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Published in: Critical Care 2/2011

Open Access 01-04-2011 | Research

Activated protein C in septic shock: a propensity-matched analysis

Authors: Farid Sadaka, Jacklyn O'Brien, Matthew Migneron, Julie Stortz, Alexander Vanston, Robert W Taylor

Published in: Critical Care | Issue 2/2011

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Abstract

Introduction

The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC.

Methods

This retrospective cohort study was completed at a large university-affiliated hospital. All patients with septic shock admitted to a 50-bed ICU between July 2003 and February 2009 were included. Patients were treated according to sepsis management guidelines.

Results

A total of 563 septic shock patients were included (110 received rhAPC and 453 did not). Treated and untreated groups were matched in patient characteristics, comorbidities, and physiologic variables in a 1:1 propensity-matched analysis (108 received rhAPC, 108 did not). Mean Acute Physiology And Chronic Health Evaluation II (APACHE II) scores were 24.5 for the matched treated and 23.9 for the matched untreated group (P = 0.54). Receipt of rhAPC was associated with reduced in-hospital mortality (35.2% vs. 53.8%, P = 0.005), similar mean days on vasopressors (2 vs. 2, P = 0.90), similar mean days on mechanical ventilation (9 vs. 8.7, P = 0.80), similar mean length of ICU stay in days (11.0 vs. 11.3, P = 0.90), and similar mean length of hospital stay in days (19.5 vs 27, P = 0.11). No patients in either group had intracranial bleeding; differences in gastrointestinal bleeding and transfusion requirements were not statistically significant.

Conclusions

Patients in our institution with septic shock who were treated with rhAPC had a reduced in-hospital mortality compared with patients with septic shock with similar acuity who were not treated with rhAPC. In addition, time on mechanical ventilation, time on vasopressors, lengths of stay and bleeding complications did not differ between the groups.
Literature
1.
go back to reference Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 10.1056/NEJMoa022139CrossRefPubMed Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 10.1056/NEJMoa022139CrossRefPubMed
2.
go back to reference Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Régnier B: Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care units. JAMA 1995, 274: 968-974. 10.1001/jama.274.12.968CrossRefPubMed Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Régnier B: Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care units. JAMA 1995, 274: 968-974. 10.1001/jama.274.12.968CrossRefPubMed
3.
go back to reference Karlsson S, Ruokonen E, Varpula T, Ala-Kokko TI, Pettilä V, Finnsepsis Study Group: Long-term outcome and quality-adjusted life years after severe sepsis. Crit Care Med 2009, 37: 1268-1274. 10.1097/CCM.0b013e31819c13acCrossRefPubMed Karlsson S, Ruokonen E, Varpula T, Ala-Kokko TI, Pettilä V, Finnsepsis Study Group: Long-term outcome and quality-adjusted life years after severe sepsis. Crit Care Med 2009, 37: 1268-1274. 10.1097/CCM.0b013e31819c13acCrossRefPubMed
4.
go back to reference Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002CrossRefPubMed Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002CrossRefPubMed
5.
go back to reference Chalfin DB, Holbein ME, Fein AM, Carlon GC: Cost-effectiveness of monoclonal antibodies to gram-negative endotoxin in the treatment of gram-negative sepsis in ICU patients. JAMA 1993, 269: 249-254. 10.1001/jama.269.2.249CrossRefPubMed Chalfin DB, Holbein ME, Fein AM, Carlon GC: Cost-effectiveness of monoclonal antibodies to gram-negative endotoxin in the treatment of gram-negative sepsis in ICU patients. JAMA 1993, 269: 249-254. 10.1001/jama.269.2.249CrossRefPubMed
6.
go back to reference Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999, 340: 207-214. 10.1056/NEJM199901213400307CrossRefPubMed Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999, 340: 207-214. 10.1056/NEJM199901213400307CrossRefPubMed
7.
go back to reference Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP: Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990, 113: 227-242.CrossRefPubMed Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP: Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990, 113: 227-242.CrossRefPubMed
8.
go back to reference Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, 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. 10.1056/NEJM200103083441001CrossRefPubMed Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, 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. 10.1056/NEJM200103083441001CrossRefPubMed
9.
go back to reference Laterre PF, Levy H, Clermont G, Ball DE, Garg R, Nelson DR, Dhainaut JF, Angus DC: Hospital mortality and resource use in subgroups of the Recombinant Human Activated Pro tein C W orldwide E valuation in S evere S epsis (PROWESS) trial. Crit Care Med 2004, 32: 2207-2218.PubMed Laterre PF, Levy H, Clermont G, Ball DE, Garg R, Nelson DR, Dhainaut JF, Angus DC: Hospital mortality and resource use in subgroups of the Recombinant Human Activated Pro tein C W orldwide E valuation in S evere S epsis (PROWESS) trial. Crit Care Med 2004, 32: 2207-2218.PubMed
10.
go back to reference Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL, Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005, 353: 1332-1341. 10.1056/NEJMoa050935CrossRefPubMed Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL, Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005, 353: 1332-1341. 10.1056/NEJMoa050935CrossRefPubMed
11.
go back to reference Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, Wong K, Wright TJ, Extended Evaluation of Recombinant Human Activated Protein C United States Investigators: Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): A single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004, 125: 2206-2216. 10.1378/chest.125.6.2206CrossRefPubMed Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, Wong K, Wright TJ, Extended Evaluation of Recombinant Human Activated Protein C United States Investigators: Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): A single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004, 125: 2206-2216. 10.1378/chest.125.6.2206CrossRefPubMed
12.
go back to reference Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, Sundin DP, Turlo MA, Janes J: Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit Care Med 2005, 33: 2266-2277. 10.1097/01.CCM.0000181729.46010.83CrossRefPubMed Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, Sundin DP, Turlo MA, Janes J: Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit Care Med 2005, 33: 2266-2277. 10.1097/01.CCM.0000181729.46010.83CrossRefPubMed
13.
go back to reference Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD: Deaths: final data for 1999. Natl Vital Stat Rep 2001, 49: 1-113. Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD: Deaths: final data for 1999. Natl Vital Stat Rep 2001, 49: 1-113.
14.
go back to reference Neilson AR, Burchardi H, Chinn C, Clouth J, Schneider H, Angus D: Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in Germany. J Crit Care 2003, 18: 217-227. 10.1016/j.jcrc.2003.10.005CrossRefPubMed Neilson AR, Burchardi H, Chinn C, Clouth J, Schneider H, Angus D: Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in Germany. J Crit Care 2003, 18: 217-227. 10.1016/j.jcrc.2003.10.005CrossRefPubMed
15.
go back to reference Angus DC, Linde-Zwirble WT, Clermont G: Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003, 31: 1-11. 10.1097/00003246-200301000-00001CrossRefPubMed Angus DC, Linde-Zwirble WT, Clermont G: Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003, 31: 1-11. 10.1097/00003246-200301000-00001CrossRefPubMed
16.
go back to reference Davies A, Ridley S, Hutton J, Chinn C, Barber B, Angus DC: Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom. Anaesthesia 2005, 60: 155-162. 10.1111/j.1365-2044.2004.04068.xCrossRefPubMed Davies A, Ridley S, Hutton J, Chinn C, Barber B, Angus DC: Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom. Anaesthesia 2005, 60: 155-162. 10.1111/j.1365-2044.2004.04068.xCrossRefPubMed
17.
go back to reference Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Gårdlund B, Marshall JC, Rhodes A: Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med 2008, 34: 1935-1947. 10.1007/s00134-008-1266-6PubMedCentralCrossRefPubMed Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Gårdlund B, Marshall JC, Rhodes A: Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med 2008, 34: 1935-1947. 10.1007/s00134-008-1266-6PubMedCentralCrossRefPubMed
19.
go back to reference Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101: 1644-1655. 10.1378/chest.101.6.1644CrossRefPubMed Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101: 1644-1655. 10.1378/chest.101.6.1644CrossRefPubMed
20.
go back to reference Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines Committee: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32: 858-873. 10.1097/01.CCM.0000117317.18092.E4CrossRefPubMed Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM, Surviving Sepsis Campaign Management Guidelines Committee: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32: 858-873. 10.1097/01.CCM.0000117317.18092.E4CrossRefPubMed
21.
go back to reference Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine, et al.: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41CrossRefPubMed Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine, et al.: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41CrossRefPubMed
22.
go back to reference Rosenbaum PR, Ross RN, Silber JH: Minimum distance matched sampling with fine balance in an observational study of treatment for ovarian cancer. JASA 2007, 102: 75-83. 10.1198/016214506000001059CrossRef Rosenbaum PR, Ross RN, Silber JH: Minimum distance matched sampling with fine balance in an observational study of treatment for ovarian cancer. JASA 2007, 102: 75-83. 10.1198/016214506000001059CrossRef
25.
go back to reference Warren HS, Suffredini AF, Eichacker PQ, Munford RS: Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002, 347: 1027-1030. 10.1056/NEJMsb020574CrossRefPubMed Warren HS, Suffredini AF, Eichacker PQ, Munford RS: Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002, 347: 1027-1030. 10.1056/NEJMsb020574CrossRefPubMed
26.
go back to reference Poole D, Bertolini G, Garattini S: Errors in the approval process and postmarketing evaluation of drotrecogin alfa (activated) for the treatment of severe sepsis. Lancet Infect Dis 2009, 9: 67-72. 10.1016/S1473-3099(08)70306-2CrossRefPubMed Poole D, Bertolini G, Garattini S: Errors in the approval process and postmarketing evaluation of drotrecogin alfa (activated) for the treatment of severe sepsis. Lancet Infect Dis 2009, 9: 67-72. 10.1016/S1473-3099(08)70306-2CrossRefPubMed
27.
go back to reference Mackenzie AF: Activated protein C: do more survive? Intensive Care Med 2005, 31: 1624-1626. 10.1007/s00134-005-2829-4CrossRefPubMed Mackenzie AF: Activated protein C: do more survive? Intensive Care Med 2005, 31: 1624-1626. 10.1007/s00134-005-2829-4CrossRefPubMed
28.
go back to reference Carlet J: Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med 2006, 34: 525-529. 10.1097/01.CCM.0000198329.85851.8ECrossRefPubMed Carlet J: Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med 2006, 34: 525-529. 10.1097/01.CCM.0000198329.85851.8ECrossRefPubMed
29.
go back to reference Lindenauer PK, Rothberg MB, Nathanson BH, Pekow PS, Steingrub JS: Activated protein C and hospital mortality in septic shock: a propensity-matched analysis. Crit Care Med 2010, 38: 1101-1107. 10.1097/CCM.0b013e3181d423b7CrossRefPubMed Lindenauer PK, Rothberg MB, Nathanson BH, Pekow PS, Steingrub JS: Activated protein C and hospital mortality in septic shock: a propensity-matched analysis. Crit Care Med 2010, 38: 1101-1107. 10.1097/CCM.0b013e3181d423b7CrossRefPubMed
Metadata
Title
Activated protein C in septic shock: a propensity-matched analysis
Authors
Farid Sadaka
Jacklyn O'Brien
Matthew Migneron
Julie Stortz
Alexander Vanston
Robert W Taylor
Publication date
01-04-2011
Publisher
BioMed Central
Published in
Critical Care / Issue 2/2011
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc10089

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