Independent contributions of hypothermia and acidosis to coagulopathy in swine.

BACKGROUND: Clinical coagulopathy occurs frequently in the presence of acidosis and hypothermia. The purpose of this study was to determine the relative contributions of acidosis and hypothermia to coagulopathy, as measured by current standard bedside and clinical laboratory analyses (i.e., bleeding time and prothrombin time). In addition, we investigated possible mechanisms of these effects using a modified prothrombin time test, thromboelastography, and thrombin kinetics analyses. An improved understanding of coagulopathy should facilitate hemorrhage control. METHODS: Twenty-four pigs were randomly allocated into normal (pH, 7.4; 39 degrees C), acidotic (pH, 7.1; 39 degrees C), hypothermic (pH, 7.4; 32 degrees C), and acidotic and hypothermic (pH, 7.1; 32 degrees C) combined groups. Acidosis was induced by the infusion of 0.2N hydrochloric acid in lactated Ringer's solution. Hypothermia was induced by using a blanket with circulating water at 4 degrees C. Development of a clinical coagulopathy was defined as a significant increase in splenic bleeding time. Measurements were compared before (pre) and 10 minutes after (post) the target condition was achieved. RESULTS: Acidosis, hypothermia, or both caused the development of coagulopathy, as indicated by 47%, 57%, and 72% increases in splenic bleeding time (p < 0.05, pre vs. post). Plasma fibrinogen concentration was decreased by 18% and 17% in the acidotic and combined groups, respectively, but not in the hypothermic group. Hypothermia caused a delay in the onset of thrombin generation, whereas acidosis primarily caused a decrease in thrombin generation rates. At 4 minutes' quench time, thrombin generation in the acidotic, hypothermic, and combined groups were 47.0%, 12.5%, and 5.7%, respectively, of the value in the control group. There were no changes in serum tumor necrosis factor-alpha and interleukin-6 in any group during the study. CONCLUSION: Acidosis and hypothermia cause a clinical coagulopathy with different thrombin generation kinetics. These results confirm the need to prevent or correct hypothermia and acidosis and indicate the need for improved techniques to monitor coagulopathy in the trauma population.

Effects of increasing doses of activated recombinant factor VII on haemostatic parameters in swine.

This study examined dose-response relationships between activated recombinant factor VII (rFVIIa) and (1) in vivo haemostasis and (2) in vitro measures of coagulation and platelet function. Anesthetized swine were used. Ear bleeding time (BT) was measured and blood was sampled following increasing doses of rFVIIa (0, 90, 180, 360 and 720 microg/kg; n=6) or saline (n=6). BT was not altered by rFVIIa. Prothrombin time (PT) using standard or pig-specific methods was decreased by rFVIIa. Activated clotting time (ACT) was decreased by rFVIIa. Thromboelastography using collagen (COLL) or pig thromboplastin (p-ThP) as agonist demonstrated shorter reaction times, shortened time to reach maximum velocity of clot formation, and increased alpha-angle in the presence of rFVIIa. rFVIIa dosing increased maximum velocity of clot formation when p-ThP was used to initiate the reaction but not when COLL was used. rFVIIa at the highest concentration increased maximum amplitude when COLL was used to initiate the reaction. Platelet aggregation was not altered by rFVIIa. Following completion of the dose escalation phase, a severe liver injury was produced. rFVIIa altered neither blood loss nor survival time following injury but improved mean arterial pressure. A small increase in systemic thrombin-antithrombin III complex occurred after administration of rFVIIa at doses of 180 microg/kg and above. However, there was no histological evidence of intravascular coagulation after rFVIIa administration. In summary, rFVIIa activity was detectable in vitro but did not change haemostasis in normal swine.

Structural design of the dry fibrin sealant dressing and its impact on the hemostatic efficacy of the product.

We compared the hemostatic efficacy of a production version of a dry fibrin sealant dressing (DFSD) to a prototype that was previously successful in large animal studies. The results were used to improve manufacturing processes. Grade-V liver injuries were induced in swine and treated with gauze sponges (GAU), the prototype dressings (DFSD-1), or the scaled-up production version dressings (DFSD-2 in experiment 1 and DFSD-3 in experiment 2). Blood loss, hemostasis, resuscitation volume, and 60-min survival were quantified. In experiment 1, the DFSD-1 treatment reduced blood loss (p < 0.01), increased hemostasis at 4 min (p < 0.05), and improved survival (p < 0.05) compared with GAU. The DFSHD-2 decreased blood loss (p < 0.05) but did not increase hemostasis or survival significantly. Based on these results, manufacturing processes were altered, producing DFSD-3. In experiment 2, the DFSD-1 and DFSD-3 were equally effective in reducing blood loss (p < 0.01) and resuscitation volume (p < 0.05) compared with GAU. Hemostasis occurred more frequently in both the DFSD-1 and DFSD-3 groups (p < 0.01) compared with GAU. The structural design of DFSD-2 did not meet the efficacy requirement for release of the product. The subsequent change incorporated in DFSD-3 improved all hemostatic parameters of the dressings equal to those of the prototype product.