Effect of Hypercarbia and Isoflurane on Brain Cell Death and Neurocognitive Dysfunction in 7-day-old Rats

• DOI: 10.1097/aln.0b013e31819c7140
• Publication Date: 2009-05-21T15:58:41Z
• Authors: Greg Stratmann; Laura D. V. May; Jeffrey W. Sall; Rehan S. Alvi; Joseph S. Bell; Brandi K. Ormerod; Vinuta Rau; Joan F. Hilton; Ran Dai; Michael T. Lee; Kavel H. Visrodia; Ban Ku; Emanuel J. Zusmer; Jeremy Guggenheim; Atoosa Firouzian
• Keywords: Male; Neurons; Memory Disorders; Time Factors; Dose-Response Relationship, Drug; Isoflurane; Cell Survival; Cell Differentiation; Fear; Carbon Dioxide; Rats; 3. Good health; Rats, Sprague-Dawley; Survival Rate; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Anesthetics, Inhalation; Conditioning, Psychological; Animals; Female; Blood Gas Analysis; Cell Proliferation

Millions of neonates undergo anesthesia each year. Certain anesthetic agents cause brain cell death and long-term neurocognitive dysfunction in postnatal day (P)7 rats. Despite its intuitive appeal, a causal link between cell death and neurocognitive decline after anesthesia has not been established. If one existed, the degree of cell death would be expected to correlate with the degree of neurocognitive dysfunction caused by anesthesia. The authors therefore tested if cell death caused by various durations of isoflurane at 1 minimum alveolar concentration causes duration-dependent long-term neurocognitive dysfunction.Isoflurane was administered to P7 rats at 1 minimum alveolar concentration for 0, 1, 2, or 4 h. To control for the respiratory depressant effects of anesthesia, a group of rats was treated with 4 h of carbon dioxide. Cell death was assessed by FluoroJade staining 12 h after the end of each intervention, and neurocognitive outcome was assessed 8 weeks later by using fear conditioning, spatial reference memory, and spatial working memory tasks.Widespread brain cell death was caused by 2 h and 4 h of isoflurane and by 4 h of carbon dioxide. The degree and distribution of thalamic cell death was similar in 4 h isoflurane-treated and 4-h carbon dioxide-treated rats. Only 4 h of isoflurane caused a long-term neurocognitive deficit affecting both spatial reference memory and spatial working memory. Working memory was improved in carbon dioxide-treated rats.Isoflurane-induced brain cell death may be partly caused by hypercarbia. The inconsistencies between cell death and neurocognitive outcome suggest that additional or alternative mechanisms may mediate anesthesia-induced long-term neurocognitive dysfunction.