EFFECT OF VOLUME SUPPORT, ANTIBIOTIC-THERAPY, AND MONOCLONAL ANTIENDOTOXIN ANTIBODIES ON MORTALITY-RATE AND BLOOD-CONCENTRATIONS OF ENDOTHELIN AND OTHER MEDIATORS IN FULMINANT INTRAABDOMINAL SEPSIS IN RATS

Objective: To study the therapeutic effects of volume support, antibio tics, and a monoclonal antiendotoxin antibody on the mortality rate an d blood concentrations of endothelin and other mediators in fulminant intraabdominal sepsis in rats. Design: Prospective, randomized, contro lled trial. Setting: Research laboratory in a university hospital. Sub jects: Adult male Wistar rats. Interventions: Fulminant polymicrobial intra-abdominal sepsis was induced by a 4-mm cecal perforation. Treatm ent was performed with saline volume support, the antibiotic imipenem/ cilastatin, and the monoclonal antiendotoxin antibody E5, both as mono therapy and as a combined regimen. Mortality rates were recorded and c oncentrations of bacteria, endotoxin, tumor necrosis factor (TNF), big endothelin, and endothelin-1 (21 amino acids) in blood were determine d. Measurements and Main Results: Substantial increases in circulating big endothelin and endothelin-1 concentrations were observed during s epsis. The combination of volume support with antibiotics reduced the mortality rate, but neither as monotherapy nor as a combined regimen d id this intervention modify plasma endothelin-1 concentrations. This f inding suggests that hypovolemia and bacteria per se are not important stimuli for endothelin synthesis and a high plasma level of endotheli n-1 does not necessarily predict poor outcome in sepsis. The inactive big endothelin is enzymatically cleaved, leaving the biologically acti ve 21-residue endothelin-1. Intervention with E5 substantially reduced the mortality rate and concentrations of endotoxin, TNF, and plasma e ndothelin-1, while big endothelin and total endothelin immunoreactivit y did not decrease. This finding indicates a suppressed conversion of big endothelin to endothelin-1 after E5 treatment. Because E5 has no d irect effect on endothelin metabolism, E5 probably reduces the synthes is 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: mortal ity rate, hemoconcentration, bacteria, endotoxin, TNF, and endothelin- 1. Conclusions: The concentration of plasma endothelin was increased d uring fulminant intra-abdominal sepsis in rats. Combining volume suppo rt with antibiotic therapy reduced the mortality rate, but did not mod ify concentrations of plasma endothelin-1. The monoclonal antiendotoxi n antibody E5 reduced the mortality rate and concentrations of endotox in, TNF, and endothelin-l, but not big endothelin. This finding indica tes that E5 therapy inhibits the conversion of big endothelin to 21-re sidue endothelin-1.