesus monkeys, have raised serious concerns about the effects of anesthesia on the developing nonhuman primate brain. Merle Paule, PhD, Director of the Division of Neurotoxicology at the National Center for Toxicological Research and SmartTots Scientific Advisory Board member, discussed these studies during his presentation titled “Ketamine Anesthesia During the First week of Life Can Cause Long-Lasting Cognitive Deficits in Nonhuman Primates.” The purpose of this presentation was 4-fold, to: (1) discuss the concern over fetal/neonatal exposures to anesthetics and sedatives during the brain growth spurt period, (2) educate the audience about the strengths and weaknesses of the animal model used to study the cognitive deficits associated with general anesthesia during the neonatal period, (3) formulate approaches that would mitigate the potential for harm from exposure to anesthetics or sedatives during critical periods of development, and (4) assess the behavioral effect of the most neurotoxic ketamine regimen.
Paule discussed his findings that a single, 24-hour exposure to ketamine during a sensitive period of brain growth results in very long-lasting deficits in brain function in nonhuman primates. According to Paule, these findings provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits.
Randall Flick, MD, MPH, Associate Professor of Anesthesiology and Pediatrics at the Mayo Clinic and Society for Pediatric Anesthesia representative on the SmartTots Affiliate Advisory Council, discussed emerging clinical data during his presentation. Flick provided an overview of recent clinical data to both support and refute animal data, information useful in advising parents of children requiring anesthesia and surgery, and findings from the United States Food and Drug Administration Anesthetic and Life Support Drugs Advisory Committee meeting, held on March 10, 2011. Flick concluded with findings from his current research, including that (1) learning, speech, and language are affected by early exposure to anesthesia whereas behavior seems to be unaffected; (2) single anesthetics do not seem to have an effect, whereas repeated anesthetic exposures consistently show an effect; and (3) these effects persist despite adjustment for comorbidity.
The growing evidence that multiple exposures to anesthesia may have deleterious effects on developing human brains presents doctors and parents with a difficult and even frightening dilemma, especially considering that surgery is rarely optional for the youngest patients. Without definitive data about the effects of anesthesia, Flick cautioned that deferring necessary surgery could cause children more harm.
In addition to the aforementioned presentations, Pediatric Anesthesia Neurotoxicity featured late-breaking abstracts that are listed in Table 1. Several related abstracts were presented during the annual meeting and are summarized in Table 2.
As evidenced by recent findings, a very reliable link between the animal and human data is rapidly emerging. At a minimum, physicians should strive to minimize the length of time a child is sedated, as well as the number of trips to the operating room. If a surgery can be deferred until after the child is 4 years old, without causing serious harm to the child, the deferral may be warranted.
The momentum of the data suggests that the concern is a potentially real one and the only way for us to reassure parents is to fund a substantial amount of research over the next several years. Findings presented during the SmartTots panel, coupled with previously reported animal studies, point to an urgent need for additional research to identify the mechanism of action of anesthesia, establish new guidelines for the use of existing anesthetics, and develop a model that will ensure the safety of new anesthetics.
For additional information, and to view the presentations discussed in this article, visit www.SmartTots.org.
Name: Vesna Jevtovic-Todorovic, MD, PhD, MBA.
Conflict of Interest: Member, SmartTots Scientific Advisory Board.