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SPA Newsletter.
Does anaesthesia harm the developing brain - evidence or speculation?Andrew Davidson and Sulpicio Soriano. Paediatric Anaesthesia 2004; 14: 199-20. The authors have written a short but thought provoking editorial in the journal, which I will try to summarize. Parents have been constantly reminded that various foods, drinks, life styles, drugs and chemicals may impair their unborn child's development. Hence, when a newborn child comes for surgery, it would not be unreasonable for the parents to inquire if the anesthetic would in any way affect the child. The anesthesiologist usually reassures the parents that the anesthetic drugs will be all gone without a trace and their child will make a swift and complete recovery. The question is whether this reassurance is based on facts or speculation, and is there really no cause for concern? Recently there have been reports in the literature that in the geriatric patient there is some cognitive dysfunction after general anesthesia. Over the past 20 years there have been reports of studies done on the newborn rat. In one study prolonged exposure to halothane, 8 hours a day for 5 days resulted in decreased synaptic activity and stunted growth. Another reported that N-methyl D-aspartate blockade resulted in significant apoptosis. In another ketamine, 20 mg/kg injected 7 times over a 9 hour period produced similar results. These are all very large doses over a protracted period of time. There was also a decrease in weight gain, but when only a single dose of ketamine was administered no changes were seen. Besides ketamine and halothane, other agents such as ethanol, phencyclidine, nitrous oxide, isoflurane, propofol, barbiturates, diazepam, clonazepan and other anticonvulsants, all increased apoptic neurodegeneration in developing rat brain. It is interesting that these same authors found a greater ketamine and nitrous oxide neurotoxicity in the adult compared to the infant rat, via another mechanism of cell death. In a recent study, 7 day old rats were exposed to various combinations and concentrations of nitrous oxide, midazolam, and isoflurane. It was found that nitrous oxide and midazolam alone caused no apoptosis, whereas isoflurane produced significant apoptosis. The same authors showed that a cocktail of 75% nitrous oxide, 0.75% isoflurane and 9 mg/kg midazolam produced the greatest apoptosis, and later the rats had memory and learning impairment, which the authors believed was clinically relevant to humans. The editorial correctly points out that for several reasons the study is not clinically comparable to human use, the dose of midazolam is very high and reflects interspecies difference in the anesthetic dose. The rats in the study, as compared to humans, were not adequately monitored and there was no indication that cerebral perfusion and oxygenation was maintained. Of greatest concern is the length of exposure. Rat brains develop over 2 weeks - a human brain develops over several years. Six hours to a neonatal rat is equivalent to a month in a human infant. If an average neonatal anesthetic were 1-2 hour, this would equate to less then a minute in a rat. In the final analysis, even if the animal data were not applicable to humans, it would be imprudent to ignore it. Evidence must be sought from human data. This is not easy. A randomized control trial would be unethical, confounders abound, and the outcome measures are hard to define. Nevertheless, cohort studies investigating outcome for neonates have been performed. One study has suggested adverse neurological outcome associated with surgery and general anesthesia in infants less then 1000g birth weight, when their sensorial outcome was assessed at 5 years. The authors do concede that there could be unidentified confounders. Amongst other factors, transportation of these infants posed a considerable risk from handling, fasting, and changes in temperature, hyperoxia or hypoxia. The authors of this editorial believe that it is not possible to draw conclusions until more relevant cohorts are examined to clarify the risk of anesthesia. The editorial brings up a very important point. What are the alternatives to anesthesia? Pain and stress response are associated with adverse outcome. If surgery is required, anesthesia is better then no anesthesia. One could ask which anesthetic is best. But all have been implicated. Can surgery be delayed, and if so for how long? Given the prolonged human development, surgery would have to be delayed by years, not a practical option. Therefore, if any statements have to be provided about the putative harmful effects of anesthesia, they need to be coupled with the realities and the benefits of anesthesia and surgery. Reviewed by: Hoshang J. Khambatta, MD Table of Contents
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