Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests.
This was a matched cohort study in which children (N = 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n = 350) before the age of 2 were matched to unexposed controls (n = 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of group-administered tests of cognition and achievement were outcomes.
Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26–3.54]), even when accounting for health status. A similar pattern was observed for decrements in group-administered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program.
Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.
We read with interest the well written article of Dr Flick et al on Cognitive and behavioral outcomes after early exposure to Anaesthesia and surgery. They point out the epidemiologically significant increase in the development of learning difficulties and speech/language impairment associated with multiple exposures to anaesthetic agents in early childhood as a possible risk factor among matched cohorts. We would like to point out that the anaesthetic agents in use during the referenced time used for the purpose of this study (1976-1982) was a period of rapid advances in the field of Anaesthesia and Critical Care. The new induction agents currently in use today (Oxygen, sevoflurane) are much less metabolized than halothane. Halothane: 20% metabolism: 20% of dose is metabolised in the liver (oxidation/dehalogenation to yield trifluoroacetic acid, trifluoroacetylethanolamide, chlorobromidifluorethylene, and chloride and bromide radicals. Compared to sevoflurane: By hepatic cytochrome P450IIEI to yield hexafluoroisopropanol, which is further conjugated to its glucoronide. 3% of the absorbed sevoflurane dose is metabolised. The solubility of halothane in tissues is also much higher, so recovery after anaesthesia is delayed. The incidence of halothane hepatitis is also noted to be higher after repeated/multiple exposures. Sevoflurane has also been implicated in neuronal degeneration in infant mice. This activity is, as the authors point out in the case of halothane, thought to occur via blockade of NMDA receptors or hyperactivity of GABA neurotransmission. In one, the researchers showed exposure of infant mice to inhaled sevoflurane resulted in learning deficits and abnormal social behaviour.
To summarise, we would like to point out that modern anaesthetic agents combined with good pre-medication are clinically different from the choice of available anaesthetic agents 35 years ago. More studies are definitely needed to elaborate on the possible neuro-degenerative side- effects with the modern anaesthetic agents in use today.
References: Cognitive and Behavioral Outcomes After Early Exposure to Anesthesia and Surgery Randall P. Flick, Slavica K. Katusic, Robert C. Colligan, Robert T. Wilder, Robert G. Voigt, Michael D. Olson, Juraj Sprung, Amy L. Weaver, Darrell R. Schroeder and David O. Warner Pediatrics 2011;128;e1053 2. CG112 Sedation in children and young people: NICE guideline. 3. Satomoto M, Satoh Y, Terui K, et al. (March 2009). "Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice". Anesthesiology 110 (3): 628-37.
Conflict of Interest:
None declared
It should be noted that, unlike a previous study by the same group[1], where more than two hours of cumulative anesthesia duration was reported as associated with increased risk of learning disabilities in children under 4, there is no mention of the impact of cumulative anesthesia duration on risk in this study.
It may certainly be the case that a single exposure of significant length is less risky than 2 or more exposures of shorter duration, however, this would seemingly conflict with animal studies where pathological and neurocognitive effects were reported after single exposures of a length exceeding 2 hours[2], and where length of exposure seems to be an important factor in inducing apoptosis[3] (assuming, of course, that apoptosis is indeed the cause of these learning deficits[2]).
If it can be ascertained that multiple short procedures are as, or more, likely than single long exposures to induce cognitive deficits in children, perhaps preclinical animal studies should also focus on the effects of repeated inductions, in addition to prolonged exposures, as they currently do. It would also be an example, seemingly rare in this topic, where clinical findings drive preclinical research. Such preclinical research should also include Halothane + Nitrous Oxide, used in this study and another[4], in order to strengthen translational validity.
Clarification on why duration was not included in the analysis, as it was in the previous study[1], would be helpful.
REFERENCES:
[1]: Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort RT Wilder, RP Flick, J Sprung, SK Katusic... - Anesthesiology, 2009
[2]:Effect of Hypercarbia and Isoflurane on Brain Cell Death and Neurocognitive Dysfunction in 7-day-old Rats G Stratmann, LDV May, JW Sall, RS Alvi, JS Bell... - Anesthesiology, 2009
[3]: Isoflurane-induced Neuroapoptosis in the Neonatal Rhesus Macaque Brain AM Brambrink, AS Evers, MS Avidan, NB Farber... - Anesthesiology, 2010
[4]: Academic Performance in Adolescence after Inguinal Hernia Repair in Infancy: A Nationwide Cohort Study TG Hansen, JK Pedersen, SW Henneberg... - Anesthesiology, 2011 TG Hansen, JK Pedersen, SW Henneberg..-Anesthesiology, 2011
Conflict of Interest:
None declared