Objective: Coagulation activation is an integral part of sepsis pathogenesis. Experimental data suggest that endothelial exposure to hypoxia activates coagulation. We aimed to test the hypothesis that the quantity of exposure to global tissue hypoxia is associated with the degree of coagulation activation during early sepsis resuscitation.
Design: Prospective, multicenter cohort study.
Setting: Emergency department and intensive care unit of three academic hospitals.
Patients: Inclusion criteria were age older than 17, acute infection with two or more signs of systemic inflammation, hypotension despite fluid challenge (or lactate >4 mM), and continuous central venous oxygen saturation (Scvo2) monitoring for quantitative resuscitation. Exclusion criteria were anticoagulant or blood product administration.
Measurements and Main Results: We recorded central venous oxygen saturation continuously for 0 to 6 hrs of resuscitation and calculated the area under the curve for central venous oxygen saturation <70%. We defined hypoxia exposure as exceeding the median area under the curve for the entire cohort. At 0, 6, and 24 hrs, we measured conventional coagulation biomarkers plus thrombin–antithrombin complex, plasmin–antiplasmin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, protein C, antithrombin, and endothelial markers (E-selectin, intracellular adhesion molecule-1, thrombomodulin). We compared changes during 0 to 6 hrs and 0 to 24 hrs in biomarkers between hypoxia exposure and nonexposure groups. We enrolled 40 patients (60% requiring vasopressors; 30% mortality). We found that exposure to hypoxia alone was not associated with a significant degree of coagulation activation. However, in secondary analyses we found that exposure to arterial hypotension induced E-selectin and thrombin–antithrombin complex, whereas concomitant exposure to both hypotension and hypoxia was associated with amplification of E-selectin and thrombomodulin, and a reduction in protein C.
Conclusion: In this sample of patients undergoing quantitative resuscitation for sepsis, we found that exposure to global tissue hypoxia (as quantified by low central venous oxygen saturation) was not associated with major coagulation activation. Further investigation to elucidate the clinical factors that trigger or intensify the procoagulant response to sepsis is warranted.
From Department of Medicine, Division of Critical Care Medicine (ST, MR, JEP, RPD) and the Department of Emergency Medicine (ST, RCA, TA), UMDNJ-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, NJ; Department of Emergency Medicine (AEJ), Carolinas Medical Center, Charlotte, NC; Department of Emergency Medicine (NIS), Beth Israel Deaconess Medical Center, Boston, MA; Novo Nordisk Research US (AEP), North Brunswick, NJ.
This study was supported by a Shock Society/Novo Nordisk research grant for Hemorrhagic Shock and Hemostasis to Dr. Trzeciak. Dr. Trzeciak is now supported by a grant from the National Institutes of Health/National Institute of General Medical Sciences (K23GM83211). Dr. Jones' effort is supported by a grant from the National Institutes of Health/National Institute of General Medical Sciences (K23GM076652). Dr. Shapiro is supported in part by grants from the National Institutes of Health HL091757 and GM076659. Software for continuous data recording was provided to the investigators by Edwards Lifesciences.
Presented in abstract form at the 6th Congress of the International Federation of Shock Societies, 31st Annual Congress on Shock, Cologne, Germany, July 1, 2008.
Dr. Trzeciak has received research support from Novo Nordisk, Biosite, Eli Lilly, and INO Therapeutics, but he does not receive personal remuneration from any commercial interest. Dr. Jones has received research support from Critical Biologics and Hutchinson Technologies, but he does not receive personal remuneration from any commercial interest. Dr. Shapiro is a past speaker for Eli Lilly, and he receives research funding from Eli Lilly, Cumberland Pharmaceuticals, Hutchinson Technologies, and Inverness Medical. Dr. Parrillo has stock options and equity interest with Deep Breeze, and has received honoraria/speaking fees from Philips. The remaining authors have not disclosed any potential conflicts of interest.
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