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Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits.

Findings: Exposure of infant rats on day 7 of life (a time of developing brain growth, synaptogenesis, and maximal sensitivity to NMDA antagonists in rats) to 6 hours of general anesthesia consisting of isoflurane alone (0.75-1.5%) or in combination with midazolam (9 mg/kg, i.p.) + N20 (75%) results in acute apoptotic neuronal depletion in the developing brain. Specific learning and memory disabilities (abnormalities in Morris Water Maze and Radial Arm Maze testing) also occur and persist into rat adolescence and adulthood. Apoptotic neurodegeneration was most dramatic in the setting of co-administration of the three anesthetic agents. Apoptosis was not seen when either midazolam (3-9 mg/kg i.p.) or N20 (50-150 vol%) was given alone. These effects where hypothesized to occur as a result of the GABA-mimetic (isoflurane and midazolam) and NMDA receptor antagonistic (N20) properties of the anesthetics tested.

Impression: While these findings raise serious concerns as to the deleterious effects of anesthetic agents on the developing brain, it is impossible to know whether these findings are clinically relevant to human neonates and infants undergoing general anesthesia. First of all, the timing of these experiments is very specific and may be critical to interpreting their results. Prior studies in rodents have shown that rodent brains are maximally sensitive to NMDA receptor antagonist-induced neuronal apoptosis in the first week of post-natal life, and effects are no longer seen by two weeks of age. In addition, effects are only seen once anesthetic duration exceed 4-6 hours.1 Hence, should we not worry if our patient's anesthetic exposure is brief? In addition, the first two weeks of post-natal life for a rat correspond to a time of human brain development beginning in the third trimester and lasting until the third year of life. One has to wonder, therefore, if there is a window of vulnerability that may occur to a different degree or at a very different time in humans, or must we instead worry that neonates through toddlers are at risk from general anesthesia.

Another caveat with this study involves variability of drug potency/effects across species. While the MAC of volatile anesthetics is very similar (less than a two-fold difference for isoflurane) across diverse species, the efficacy of many intravenous drugs is not. Here, for example, the authors suggest that because they observe sedation in rats with a dose of midazolam of 3-9 mg/kg i.p. that this should be comparable to our dosing of midazolam in humans (0.1 mg/kg IV/IM -1.0 mg/kg p.o.). This difference in potency, however, suggests that various receptor densities across different species may be grossly different and, thus, sensitivity to toxic effects of drugs may differ as well. Thirdly, prior studies in rodents demonstrating the toxic effects of ethanol on the developing brain have a clear corollary in human disease (fetal alcohol syndrome). However, to date, despite years of providing anesthesia to patients ranging from fetuses to critically ill preterm babies to healthy neonates and infants, there is no clear clinical corollary in humans to the findings presented here. While this may be related to the subtlety of the neurodevelopmental changes observed (what is the human equivalent of a Water Maze challenge?), or to other confounding variables, as the authors suggest, it is also possible that the findings seen here cannot be directly translated from the rat brain to the grossly different human brain.

In conclusion, this study raises some important questions about the effects of drugs that are integral to our every day practice. Real changes in practice, however, should await laboratory studies in which these experiments are extended to higher mammals, as well as controlled clinical studies designed to assess neurodevelopmental development in children who undergo general anesthesia in the fetal, neonatal, and toddler periods.

1. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 293:70-74.

Table of Contents

• President's Message
• Editor's Corner
• Joint Meeting of SPA and JSPA
• Out and About the ASA
  • Pediatric Clinical Forum at ASA
  • Pediatric Panel: Pediatric Pain Management
  • Controversies in Malignant Hyperthermia, Cases from the MH Hotline
  • American Academy of Pediatrics Secion on Anesthesiology Breakfast Panel
  • Tuesday Morning general Pediatric Anesthesia Poster Discussions and Poster Sessions of General Pediatric and Pediatric Cardiac Anesthesia
• American Academy of Pediatrics Section on Anesthesia and Pain Medicine Update
• Fellows Corner
  • Non-ACGME Approved Fellowship Training Programs for Pediatric Anesthesia
• WEB ONLY
  • SPA Governmental Affairs Committee Report
  • Literature Review: Hyperkalemia and Pyloric Stenosis
  • Literature Review: Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits
  • Laryngeal mask insertion in children: a rational approach
  • Remifentanil Infusion for Cleft Palate Surgery in Young Infants
  • Tuesday Morning General Pediatric Anesthesia Poster Discussions and Poster Sessions of General Pediatric and Pediatric Cardiac Anesthesia

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