Antithrombin III (AT) and recombinant tissue plasminogen activator (R-TPA) used singly and in combination versus supportive care for treatment of endotoxin-induced disseminated intravascular coagulation (DIC) in the neonatal pig

BACKGROUND Disseminated intravascular coagulation (DIC) is a pathological disturbance of the complex balance between coagulation and anticoagulation that is precipitated by vascular injury, acidosis, endotoxin release and/or sepsis and characterized by severe bleeding and excessive clotting. The innately low levels of coagulation factors found in newborn infants place them at extremely high risk for DIC. Anecdotal reports suggest that either anticoagulant or fibrinolytic therapy may alleviate some of the manifestations of DIC. To test the hypothesis that replacement of both anticoagulants and fibrinolytics may improve survival and outcome better than either single agent or supportive care alone, we utilized a neonatal piglet model of endotoxin-induced DIC. METHODS DIC was induced in twenty-seven neonatal pigs (7 to 14 days of age) by intravenous administration of E. coli endotoxin (800 microg/kg over 30 min). The piglets were divided into 4 groups on the basis of treatment protocol [A: supportive care alone; B: Antithrombin III (AT, 50 microg/kg bolus, 25 microg/kg per hr continuous infusion) and supportive care; C: Recombinant Tissue Plasminogen Activator (R-TPA, 25 microg/kg per hr continuous infusion) and supportive care; D: AT, R-TPA and supportive care] and monitored for 3 primary outcome parameters (survival time, macroscopic and microscopic organ involvement) and 4 secondary outcome parameters (hematocrit; platelet count; fibrinogen level; and antithrombin III level). RESULTS Compared with supportive care alone, combination therapy with AT and R-TPA resulted in a significant improvement of survival time, hematocrit, AT level, macroscopic and microscopic organ involvement, p < 0.05. Compared with supportive care alone, R-TPA alone significantly reduced macroscopic organ involvement and AT alone increased AT levels. CONCLUSION The findings suggest that combining AT, R-TPA and supportive care may prove more advantageous in treating the clinical manifestations of DIC in this neonatal pig model than either single modality or supportive care alone.