title: Depression of neuronal activity by sedatives is associated with adverse effects after brain injury.
abstract: Analgesics and sedatives are frequently used in the treatment of acute brain injury and subsequent brain swelling. Most agents act on specific receptors to modulate neuronal activity, which is normally involved in feedback loops that direct system building and maintenance. We investigated the neurodegenerative effects of midazolam and isoflurane in a rat model of controlled cortical impact injury (CCII). Two hours prior to CCII, four experimental groups were treated with different agents including a minimum alveolar concentration (MAC 1.0) of isoflurane. For additional sedation, isoflurane MAC 1.67, midazolam alone, or midazolam in combination with flumazenil was used. Blood pressure and blood gas analysis were monitored to investigate systemic side effects. Two days after treatment, relative apoptotic cell counts were determined by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. With isoflurane and midazolam, electroencephalographic (EEG) recordings revealed a decrease in amplitude size and altered frequency distribution. Treatment using deep sedation with isoflurane MAC 1.67 or midazolam increased relative apoptotic cell count by 14.8% (95% CI 3.6 to 26.1, p<0.01) and 18.0% (95% CI 6.8 to 29.3, p<0.01), respectively. Co-treatment with flumazenil reversed the neurodegenerative effect of midazolam by -13.2% (95% CI -24.5 to -2.0, p<0.05). Functional neurological outcome was worse after isoflurane MAC 1.67 (18.8 score points; p<0.01) and midazolam (21.4 score points, p<0.001). Flumazenil antagonized the neurodegenerative effects of midazolam. In conclusion, neuronal survival and functional recovery are reduced by sedative use in a rat model of acute brain injury.
authors.affiliation: Department of Neurosurgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. daniel.hertle@med.uni-heidelberg.de
authors.forename: D
authors.initials: D
authors.lastname: Hertle
authors.forename: L
authors.initials: L
authors.lastname: Werhahn
authors.forename: C
authors.initials: C
authors.lastname: Beynon
authors.forename: K
authors.initials: K
authors.lastname: Zweckberger
authors.forename: B
authors.initials: B
authors.lastname: Vienenkötter
authors.forename: C S
authors.initials: CS
authors.lastname: Jung
authors.forename: A
authors.initials: A
authors.lastname: Unterberg
authors.forename: K
authors.initials: K
authors.lastname: Kiening
authors.forename: O
authors.initials: O
authors.lastname: Sakowitz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004569:Electroencephalography; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D020287:In Situ Nick-End Labeling; D007530:Isoflurane / Q000009:adverse effects*; D008297:Male; D008874:Midazolam / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D007530:Isoflurane; D008874:Midazolam