Venous and arterial thromboembolism in severe sepsis

Robert L. Levine; Jacques R. LeClerc; Joan E. Bailey; Matthew J. Monberg; Samiha Sarwat

doi:10.1160/TH08-01-0004

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(05): 892-898
DOI: 10.1160/TH08-01-0004

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Venous and arterial thromboembolism in severe sepsis

Robert L. Levine

¹Department of Neurosurgery, University of Texas School of Medicine at Houston, Houston, Texas, USA

,

Jacques R. LeClerc

²Retired employee and current shareholder/beneficiary of Eli Lilly & Co., 2404 Sunny Slope, Bridgewater, New Jersey, USA

,

Joan E. Bailey

³Eli Lilly and Company, Lilly Corporate Center, Drop Code 6072, Indianapolis, Indiana, USA

,

Matthew J. Monberg

⁴Eli Lilly and Company, Drop Code 6831, Indianapolis, Indiana, USA

,

Samiha Sarwat

⁵Eli Lilly and Company, Lilly Corporate Center, Drop Code 6025, Indianapolis, Indiana, USA

› Author Affiliations

Abstract

Summary

The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA)and secretory phospholipase A2 inhibitor (sPLA₂I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA₂I =578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly threequarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA₂I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.

Keywords

Sepsis - thromboembolism - stroke - venous thrombosis - pulmonary embolism - drotrecogin alfa (activated)

Full Text

References

References
1 Heit JA, Silverstein MD, Mohr DN. et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999; 159: 445-453.
2 Bellomo R, Goldsmith D, Russell S. et al. Postoperative serious adverse events in a teaching hospital: a prospective study. MJA 2002; 176: 216-218.
3 Lawall H, Hoffmanns W, Hoffmanns P. et al. Prevalence of deep venous thrombosis (DVT) in non-surgical patients at hospital admission. Thromb Haemost 2007; 98: 765-770.
4 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
5 Heit JA, Silverstein MD, Mohr DN. et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-815.
6 Anderson FA, Jr. Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: SI9-S16.
7 Davidson BL. Risk assessment and prophylaxis of venous thromboembolism in acutely and/or critically ill patients. Haemostasis 2000; 30: S77-S81.
8 Attia J, Ray JG, Cook DJ. et al. Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001; 161: 1268-1279.
9 Graziano JN, Charpie JR. Thrombosis in the intensive care unit: etiology, diagnosis, management, and prevention in adults and children. Cardiol Rev 2001; 9: 173-182.
10 Ibrahim E, Iregui M, Prentice D. et al. Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med 2002; 30: 771-774.
11 Gardlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group. Lancet 1996; 347: 1357-1361.
12 Herwald H. Haemostasis, vascular biology, and infectious agents. Thromb Haemost 2007; 98: 483-484.
13 Bergmann S, Hammerschmidt S. Fibrinolysis and host response in bacterial infections. Thromb Haemost 2007; 98: 512-520.
14 Frick IM, Bjorck L, Herwald H. The dual role of the contact system in bacterial infectious disease. Thromb Haemost 2007; 98: 497-502.
15 Esmon CT. Coagulation and inflammation. J Endotoxin Res 2003; 9: 192-198.
16 Paganini-Hill A, Lozano E, Fischberg G. et al. Infection and risk of ischemic stroke: differences among stroke subtypes. Stroke 2003; 34: 452-457.
17 Levi M, Levy M, Williams MD. et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176: 483-490.
18 Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol 2007; 4: 306-311.
19 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362-365.
20 Lindsberg PJ, Grau AJ. Inflammation and infections as risk factors for ischemic stroke. Stroke 2003; 34: 2518-2532.
21 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. J Am Med Assoc 1995; 274: 335-337.
22 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10: 448-450.
23 Noble JS, Reid AM, Jordan LV. et al. Troponin I and myocardial injury in the ICU. Br J Anaesth 1999; 82: 41-46.
24 Kollef MH, Ladenson JH, Eisenberg PR. Clinically recognized cardiac dysfunction: an independent determinant of mortality among critically ill patients: is there a role for serial measurement of cardiac troponin I?. Chest 1997; 111: 1340-1347.
25 Guest TM, Ramanathan AV, Tuteur PG. et al. Myocardial injury in critically ill patients. A frequently unrecognized complication. J Am Med Assoc 1995; 273: 1945-1949.
26 Arlati S, Brenna S, Prencipe L. et al. Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study. Intensive Care Med 2000; 26: 31-37.
27 Bleck TP, Smith MC, Pierre-Louis SJ. et al. Neurologic complications of critical medical illnesses. Crit Care Med 1993; 21: 98-103.
28 Wijdicks EFM, Scott JP. Stroke in the Medical Intensive- Care Unit. Mayo Clin Proc 1998; 73: 642-646.
29 Bernard GR, Vincent JL, Laterre PF. et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
30 Abraham E, Naum C, Bandi V. et al. Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure. Crit Care Med 2003; 31: 718-28.
31 Zeiher BG, Steingrub J, Laterre PF. et al. LY315920Na/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit Care Med 2005; 33: 1741-1748.
32 Taylor FB, Jr Toh CH, Hoots WK. et al. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327-1330.
33 Levi M, Joyce D, Yan SB. Disseminated intravascular coagulation in severely septic patients: Comparing current definitions. Intensive Care Med 2004; 29: S33.
34 Knaus WA, Draper EA, Wagner DP. et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13: 818-829.
35 Cook D, Attia J, Weaver B. et al. Venous thromboembolic disease: an observational study in medicalsurgical intensive care unit patients. J Crit Care 2000; 15: 127-132.
36 Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in ICU patients. Chest 1997; 111: 661-664.
37 Turner A, Tsamitros M, Bellomo R. Myocardial cell injury in septic shock. Crit Care Med 1999; 27: 1775-1780.
38 Ely EW, Angus DC, Williams MD. et al. Drotrecogin alfa (activated) treatment of older patients with severe sepsis. Clin Infect Dis 2003; 37: 187-195.
39 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28: 555-568.
40 Dhainaut JF, Laterre PF, Janes JM. et al. Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003; 29: 894-903.
41 Levine RL, Hergenroeder GW, Miller CCIII. et al. Venous thromboembolism prophylaxis in emergency department admissions. J Hosp Med 2007; 2: 79-85.
42 Hoffmann JN, Wiedermann CJ, Juers M. et al. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95: 850-856.
43 Jilma B. Antithrombin for severe sepsis? Try it again, but without heparin!. Thromb Haemost 2006; 95: 755.
44 Cornet AD, Smit EGM, Beishuizen A. et al. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98: 579-586.
45 Mahyar E, Carleton B, Rochon PA. Quantifying adverse drug events. Are systematic reviews the answer?. Drug Saf 2004; 27: 757-761.