Anesth Analg 2003;97:1769-1772
© 2003 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
The Dose-Related Effects of Ketamine on Mortality and Cytokine Responses to Endotoxin-Induced Shock in Rats
Takumi Taniguchi, MD*,
Yasuhiro Takemoto, MD
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Hiroko Kanakura, MD,
Yoko Kidani, MD, and
Ken Yamamoto, MD
Departments of *Emergency and Critical Care Medicine and
Anesthesiology and Intensive Care Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
Address correspondence and reprint requests to Takumi Taniguchi, MD, Department of Emergency and Critical Care Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Address e-mail to taniyan{at}med.kanazawa-u.ac.jp
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Abstract
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IMPLICATIONS: IV administered ketamine dose-independently inhibited hypotension, metabolic acidosis, and proinflammatory cytokine responses, and improved survival rates of rats receiving a single IV bolus of endotoxin.
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Introduction
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Endotoxin shock, a common problem in patients with endotoxemia that often resists even intensive medical treatment, is characterized by profound hypotension, progressive metabolic acidosis, and dysfunction of multiple organs (1,2). Our previous study (3) found that ketamine administration inhibited hypotension, metabolic acidosis, and cytokine responses in rats injected with endotoxin. Several other investigators also have documented that ketamine attenuates the production and release of cytokines in endotoxemia (4–7). However, only a few studies have indicated whether ketamine may have the dose-related beneficial effects after endotoxin injection. This study was undertaken to clarify the dose-related effects of ketamine on mortality and cytokine responses to endotoxin-induced shock in rats.
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Methods
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Sixty-five male Wistar rats, weighing 374 ± 14 g (mean ± SD), were studied. All experimental procedures were approved by the Animal Care Committee of Kanazawa University, and were in accordance with the National Institutes of Health guidelines for animal use. The method of animal preparation was reported previously (3). Briefly, after an intraperitoneal injection of pentobarbital sodium (30 mg/kg), ventilation was performed through a tracheotomy. The femoral artery and vein were cannulated, and lactated Ringer’s solution containing pancuronium bromide (0.02 mg/mL) and pentobarbital sodium (0.5 mg/mL) was infused continuously (10 mL · kg-1 · h-1). The rats were connected to a pressure-controlled ventilator (Servo 900C; Siemens-Elema, Solna, Sweden), which delivered 100% oxygen at a frequency of 30 breaths/min with an inspiratory/expiratory ratio of 1:1. After this procedure, the animals were rested for more than 15 min to allow the blood gases and hemodynamic variables to stabilize.
After baseline measurements, animals were divided at random among five groups (n = 13 per group): 1) saline control group (Group C) received 0.9% saline alone (did not receive endotoxin), 2) endotoxin alone group (Group E) received endotoxin (10 mg/kg) (Escherichia coli 0111:B4; Difco Laboratories, Detroit, MI) alone, 3) small-dose treatment group (Group L) received an infusion of ketamine (5 mg · kg-1 · h-1) followed by the endotoxin injection, 4) medium-dose treatment group (Group M) received an infusion of ketamine (10 mg · kg-1 · h-1), and 5) large-dose treatment group (Group H) received an infusion of ketamine (20 mg · kg-1 · h-1).
Rectal temperature was maintained between 36° and 38°C. Arterial blood samples were drawn after the endotoxin injection for the measurement of arterial pH (pHa), O2 tension (PaO2), CO2 tension (PaCO2), and plasma cytokine concentrations. Cytokine concentrations (tumor necrosis factor [TNF]-
and interleukin [IL]-6) were measured with enzyme-linked immunosorbent assays (BioSource, Camarillo, CA). The rats were observed for 8 h after endotoxin injection.
Data were presented as mean ± SD. Differences among groups at baseline were analyzed with the unpaired Student’s t-test. Hemodynamic and cytokine changes were analyzed by means of two-way analysis of variance with repeated measures followed by a post hoc test (Bonferroni’s method). Comparisons among mortality rates of the groups were made with the Kaplan Meier and Mantel-Cox methods. Statistical significance was defined as P < 0.05.
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Results
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Hemodynamics and Mortality Rate
Endotoxin injection reduced arterial pressure in Groups E, L, and H, but not in Group M (Fig. 1). The mortality rates for Groups C, L, M, and H were significantly smaller than that for Group E (P < 0.05) (Fig. 2). Eight hours after endotoxin injection, the mortality rates were 0% for Group C, 92% for Group E, 48% for Group L, 0% for Group M, and 32% for Group H. The mortality rate was significantly less for Group M than for Groups L and H (P < 0.05).
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Figure 1. The heart rate (top) and systolic arterial pressure (bottom) at baseline and after injection of endotoxin (mean ± SD). Closed squares = saline control group, closed circles = endotoxin alone group, open squares = small-dose treatment group, open circles = medium-dose treatment group, open triangles = large-dose treatment group. *P < 0.05 versus endotoxin alone group.
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Figure 2. Survival curves for saline control, endotoxin alone, small-dose treatment, medium-dose treatment, and large-dose treatment groups. *P < 0.05 versus endotoxin alone group. #P < 0.05 versus small-dose treatment groups. **P < 0.05 versus large-dose treatment groups.
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Plasma Cytokine Concentrations
Endotoxin injection increased the TNF- concentration in all groups, but the concentration remained significantly less in the M group than in the other two ketamine-administered groups 2 h after injection (P < 0.05). Plasma concentrations of IL-6 became increased in all groups, but were significantly smaller in Groups C, M, and H than in Groups E and L (P < 0.05) (Fig. 3).
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Figure 3. Changes of plasma tumor necrosis factor (TNF)- (top) and interleukin (IL)-6 (bottom) at baseline and after injection of endotoxin (mean ± SD). Closed squares = saline control group, closed circles = endotoxin alone group, open squares = small-dose treatment group, open circles = medium-dose treatment group, open triangles = large-dose treatment group. *P < 0.05 versus endotoxin alone group.
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Blood Gases
PaCO2 and PaO2 did not differ significantly among the five groups at any point during the experimental period (Table 1). The endotoxin injection reduced pHa in all groups, but 5 h after the injection, a significantly larger pHa was observed in Groups C and M than in the other three groups (P < 0.05).
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Discussion
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Previous reports have described the dose-dependent antiinflammatory effects of ketamine on endotoxemia. In vitro, Kawasaki et al. (5) showed that ketamine dose-dependently inhibited the production of TNF-, IL-6, and IL-8 in human blood, and Weigand et al. (7) demonstrated that ketamine had a similar effect on lipopolysaccharide-stimulated neutrophil functions such as oxygen radical generation. In vivo, Koga et al. (8) found that ketamine dose-dependently inhibited the lipopolysaccharide-stimulated TNF- response and liver injury in mice. In other words, these previous studies all found that ketamine has dose-dependent antiinflammatory effects on endotoxemia both in vitro and in vivo. However, our study showed that a large dose of ketamine resulted in a more frequent mortality rate and proinflammatory cytokine concentration than resulted from a medium dose to endotoxemia in vivo, which suggests that ketamine has dose-independent antiinflammatory effects.
This suggests that there are several reasons for the difference between this and previous studies. One is the ketamine dose: a much larger dose of ketamine than that used in our study was administered in several in vitro studies. The other reason is the method of ketamine administration: both IV and subcutaneous administrations of ketamine were used in a previous in vivo study reported by Koga et al. (8). Further investigations are needed to clarify the effects of these differences.
Ketamine has been recommended for the induction of anesthesia and sedation of patients with circulatory failure because of its actions in increasing sympathetic nervous system activity, which tends to maintain blood pressure and preserve cardiovascular function (9). However, some investigators have reported that in patients with shock, including endotoxin shock, the induction of anesthesia with ketamine can cause marked cardiovascular depression (10). Our study showed that a large dose of ketamine did not improve survival or attenuate proinflammatory cytokine responses as much as a medium dose. These findings suggest that the antiinflammatory effects of ketamine may be less prominent than its inhibition of cardiac function, and may be one of the reasons that the antiinflammatory effects of ketamine were not dose-dependent in our in vivo study.
In summary, although the mechanisms responsible for the inhibitory effects require further investigation, our study showed that the administration of ketamine dose-independently inhibited hypotension, metabolic acidosis, and cytokine responses, and improved survival rates of rats receiving a single IV bolus of endotoxin.
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Acknowledgments
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This work was supported by the Japan Research Foundation for Clinical Pharmacology.
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References
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Accepted for publication June 19, 2003.
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Abstract
Introduction
