KETAMINE SUPPRESSES TUMOR-NECROSIS-FACTOR-ALPHA ACTIVITY AND MORTALITY IN CARRAGEENAN-SENSITIZED ENDOTOXIN-SHOCK MODEL

We have reported that an intravenous anesthetic, ketamine, has a poten t suppressive effect on lipopolysaccharide (LPS)-induced TNF-alpha pro duction in vitro [Takenaka et al., Anesthesiology 80:402-408, 1994]. T he purpose of the present study was to investigate the overall effects of ketamine on hemodynamics, serum TNF-alpha level, arterial blood ga ses (ABGs), blood glucose level, liver function, and lethality in carr ageenan (CAR)-sensitized endotoxemic models. All animals were pretreat ed intraperitoneally with CAR (150 mg/kg) 16 hr before LPS stimulation . The control rats were injected LPS with 0.5 mg/kg intravenously (i.v .). The ketamine-treated rats were injected with 100 mg/kg of ketamine intramuscularly 30 min before LPS (0.5 mg/kg) i.v. injection, followe d by an i.v, infusion at 0, 5, or 10 mg/kg/hr, Serum TNF-alpha, ABGs, blood glucose, and hematological studies were determined at 0, 2, and 6 hr after the LPS challenge. Serum hepatocellular enzyme levels were measured at 6 hr after the injection. In CAR-sensitized rats, serum TN F-alpha activity remarkably increased in accordance with the mild decr ease of mean arterial pressure (MAP) at 2 hr after LPS stimulation. In addition, severe metabolic acidosis, hypoglycemia as well as severe h epatic injury were induced at 6 hr after the LPS challenge. By contras t, ketamine treatment significantly attenuated the decrease in MAP and LPS-induced TNF-alpha activity. Ketamine also significantly improved arterial oxygen tension (PaO2), metabolic acidosis and hypoglycemia, a nd attenuated endotoxin-induced hepatic injury in a dose-dependent fas hion. In addition, ketamine treatment significantly improved LPS-induc ed lethality in CAR-sensitized mice. We therefore concluded that ketam ine significantly attenuated hypotension, hypoxemia, metabolic acidosi s, hypoglycemia and liver injury, and even mortality in CAR-sensitized endotoxemic models. (c) 1995 Wiley-Liss, Inc.