Fluid resuscitation improves survival of endotoxemic or septicemic rats: possible contribution of tumor necrosis factor.
The present study was designed to investigate the effects of fluid administration on survival in endotoxemic or septicemic male Sprague-Dawley rats. Endotoxemia was induced by intravenous injection of Escherichia coli lipopolysaccharide (LPS), and septicemia produced by cecal ligation and puncture (CLP). In endotoxemic animals deprived of fluid resuscitation, 7-day survival following injection of LPS at doses of 1, 3, or 10 mg/kg LPS were 70% (n = 10), 30% (n = 10), and 0% (n = 10), respectively. In rats resuscitated with 3.3 ml/kg/h of 0.9% NaCl, the dose-response curve for survival was shifted 5-fold rightward in a parallel manner (p < 0.001, between the fluid-resuscitated and nonfluid resuscitated LPS groups), indicating a reduced sensitivity to the effects of LPS following fluid resuscitation. LPS increased serum tumor necrosis factor (TNF alpha) concentrations in fluid-resuscitated endotoxemic animals from a baseline value of 20 U/ml to 2,350 U/ml at 1 h, which returned to 200 U/ml at 2 h. In endotoxemic animals not receiving fluid resuscitation, serum TNF alpha levels at 1 and 2 h were 5-fold and 27-fold higher, respectively, than in fluid-resuscitated animals. There were no differences in arterial blood pressure or heart rate between the two groups of endotoxemic animals; total peripheral resistance was significantly lower at 1 h, and cardiac index was significantly greater at 3 h in the fluid-resuscitated LPS group; otherwise there were no further differences in hemodynamic parameters between the two groups. The survival rate at 4 days following CLP without fluid resuscitation was 14%, whereas CLP with fluid resuscitation improved survival to 74% (p < 0.01). TNF alpha was undetectable (i.e., < 20 U/ml) in the serum of animals subjected to CLP. The improvement in survival with fluid infusion in the LPS and CLP models cannot be attributed to catheter implantation, or to improved hemodynamic parameters in the LPS model. The improvement in survival in the LPS model with fluid infusion was associated with attenuated increases in TNF alpha levels. Furthermore, these studies illustrate that fluid-resuscitated and nonfluid-resuscitated experimental animal models should not be considered equivalent.
Smith
E F
EF
SmithKline Beecham Pharmaceuticals, Department of Pharmacology, King of Prussia, Pa 19406.
Slivjak
M J
MJ
Egan
J W
JW
Gagnon
R
R
Arleth
A J
AJ
Esser
K M
KM
D000818:Animals; D002395:Catecholamines / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004731:Endotoxins; D005440:Fluid Therapy / Q000706:statistics & numerical data; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology / Q000628:therapy*; D015996:Survival Rate; D014115:Toxemia / Q000503:physiopathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*
D002395:Catecholamines; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha