Correspondence
Low-Dose Heparin for Severe Sepsis
N Engl J Med 2002; 347:1036-1037September 26, 2002
- Article
To the Editor:
In their report on the efficacy of activated protein C in reducing mortality from sepsis at 28 days (March 8, 2001, issue),1 Bernard et al. presented the results of a retrospective subgroup analysis, which showed that the administration of low-dose heparin, in addition to activated protein C, had no effect on safety.1 Heparin and low-molecular-weight heparin are anticoagulants with antiinflammatory properties.2 Heparin is recommended for prophylaxis against thromboembolism in patients with sepsis.3 We conducted a study to determine whether the administration of heparin affected efficacy, hypothesizing that the use of low-dose (or low-molecular-weight) heparin would improve survival in patients with sepsis.
We searched Medline for reports published between 1991 and 2001 in order to identify trials of treatment for sepsis that were of high methodologic quality, in which the use of heparin was allowed, and in which mortality rates could be determined for patients who received heparin and those who did not. We found two trials, one evaluating activated protein C1,4 and one evaluating antithrombin III.5 Seventy-five percent of the patients in one study1 and 70 percent of the patients in the other study5 received heparin or low-molecular-weight heparin. Among 1995 pooled placebo recipients from the two trials, the odds of survival for the patients who received heparin, as compared with those who did not, was 1.45 (95 percent confidence interval, 1.18 to 1.78; P<0.001) (Table 1Table 1
Survival at 28 Days among Patients with Sepsis Who Received Low-Dose (or Low-Molecular-Weight) Heparin as Compared with Those Who Did Not.). In each trial, heparin use was associated with improved survival among placebo recipients. Heparin is relatively inexpensive (in contrast, a 96-hour infusion of activated protein C costs $6,700).Our findings are hypothesis-generating only, and caution is warranted in their interpretation. The primary limitation is that the administration of heparin was not randomly assigned, and selection bias is therefore possible (i.e., heparin might have been withheld from patients at higher risk for bleeding and also for death). However, we consider this explanation unlikely, since both trials administered experimental anticoagulants and excluded patients at high risk for bleeding. We estimate that the number needed to treat with heparin to prevent one death is 11, but this effect size is also uncertain, because the heparin dosage was not controlled.
Treatment with activated protein C represents an important advance in the care of selected patients with sepsis. Further study of low-dose heparin and related agents in such patients is warranted.
5 ReferencesBruce L. Davidson, M.D., M.P.H.
Swedish Medical Center, Seattle, WA 98122
brucedavidson@pobox.com William H. Geerts, M.D.
Sunnybrook and Women's College Health Sciences Centre, Toronto, ON M5S 1B2, CanadaAnthonie W.A. Lensing, M.D., Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands1
Bernard GR ,Vincent J-L ,Laterrie P-F , et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
Full Text | Web of Science | Medline2
Ahmed T ,Gonzalez BJ ,Danta I . Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 1999;160:576-581
Web of Science | Medline3
Wheeler AP ,Bernard GR . Treating patients with severe sepsis. N Engl J Med 1999;340:207-214
Full Text | Web of Science | Medline4
Anti-Infective Advisory Committee. FDA briefing document: drotrecogin alfa (activated) [recombinant human activated protein C (rhAPC)] Xigris. BLA #125029/0. Rockville, Md.: Food and Drug Administration, September 12, 2001. (Accessed September 6, 2002, at http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_02_FDAbriefing.pdf.)
5
Warren BL ,Eid A ,Singer P , et al. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878
CrossRef | Web of Science | Medline
- Citing Articles (29)
Citing Articles
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Qi Li, Rui Xia Lei, Xiang Dong Zhou, Victor P. Kolosov, Juliy M. Perelman. (2011) Regulation of PMA-induced MUC5AC expression by heparin in human bronchial epithelial cells. Molecular and Cellular Biochemistry
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Peter C. Minneci, Katherine J. Deans, Michael Haley, Xizhong Cui, Charles Natanson, Peter Q. Eichacker. 2010. Factors Influencing the Efficacy of Mediator-Specific Anti-Inflammatory, Glucocorticoid, and Anticoagulant Therapies for Sepsis. .
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K. Hayashida, W. C. Parks, P. W. Park. (2009) Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines. Blood 114:14, 3033-3043
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Amisha V. Barochia, Yan Li, Xizhong Cui, Daniel A. Sweeney, Charles Natanson, Peter Q. Eichacker. (2009) Antithrombosis Trials: Should we test therapeutic heparin adjusted based on activated partial thromboplastin time in septic shock?*. Critical Care Medicine 37:4, 1486-1487
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M. Angstwurm, J. Hoffmann, H. Ostermann, L. Frey, M. Spannagl. (2009) Schwere Sepsis und disseminierte intravasale Gerinnung. Der Anaesthesist 58:2, 171-179
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Tarek A. Dernaika, Gary T. Kinasewitz. (2008) Heparin in the treatment of severe sepsis: A new look at an old therapy*. Critical Care Medicine 36:11, 3098-3099
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Ryan Zarychanski, Steven Doucette, Dean Fergusson, Daniel Roberts, Donald S. Houston, Satendra Sharma, Harlena Gulati, Anand Kumar. (2008) Early intravenous unfractionated heparin and mortality in septic shock*. Critical Care Medicine 36:11, 2973-2979
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Andre C. Kalil, Junfeng Sun. (2008) How many patients with severe sepsis are needed to confirm the efficacy of drotrecogin alfa activated? A Bayesian design. Intensive Care Medicine 34:10, 1804-1811
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Hartmut Weiler, Wolfram Ruf. (2008) Activated protein C in sepsis: the promise of nonanticoagulant activated protein C. Current Opinion in Hematology 15:5, 487-493
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Linda A. Kirschenbaum, Wilma Correa Lopez, Patricia Ohrum, Anita Tsen, John Khazin, Mark E. Astiz. (2006) Effect of recombinant activated protein C and low-dose heparin on neutrophil-endothelial cell interactions in septic shock*. Critical Care Medicine 34:8, 2207-2212
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Peter C. Minneci, Katherine J. Deans, Xizhong Cui, Steven M. Banks, Charles Natanson, Peter Q. Eichacker. (2006) Antithrombotic therapies for sepsis: A need for more studies*. Critical Care Medicine 34:2, 538-541
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Michael K. Gould. (2005) Preventing venous thromboembolism in the intensive care unit: a no-brainer?. Journal of Critical Care 20:4, 304-305
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Sjoukje H. Slofstra, Cornelis van ???t Veer, Wim A. Buurman, Pieter H. Reitsma, Hugo ten Cate, C Arnold Spek. (2005) Low molecular weight heparin attenuates multiple organ failure in a murine model of disseminated intravascular coagulation*. Critical Care Medicine 33:6, 1365-1370
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Katherine J. Deans, Michael Haley, Charles Natanson, Peter Q. Eichacker, Peter C. Minneci. (2005) Novel Therapies for Sepsis: A Review. The Journal of Trauma: Injury, Infection, and Critical Care 58:4, 867-874
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Mark Oltermann. 2005. Systemic Inflammatory Response and Sepsis. , 565-577.
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Todd W. Rice, Gordon R. Bernard. (2005) Therapeutic Intervention and Targets for Sepsis*. Annual Review of Medicine 56:1, 225-248
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Toshiaki Iba, Akio Kidokoro. (2004) WHAT CAN WE LEARN FROM THE THREE MEGATRIALS USING ANTICOAGULANTS IN SEVERE SEPSIS?. Shock 22:6, 508-512
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Michael Haley, Xizhong Cui, Peter C. Minneci, Katherine J. Deans, Charles Natanson, Peter Q. Eichacker. (2004) Recombinant Human Activated Protein C in Sepsis: Assessing Its Clinical Use. The American Journal of the Medical Sciences 328:4, 215-219
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Michael Haley, Xizhong Cui, Peter C Minneci, Katherine J Deans, Charles Natanson, Peter Q Eichacker. (2004) Recombinant human activated protein C in sepsis: previous concerns and current usage. Therapy 1:1, 123-129
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Michael Haley, Xizhong Cui, Peter C Minneci, Katherine J Deans, Charles Natanson, Peter Q Eichacker. (2004) Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness. Current Opinion in Infectious Diseases 17:3, 205-211
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Steven M. Opal. (2004) Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy. Critical Care Medicine 32:3, 874-875
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Thomas Gl??ck, Steven M Opal. (2004) Advances in Sepsis Therapy. Drugs 64:8, 837-859
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E. Wiel, B. Vallet. (2003) A definite role for treatment with activated protein C in sepsis? Yes. Journal of Thrombosis and Haemostasis 1:12, 2466-2468
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James M. O'Brien, Edward Abraham. (2003) New approaches to the treatment of sepsis. Clinics in Chest Medicine 24:4, 521-548
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Christopher James Doig, Kevin B Laupland, David A Zygun, Braden J Manns. (2003) The epidemiology of severe sepsis syndrome and its treatment with recombinant human activated protein C. Expert Opinion on Pharmacotherapy 4:10, 1789-1799
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Bulent Cuhaci. (2003) Plasma exchange in multiple organ failure: Changing gears in sepsis and organ failure *. Critical Care Medicine 31:6, 1875-1877
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(2003) Low-Dose Heparin for Severe Sepsis. New England Journal of Medicine 348:12, 1185-1186
Full Text29
Guenther Mathiak, Lewis F. Neville, Guido Grass. (2003) Targeting the coagulation cascade in sepsis: Did we find the “magic bullet”? *. Critical Care Medicine 31:1, 310-311
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