OBJECTIVE: Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis. We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release. DESIGN: A prospective, randomized controlled trial. SETTING: An experimental animal laboratory in a university hospital. SUBJECTS: Two hundred fourteen male Sprague-Dawley rats. INTERVENTIONS: Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment. A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations. Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin. MEASUREMENTS AND MAIN RESULTS: Over the 7-day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis. Mean whole blood lactate for each group peaked at 6 hrs after induction of infection. There were no significant differences in lactate concentration among the groups at any of the time points examined. Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha. In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha. CONCLUSIONS: We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats. The importance of excessive intracellular calcium release in sepsis remains to be elucidated.
OBJECTIVE: Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis. We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release. DESIGN: A prospective, randomized controlled trial. SETTING: An experimental animal laboratory in a university hospital. SUBJECTS: Two hundred fourteen male Sprague-Dawley rats. INTERVENTIONS:Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment. A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations. Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin. MEASUREMENTS AND MAIN RESULTS: Over the 7-day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis. Mean whole blood lactate for each group peaked at 6 hrs after induction of infection. There were no significant differences in lactate concentration among the groups at any of the time points examined. Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha. In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha. CONCLUSIONS: We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats. The importance of excessive intracellular calcium release in sepsis remains to be elucidated.
Authors: Antoine Guillon; Sebastien Preau; Jérôme Aboab; Eric Azabou; Boris Jung; Stein Silva; Julien Textoris; Fabrice Uhel; Dominique Vodovar; Lara Zafrani; Nicolas de Prost; Peter Radermacher Journal: Ann Intensive Care Date: 2019-06-10 Impact factor: 6.925