XYLAZINE-/DIAZEPAM-KETAMINE AND ISOFLURANE DIFFERENTIALLY AFFECT HEMODYNAMICS AND ORGAN INJURY UNDER HEMORRHAGIC/ TRAUMATIC SHOCK AND RESUSCITATION IN RATS Soheyl Bahrami,* Christian Benisch,* Clara Zifko,* Mohammad Jafarmadar,* Herbert Scho ¨ chl, † and Heinz Redl* *Ludwig Boltzmann Institute for Experimental & Clinical Traumatology in the Research Center of AUVA, Vienna; and † Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Center, Salzburg, Austria Received 29 Nov 2010; first review completed 13 Dec 2010; accepted in final form 18 Jan 2011 ABSTRACT—Most experimental studies on hemorrhage and trauma are performed under anesthesia. We determined the effects of three commonly used anesthetic regimens on hemodynamics and organ damage under normal and hemorrhagic/ traumatic shock (HTS) conditions in rats. Animals were anesthetized with ketamine/diazepam (K/D), ketamine/xylazine (K/X), or isoflurane (ISO). Hemorrhagic/traumatic shock was induced by a midline laparotomy, bleeding to a mean arterial pressure of 30 to 35 mmHg until decompensation, followed by restrictive and adequate phases of resuscitation. The experiment was terminated 120 min after the completion of resuscitation. Under normal conditions, K/D anesthesia resulted in higher mean arterial pressure and heart rate than K/X and higher systemic vascular resistance index (SVRI) than ISO. Stroke volume was significantly lower in K/D group than in K/X and ISO groups. Under normal conditions, ISO anesthesia was accompanied by the highest cardiac index. During shock and resuscitation, heart rate remained higher in the K/D than K/X. During shock, SVRI decreased in the K/D group but increased in K/X and ISO groups. After resuscitation, SVRI was lower, and cardiac index was higher in the ISO group than in the K/D group. Despite higher shed blood volume, the rats anesthetized with ISO did not decompensate within the time frame compared with other groups. Cellular damage (plasma creatine kinase, lactate dehydrogenase, uric acid) was more pronounced with K/D compared with ISO. Histological examinations revealed frequent HTS-induced damage to adrenals, kidney, and liver of animals anesthetized with K/D and K/X but not with ISO. Anesthetics differentially affect HTS-induced hemodynamic alterations and organ injury. Thus, when interpreting data from HTS models, the individual effect of anesthetics should be considered. KEYWORDS—Ketamine, diazepam, xylazine, isoflurane, organ failure INTRODUCTION Although increasing progress has been made in the resusci- tation of trauma victims, hemorrhage/trauma is still the leading cause of death in those younger than 40 years (1, 2). The pathophysiology of hemorrhage and trauma is not yet fully understood. Thus, experimental models are indispensable to investigate the pathophysiology and to develop new treatment strategies. The related literature is extensive, but because of too many variables, the results of hemorrhage and trauma models are difficult to compare. The criteria that should be considered for an experimental model of hemorrhagic/traumatic shock (HTS) include species, age, sex, type of hemorrhage/trauma, mode of resuscitation, and most importantly the presence or absence of anesthesia (3, 4). As a traumatized and hemorrhaged patient is not anesthetized at the time of injury, conscious models of HTS are considered of being the best clinically relevant (5). Nevertheless, it should be recognized that, even in conscious models, the preceding surgical interventions, including instrumentation and/or trauma induction, are typically performed under anesthesia (6, 7). Anesthetics differ in their effects on hemodynamics (8), inflammation (9), oxidative stress (10), adhesion (11, 12), and neuronal damage (13). Moreover, anesthetics may not only affect physiologic conditions but also influence the pro- gression of disease experimentally mimicked (8, 14). The proper choice of anesthetics in experiments is challenging and should be carefully tailored, depending on the model and end points. The three commonly used anesthetic regimens are ketamine/diazepam (K/D), ketamine/xylazine (K/X), and iso- flurane (ISO). Ketamine is an anesthetic agent advocated in conditions of compromised circulation. Constriction of small arterioles is the predominant response with ketamine (15). Diazepam, a benzodiazepine with central nervous system depressant properties, produces dose dependently taming, sedative, anticonvulsant, muscle relaxant, ataxic, and hypnotic effects in laboratory animals and is often used in combination with ketamine. Xylazine, a clonidine analog, acts on presyn- aptic and postsynaptic receptors of the central and peripheral nervous systems as a 2-adrenergic agonist and is used pri- marily for sedation, anesthesia, analgesia, and muscle relaxa- tion, often in combination with ketamine (16). However, xylazine has numerous other pharmacological effects, includ- ing bradycardia and hypotension and inhibition of the effects of postganglionic nerve stimulation (17). Finally, ISO is a halogenated volatile anesthetic that induces and maintains general anesthesia by depression of the central nervous system and resultant loss of consciousness. Address reprint requests to Soheyl Bahrami, PhD, Ludwig Boltzmann Institute for Experimental & Clinical Traumatology, Donaueschingenstrasse 13, 1200 Vienna, Austria. E-mail: Soheyl.Bahrami@trauma.lbg.ac.at. DOI: 10.1097/SHK.0b013e318212266b Copyright Ó 2011 by the Shock Society 573 SHOCK, Vol. 35, No. 6, pp. 573Y578, 2011 Copyright © 2011 by the Shock Society. 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