Effect of volume support, antibiotic therapy, and monoclonal antiendotoxin antibodies on mortality rate and blood concentrations of endothelin and other mediators in fulminant intra-abdominal sepsis in rats.
OBJECTIVE
To 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.


METHODS
Prospective, randomized, controlled trial.


METHODS
Research laboratory in a university hospital.


METHODS
Adult male Wistar rats.


METHODS
Fulminant 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.


RESULTS
Substantial 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.


CONCLUSIONS
The 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.
Lundblad
R
R
Norwegian Radium Hospital, Oslo.
Giercksky
K E
KE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001810:Blood Volume; D015377:Cilastatin / Q000627:therapeutic use; D000077728:Cilastatin, Imipenem Drug Combination; D003131:Combined Modality Therapy; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination / Q000627:therapeutic use*; D016232:Endothelins / Q000097:blood*; D005440:Fluid Therapy / Q000379:methods*; D015378:Imipenem / Q000627:therapeutic use; D007136:Immunoglobulins / Q000627:therapeutic use*; D008297:Male; D010538:Peritonitis / Q000097:blood / Q000401:mortality / Q000628:therapy; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000097:blood / Q000401:mortality / Q000628:therapy*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D016232:Endothelins; D007136:Immunoglobulins; C042866:antilipopolysaccharide antibodies; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination