Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Stratmann
Greg
G
Department of Anesthesia and Perioperative Car, University of California, San Francisco, California 94143, USA. stratman@anesthesia.ucsf.edu
May
Laura D V
LD
Sall
Jeffrey W
JW
Alvi
Rehan S
RS
Bell
Joseph S
JS
Ormerod
Brandi K
BK
Rau
Vinuta
V
Hilton
Joan F
JF
Dai
Ran
R
Lee
Michael T
MT
Visrodia
Kavel H
KH
Ku
Ban
B
Zusmer
Emanuel J
EJ
Guggenheim
Jeremy
J
Firouzian
Atoosa
A
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005239:Fear; D005260:Female; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
D018685:Anesthetics, Inhalation; D002245:Carbon Dioxide; D007530:Isoflurane