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
R. Lundblad et Ke. Giercksky, 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, Critical care medicine, 23(8), 1995, pp. 1382-1390
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.