Two Decades of Mortality Trends Among Patients With Severe Sepsis: A Comparative Meta-Analysis*

Objectives:Trends in severe sepsis mortality derived from administrative data may be biased by changing International Classification of Diseases, 9th Revision, Clinical Modification, coding practices. We sought to determine temporal trends in severe sepsis mortality using clinical trial data that does not rely on International Classification of Diseases, 9th Revision, Clinical Modifications coding and compare mortality trends in trial data with those observed from administrative data. Design:We searched MEDLINE for multicenter randomized trials that enrolled patients with severe sepsis from 1991 to 2009. We calculated standardized mortality ratios for each trial from observed 28-day mortality of usual care participants and predicted mortality from severity-of-illness scores. To compare mortality trends from clinical trials to administrative data, we identified adult severe sepsis hospitalizations in the Nationwide Inpatient Sample, 1993–2009, using two previously validated algorithms. Setting:In-patient. Patients:Patients with severe sepsis or septic shock. Interventions:None. Measurements and Main Results:Of 3,244 potentially eligible articles, we included 36 multicenter severe sepsis trials, with a total of 14,418 participants in a usual care arm. Participants with severe sepsis receiving usual care had a 28-day mortality of 33.2%. Observed mortality decreased 3.0% annually (95% CI, 0.8%–5.0%; p = 0.009), decreasing from 46.9% (standardized mortality ratio 0.94; 95% CI, 0.86–1.03) during years 1991–1995 to 29% (standardized mortality ratio 0.53; 95% CI, 0.50–0.57) during years 2006–2009 (3.0% annual change). Trends in hospital mortality among patients with severe sepsis identified from administrative data (Angus definition, 4.7% annual change; 95% CI, 4.1%–5.3%; p = 0.69 and Martin definition, 3.5% annual change; 95% CI, 3.0%–4.1%; p = 0.97) were similar to trends identified from clinical trials. Conclusion:Since 1991, patients with severe sepsis enrolled in usual care arms of multicenter randomized trials have experienced decreasing mortality. The mortality trends identified in clinical trial participants appear similar to those identified using administrative data and support the use of administrative data to monitor mortality trends in patients with severe sepsis.

[1]  R. Rossaint,et al.  Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. , 2005, The New England journal of medicine.

[2]  Matthew Taecker.  Hospitalizations, Costs, and Outcomes of Severe Sepsis in the United States 2003 to 2007 , 2012 .

[3]  Karen A Robinson,et al.  Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. , 2002, International journal of epidemiology.

[4]  J. Barker.  Incident Stroke and Mortality Associated With New-Onset Atrial Fibrillation in Patients Hospitalized With Severe Sepsis , 2012 .

[5]  E. Draper,et al.  APACHE II: A severity of disease classification system , 1985, Critical care medicine.

[6]  G. Kumar,et al.  Nationwide trends of severe sepsis in the 21st century (2000-2007). , 2011, Chest.

[7]  Brian H Cuthbertson,et al.  Hydrocortisone therapy for patients with septic shock. , 2008, The New England journal of medicine.

[8]  S. Opal,et al.  Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis* , 2010, Critical care medicine.

[9]  Stephen F. Lowry,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 , 2003, Critical care medicine.

[10]  Michael B. Rothberg,et al.  Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007 , 2012, Critical care medicine.

[11]  D. Harrison,et al.  The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database , 2006, Critical care.

[12]  S. Carson,et al.  The implications of long-term acute care hospital transfer practices for measures of in-hospital mortality and length of stay. , 2012, American journal of respiratory and critical care medicine.

[13]  M. Mikkelsen,et al.  Severe Sepsis Cohorts Derived From Claims-Based Strategies Appear to be Biased Toward a More Severely Ill Patient Population* , 2013, Critical care medicine.

[14]  M. Schaller,et al.  Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group. , 1998, Critical care medicine.

[15]  M. Büchler,et al.  Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. , 2012, JAMA.

[16]  M. Antonelli,et al.  Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. , 2009, JAMA.

[17]  Jon Cohen,et al.  A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis* , 2010, Critical care medicine.

[18]  J. Tenhunen,et al.  Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. , 2012, The New England journal of medicine.

[19]  B. Guidet,et al.  Incidence and impact of organ dysfunctions associated with sepsis. , 2005, Chest.

[20]  Rolf Rossaint,et al.  Epidemiology of sepsis in Germany: results from a national prospective multicenter study , 2007, Intensive Care Medicine.

[21]  E. Ivers,et al.  Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock , 2001 .

[22]  J. Bakker,et al.  Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock* , 2004, Critical care medicine.

[23]  Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock , 2003, Current infectious disease reports.

[24]  Richard Beale,et al.  The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis , 2010, Intensive Care Medicine.

[25]  O. Gajic,et al.  Comparison of International Classification of Disease-Ninth Revision (ICD-9) Coding with Retrospective Case Review for the Diagnosis of Septic Shock. , 2009, Asian Test Symposium.

[26]  E. Vicaut,et al.  Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: A randomized controlled trial* , 2009, Critical care medicine.

[27]  Richard Beale,et al.  The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis* , 2010, Critical care medicine.

[28]  J. Bakker,et al.  CD14 receptor occupancy in severe sepsis: Results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14)* , 2004, Critical care medicine.

[29]  Rolf Rossaint,et al.  Intensive insulin therapy and pentastarch resuscitation in severe sepsis. , 2008, The New England journal of medicine.

[30]  S Lemeshow,et al.  The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. , 1996, JAMA.

[31]  S. Opal,et al.  Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial* , 2004, Critical care medicine.

[32]  D. Cook,et al.  Fluid resuscitation in the management of early septic shock (FINESS): a randomized controlled feasibility trial , 2008, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[33]  E. Feuer,et al.  Permutation tests for joinpoint regression with applications to cancer rates. , 2000, Statistics in medicine.

[34]  J. Vincent,et al.  Has the mortality of septic shock changed with time. , 1998, Critical care medicine.

[35]  Ricard Ferrer,et al.  Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. , 2009, American journal of respiratory and critical care medicine.

[36]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[37]  Peter J Pronovost,et al.  Physician staffing patterns and clinical outcomes in critically ill patients: a systematic review. , 2002, JAMA.

[38]  Jiaquan Xu,et al.  Death in the United States, 2007. , 2009, NCHS data brief.

[39]  J. Sunderram,et al.  Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003* , 2007, Critical care medicine.

[40]  R. Postier,et al.  Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: A multicenter, randomized, placebo-controlled, single-blind, dose escalation study , 2001, Critical care medicine.

[41]  Jesús Blanco,et al.  Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study , 2008, Critical care.

[42]  S. Opal,et al.  The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. , 2006, The Journal of infectious diseases.

[43]  Peter K Lindenauer,et al.  Association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia, 2003-2009. , 2012, JAMA.

[44]  Theodore J Iwashyna,et al.  Identifying Patients With Severe Sepsis Using Administrative Claims: Patient-Level Validation of the Angus Implementation of the International Consensus Conference Definition of Severe Sepsis , 2014, Medical care.

[45]  J. Schüttler,et al.  Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo‐controlled, multiple‐center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock* , 2007, Critical care medicine.

[46]  C. Sprung,et al.  Sepsis in European intensive care units: Results of the SOAP study* , 2006, Critical care medicine.

[47]  Arise.  The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand. , 2007, Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine.

[48]  S. Lemeshow,et al.  A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. , 1993, JAMA.

[49]  W. Knaus,et al.  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. 1992. , 2009, Chest.

[50]  M. Levy,et al.  Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. , 2008, JAMA.

[51]  W. Knaus,et al.  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. , 1992, Chest.

[52]  H. Wunsch,et al.  Population Burden of Long‐Term Survivorship After Severe Sepsis in Older Americans , 2012, Journal of the American Geriatrics Society.

[53]  Andrew Rhodes,et al.  Drotrecogin alfa (activated) in adults with septic shock. , 2012, The New England journal of medicine.

[54]  E. Benjamin,et al.  Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. , 2011, JAMA.

[55]  S. Opal,et al.  Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: Results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial , 2009, Critical care medicine.

[56]  F. Burzotta,et al.  A simple hint to improve Robinson and Dickersin's highly sensitive PubMed search strategy for controlled clinical trials. , 2004, International journal of epidemiology.

[57]  S. Opal,et al.  Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial. , 2003, Critical care medicine.

[58]  J. Vincent,et al.  Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis* , 2003, Critical care medicine.

[59]  S. Keenan,et al.  A prospective, observational registry of patients with severe sepsis: The Canadian Sepsis Treatment and Response Registry* , 2009, Critical care medicine.

[60]  Steven B. Johnson,et al.  Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels* , 2004, Critical care medicine.

[61]  J. Dhainaut,et al.  CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group. , 1995, Critical care medicine.

[62]  D. Annane,et al.  Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. , 2010, JAMA.

[63]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[64]  Corinne Alberti,et al.  The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. , 1996, JAMA.

[65]  C. Sprung,et al.  Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. , 2003, JAMA.

[66]  J. A. Kruse,et al.  E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. , 2000, JAMA.

[67]  J. Carlet,et al.  INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. , 1996, Critical care medicine.

[68]  L. Trinquart,et al.  Influence of trial sample size on treatment effect estimates: meta-epidemiological study , 2013, BMJ : British Medical Journal.

[69]  Isabelle Boutron,et al.  Single-Center Trials Show Larger Treatment Effects Than Multicenter Trials: Evidence From a Meta-epidemiologic Study , 2011, Annals of Internal Medicine.

[70]  R. Bellomo,et al.  Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis , 2010, Intensive Care Medicine.

[71]  S. Opal,et al.  Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. , 2001, JAMA.

[72]  E. Ruokonen,et al.  Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study , 2007, Intensive Care Medicine.

[73]  K. Steinberg,et al.  Intensivist physician staffing and the process of care in academic medical centres , 2007, Quality and Safety in Health Care.

[74]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[75]  Craig R Ramsay,et al.  INTERRUPTED TIME SERIES DESIGNS IN HEALTH TECHNOLOGY ASSESSMENT: LESSONS FROM TWO SYSTEMATIC REVIEWS OF BEHAVIOR CHANGE STRATEGIES , 2003, International Journal of Technology Assessment in Health Care.

[76]  J. Dhainaut,et al.  Platelet‐activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: A randomized, double‐blind, placebo‐controlled, multicenter clinical trial , 1994 .

[77]  A. Dmitrienko,et al.  LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis* , 2005, Critical care medicine.

[78]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[79]  F Doyon,et al.  Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. , 1995, JAMA.

[80]  D. Annane,et al.  Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study , 2007, Critical care.

[81]  J. Vincent,et al.  Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study , 2001, Critical care medicine.

[82]  Binbing Yu,et al.  Comparability of Segmented Line Regression Models , 2004, Biometrics.

[83]  Sangeeta Mehta,et al.  Vasopressin versus norepinephrine infusion in patients with septic shock. , 2008, The New England journal of medicine.