• R Lundblad and K E Giercksky.
• Norwegian Radium Hospital, Oslo.
• Crit. Care Med. 1995 Aug 1;23(8):1382-90.

ObjectiveTo study the therapeutic effects of volume support, antibiotics, and a monoclonal antiendotoxin antibody on the mortality rate and blood concentrations of endothelin and other mediators in fulminant intra-abdominal sepsis in rats.DesignProspective, randomized, controlled trial.SettingResearch laboratory in a university hospital.SubjectsAdult male Wistar rats.InterventionsFulminant polymicrobial intra-abdominal sepsis was induced by a 4-mm cecal perforation. Treatment was performed with saline volume support, the antibiotic imipenem/cilastatin, and the monoclonal antiendotoxin antibody E5, both as monotherapy and as a combined regimen. Mortality rates were recorded and concentrations of bacteria, endotoxin, tumor necrosis factor (TNF), big endothelin, and endothelin-1 (21 amino acids) in blood were determined.Measurements And Main ResultsSubstantial increases in circulating big endothelin and endothelin-1 concentrations were observed during sepsis. The combination of volume support with antibiotics reduced the mortality rate, but neither as monotherapy nor as a combined regimen did this intervention modify plasma endothelin-1 concentrations. This finding suggests that hypovolemia and bacteria per se are not important stimuli for endothelin synthesis and a high plasma level of endothelin-1 does not necessarily predict poor outcome in sepsis. The inactive big endothelin is enzymatically cleaved, leaving the biologically active 21-residue endothelin-1. Intervention with E5 substantially reduced the mortality rate and concentrations of endotoxin, TNF, and plasma endothelin-1, while big endothelin and total endothelin immunoreactivity did not decrease. This finding indicates a suppressed conversion of big endothelin to endothelin-1 after E5 treatment. Because E5 has no direct effect on endothelin metabolism, E5 probably reduces the synthesis of endothelin-1 by suppressing the endothelin-activators endotoxin and TNF. A triple combination of volume support, imipenem/cilastatin, and E5 was the only regimen that reduced all of the end points: mortality rate, hemoconcentration, bacteria, endotoxin, TNF, and endothelin-1.ConclusionsThe concentration of plasma endothelin was increased during fulminant intra-abdominal sepsis in rats. Combining volume support with antibiotic therapy reduced the mortality rate, but did not modify concentrations of plasma endothelin-1. The monoclonal antiendotoxin antibody E5 reduced the mortality rate and concentrations of endotoxin, TNF, and endothelin-1, but not big endothelin. This finding indicates that E5 therapy inhibits the conversion of big endothelin to 21-residue endothelin-1.

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