The Effects of Neonatal Isoflurane Exposure in Mice on Brain Cell Viability, Adult Behavior, Learning, and Memory

• Published in: Anesthesia and analgesia Vol. 108; no. 1; pp. 90 - 104
• Main Authors: LOEPKE, Andreas W, ISTAPHANOUS, George K, DANZER, Steve C, MCAULIFFE, John J, MILES, Lili, HUGHES, Elizabeth A, MCCANN, John C, HARLOW, Kathryn E, KURTH, C. Dean, WILLIAMS, Michael T, VORHEES, Charles V
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 2009
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Inhalation - toxicity; Animals; Animals, Newborn; Apoptosis - drug effects; Behavior, Animal - drug effects; Biological and medical sciences; Blood Glucose - drug effects; Brain - drug effects; Brain - pathology; Brain - physiopathology; Carbon Dioxide - blood; Cell Survival - drug effects; Female; Glucose - administration & dosage; Hydrogen-Ion Concentration; Isoflurane - toxicity; Lactic Acid - blood; Male; Maze Learning - drug effects; Medical sciences; Memory - drug effects; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Neurons - drug effects; Neurons - pathology; Oxygen - blood; Time Factors; Volatile compound; Human; Rodentia; Isoflurane; Encephalon; Learning; Vertebrata; Mammalia; Newborn; General anesthetic; Mouse; Animal; Anesthesia; Halogen Organic compounds
• ISSN: 0003-2999; 1526-7598
• DOI: 10.1213/ane.0b013e31818cdb29

Volatile anesthetics, such as isoflurane, are widely used in infants and neonates. Neurodegeneration and neurocognitive impairment after exposure to isoflurane, midazolam, and nitrous oxide in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. In neonatal mice, prolonged isoflurane exposure triggers hypoglycemia, which could be responsible for the neurocognitive impairment. We examined the effects of neonatal isoflurane exposure and blood glucose on brain cell viability, spontaneous locomotor activity, as well as spatial learning and memory in mice. Seven-day-old mice were randomly assigned to 6 h of 1.5% isoflurane with or without injections of dextrose or normal saline, or to 6 h of room air without injections (no anesthesia). Arterial blood gases and glucose were measured. After 2 h, 18 h, or 11 wk postexposure, cellular viability was assessed in brain sections stained with Fluoro-Jade B, caspase 3, or NeuN. Nine weeks postexposure, spontaneous locomotor activity was assessed, and spatial learning and memory were evaluated in the Morris water maze using hidden and reduced platform trials. Apoptotic cellular degeneration increased in several brain regions early after isoflurane exposure, compared with no anesthesia. Despite neonatal cell loss, however, adult neuronal density was unaltered in two brain regions significantly affected by the neonatal degeneration. In adulthood, spontaneous locomotor activity and spatial learning and memory performance were similar in all groups, regardless of neonatal isoflurane exposure. Neonatal isoflurane exposure led to an 18% mortality, and transiently increased Paco(2), lactate, and base deficit, and decreased blood glucose levels. However, hypoglycemia did not seem responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss. Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions in adult neuronal density or deficits in spontaneous locomotion, spatial learning, or memory function were observed.