EFFECTS OF NONANTICOAGULANT HEPARIN ON CARDIOVASCULAR AND HEPATOCELLULAR FUNCTION AFTER HEMORRHAGIC-SHOCK

Although heparinization of animals before hemorrhage improves cell and organ function, the potent anticoagulant activity of conventional hep arin sodium precludes its potential clinical use. To determine whether a novel nonanticoagulant heparin, GM1892, would have any beneficial e ffects on cardiovascular and hepatocellular functions and would decrea se susceptibility to sepsis after hemorrhage, laparotomy was performed on rats (i.e., trauma induced), after which they were bled to and mai ntained at a mean arterial pressure of 40 mmHg until 40% of maximal bl eedout volume was returned in the form of Ringer lactate solution (RL) . The rats were then resuscitated with three times the volume of shed blood with RL over 45 min, followed by infusion of two times RL plus G M1892 (7 mg/kg body wt; similar to 2% the anticoagulant activity of re gular heparin) or saline over 60 min. At 2 and 4 h after the completio n of resuscitation, cardiac output, hepatocellular function, and micro vascular blood flow were determined. The results indicated that cardia c output, hepatocellular function, and microvascular blood flow in the liver, spleen, and small intestine decreased significantly after hemo rrhage and resuscitation. Administration of GM1892, however, restored these parameters. The morphological abnormality observed after hemorrh age in the liver, kidney, and small gut was also attenuated with GM189 2 treatment. Moreover, GM1892 normalized the elevated plasma prostagla ndin E(2) levels. Sepsis was induced in additional rats by cecal ligat ion and puncture (CLP) 20 h after hemorrhage, and the necrotic cecum w as excised 10 h thereafter. GM1892 treatment significantly decreased m ortality after CLP and cecal excision. Thus GM1892 appears to be a use ful adjunct to fluid resuscitation, since it restores the depressed ca rdiovascular responses and decreases susceptibility to sepsis after tr auma and hemorrhage.