Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascular coagulation and acute lung injury in pigs.
We hypothesized that thrombin activation may play a prominent role in endotoxin-induced secondary organ failure, such as acute lung injury. To test this hypothesis, we administered a thrombin-specific inhibitor, recombinant hirudin, in endotoxemic pigs. The pigs were anesthetized, mechanically ventilated, and prepared with Swan-Ganz and extravascular lung water (EVLW) catheters. A total of 18 randomly selected animals received a pretreatment of 1,000 U/kg of hirudin, followed by a continuous infusion over 6 h of 500 U/kg/h given simultaneously with the infusion of 10 micrograms/kg/h of Salmonella abortus equi endotoxin. Another 18 animals received a continuous infusion over 6 h of endotoxin but did not receive hirudin. All animals were fluid resuscitated with 17 ml/kg/h of saline for the duration of the experiment. Data are expressed as the mean (95% confidence interval). Hirudin reduced the endotoxin-induced consumption of plasma fibrinogen from -110 (-138 to -82) mg/100 ml to -39 (-67 to -12) mg/100 ml (p = 0.0001) and endotoxin-induced increases in the soluble fibrin in plasma from 434 (369 to 499) ng/ml to 236 (171 to 300) ng/ml (p = 0.0002). These data suggest an effective inhibition of the endotoxin-generated thrombin by hirudin. Furthermore, hirudin significantly reduced endotoxin-induced increases in pulmonary vascular resistance from 32 (27 to 37) kdyn x s x cm-5 x kg to 20 (15 to 25) kdyn x s x cm-5 x kg (p = 0.0015) and increases in EVLW from 15.4 (13.2 to 17.6) ml/kg to 12.2 (10.0 to 14.4) ml/kg (p = 0.0299).(ABSTRACT TRUNCATED AT 250 WORDS)
Hoffmann
H
H
Department of Surgery, Ludwig Maximilians University, Munich, FRG.
Siebeck
M
M
Spannagl
M
M
Weis
M
M
Geiger
R
R
Jochum
M
M
Fritz
H
H
D000208:Acute Disease; D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D001772:Blood Cell Count / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D005340:Fibrinogen / Q000032:analysis; D006439:Hemodynamics / Q000187:drug effects; D006629:Hirudins / Q000494:pharmacology*; D007962:Leukocytes / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000502:physiology; D010196:Pancreatic Elastase / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D011516:Prothrombin / Q000032:analysis; D011994:Recombinant Proteins; D012475:Salmonella; D013552:Swine; D013556:Swine, Miniature; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*
D004731:Endotoxins; D006629:Hirudins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D000990:Antithrombin III; D011516:Prothrombin; D005340:Fibrinogen; D010196:Pancreatic Elastase; D013917:Thrombin