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Original Contributions |

The Natural History of the Systemic Inflammatory Response Syndrome (SIRS): Title and subTitle BreakA Prospective Study

M. Sigfrido Rangel-Frausto, MD, MSc; Didier Pittet, MD; Michele Costigan, RN, BSN; Taekyu Hwang, MS; Charles S. Davis, PhD; Richard P. Wenzel, MD, MSc
[+] Author Affiliations

Reprint requests to Division of General Medicine, C-41 GH, University of Iowa Hospitals and Clinics, Iowa City, IA 52242 (Dr Wenzel).


From the Division of General Medicine, Clinical Epidemiology, and Health Services Research, Department of Internal Medicine (Drs Rangel-Frausto and Wenzel and Ms Costigan), and Division of Biostatistics, Department of Preventive Medicine (Dr Davis and Mr Hwang), University of Iowa College of Medicine, Iowa City; and Infection Control Group, Division of Infectious Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland (Dr Pittet). Dr Wenzel has served as a consultant for Pfizer Roerig, New York, NY.


JAMA. 1995;273(2):117-123. doi:10.1001/jama.1995.03520260039030
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Objective.  —Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock.

Design.  —Prospective cohort study with a follow-up of 28 days or until discharge if earlier.

Setting.  —Three intensive care units and three general wards in a tertiary health care institution.

Methods.  —Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count.

Main Outcomes Measures.  —Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death.

Results.  —During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857,804, and 542 episodes per 1000 patient-days, respectively, and 671,495, and 320 per 1000 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patients progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations.

Conclusions.  —This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.(JAMA. 1995;273:117-123)

REFERENCES

Parker MM, Parrillo JE.  Septic shock: hemodynamics and pathogenesis. JAMA . 1983;;250:3324-3327.
Wenzel RP.  Anti-endotoxin monoclonal antibodies: a second look. N Engl J Med . 1992;;326:1151-1153.
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA.  A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med . 1987;;317:653-658.
Niederman MS, Fein AM.  Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia: a common clinical sequence. Clin Chest Med . 1990;;11:633-656.
Centers for Disease Control and Prevention, National Center for Health Statistics.  Mortality Patterns—United States, 1990. Monthly Vital Stat Rep . 1993;;41:5.
Bone RC.  Sepsis syndrome: new insights into its pathogenesis and treatment. Infect Dis Clin North Am . 1991;;5:793-805.
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA.  Sepsis syndrome: a valid clinical entity. Crit Care Med . 1989;;17:389-393.
Bone RC.  Sepsis, the sepsis syndrome, multiorgan failure: a plea for comparable definitions. Ann Intern Med . 1991;;114:332-333.
American College of Chest Physicians—Society of Critical Care Medicine Consensus Conference.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med . 1992;;20:864-875.
Parrillo JE.  Pathogenetic mechanisms of septic shock. N Engl J Med . 1993;;328:1471-1477.
Nathan CF.  Secretory macrophages. J Clin Invest . 1987;;79:319-326.
Ziegler EJ, McCutchan JA, Fierer J, et al.  Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med . 1982;;307:1225-1230.
Ziegler EJ, Fisher CJ Jr, Sprung CL, et al.  Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med . 1991;;324:429-436.
Greenman RL, Schein RMH, Martin MA, et al.  A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA . 1991;;266:1097-1102.
Exley AR, Cohen J, Buurman W, et al.  Monoclonal antibody to TNF in severe septic shock. Lancet . 1990;;335:1275-1277.
Wherry J, Wenzel R, Wunderink R, et al.  Monoclonal antibody to human necrosis factor (TNF Mab): multi-center efficacy and safety study in patients with the sepsis syndrome.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 17-20, 1993;; New Orleans, La. Abstract 696:246.
Opal SM, Fisher CJ, Slotman GJ, et al.  The phase II interleukin-1 receptor antagonist (IL-1ra) sepsis syndrome trial: analysis of clinical, cytokine, and microbial features with outcome.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 11-14, 1992;; Anaheim, Calif. Abstract 1570:372.
Pittet D, Rangel-Frausto MS, Tarara D, Costigan M, Wenzel RP.  SIRS, sepsis, and severe sepsis: incidence, morbidities, and outcomes in SICU patients.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 17-20, 1993;; New Orleans, La. Abstract 1301:358.
Broderick A, Mori M, Nettleman M, Streed S, Wenzel RP.  Nosocomial infections: validation of surveillance and computer modeling to identify patients at risk. Am J Epidemiol . 1990;;131:734-742.
Pittet D, Omahen J, Tarara D, Wenzel RP.  Current risk factors for nosocomial bloodstream infection in a tertiary health care center.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; September 29-October 2, 1991;; Chicago, Ill. Abstract 800:232.
Murray JF, Matthay MA, Luce JM, Flick MR.  An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis . 1988;;138:720-723.
Teasdale G, Jennett B.  Assessment of coma and impaired consciousness: a practical scale. Lancet . 1974;;2:81-84.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE.  APACHE II: a severity of disease classification system. Crit Care Med . 1985;;13:818-829.
McCabe WR, Jackson GG.  Gram-negative bacteremia, II: clinical, laboratory, and therapeutic observations. Arch Intern Med . 1962;;110:856-864.
Owens WD, Felts JA, Spitznagel EL Jr.  ASA physical status classifications: a study of consistency of ratings. Anesthesiology . 1978;;49:239-243.
Woolson R. Statistical Methods for the Analysis of Biomedical Data . New York, NY: John Wiley & Sons Inc; 1987;:252-260.
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data . New York, NY: John Wiley & Sons Inc; 1980;:10-20.
SAS Institute. SAS/STAT User's Guide: Version 6 .4th ed. Vol 2. Cary, NC: SAS Institute; 1990;.
Freeman J, Hutchinson GB.  Prevalence, incidence, and duration. Am J Epidemiol . 1980;;112: 707-723.

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Parker MM, Parrillo JE.  Septic shock: hemodynamics and pathogenesis. JAMA . 1983;;250:3324-3327.
Wenzel RP.  Anti-endotoxin monoclonal antibodies: a second look. N Engl J Med . 1992;;326:1151-1153.
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA.  A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med . 1987;;317:653-658.
Niederman MS, Fein AM.  Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia: a common clinical sequence. Clin Chest Med . 1990;;11:633-656.
Centers for Disease Control and Prevention, National Center for Health Statistics.  Mortality Patterns—United States, 1990. Monthly Vital Stat Rep . 1993;;41:5.
Bone RC.  Sepsis syndrome: new insights into its pathogenesis and treatment. Infect Dis Clin North Am . 1991;;5:793-805.
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA.  Sepsis syndrome: a valid clinical entity. Crit Care Med . 1989;;17:389-393.
Bone RC.  Sepsis, the sepsis syndrome, multiorgan failure: a plea for comparable definitions. Ann Intern Med . 1991;;114:332-333.
American College of Chest Physicians—Society of Critical Care Medicine Consensus Conference.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med . 1992;;20:864-875.
Parrillo JE.  Pathogenetic mechanisms of septic shock. N Engl J Med . 1993;;328:1471-1477.
Nathan CF.  Secretory macrophages. J Clin Invest . 1987;;79:319-326.
Ziegler EJ, McCutchan JA, Fierer J, et al.  Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med . 1982;;307:1225-1230.
Ziegler EJ, Fisher CJ Jr, Sprung CL, et al.  Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med . 1991;;324:429-436.
Greenman RL, Schein RMH, Martin MA, et al.  A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA . 1991;;266:1097-1102.
Exley AR, Cohen J, Buurman W, et al.  Monoclonal antibody to TNF in severe septic shock. Lancet . 1990;;335:1275-1277.
Wherry J, Wenzel R, Wunderink R, et al.  Monoclonal antibody to human necrosis factor (TNF Mab): multi-center efficacy and safety study in patients with the sepsis syndrome.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 17-20, 1993;; New Orleans, La. Abstract 696:246.
Opal SM, Fisher CJ, Slotman GJ, et al.  The phase II interleukin-1 receptor antagonist (IL-1ra) sepsis syndrome trial: analysis of clinical, cytokine, and microbial features with outcome.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 11-14, 1992;; Anaheim, Calif. Abstract 1570:372.
Pittet D, Rangel-Frausto MS, Tarara D, Costigan M, Wenzel RP.  SIRS, sepsis, and severe sepsis: incidence, morbidities, and outcomes in SICU patients.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; October 17-20, 1993;; New Orleans, La. Abstract 1301:358.
Broderick A, Mori M, Nettleman M, Streed S, Wenzel RP.  Nosocomial infections: validation of surveillance and computer modeling to identify patients at risk. Am J Epidemiol . 1990;;131:734-742.
Pittet D, Omahen J, Tarara D, Wenzel RP.  Current risk factors for nosocomial bloodstream infection in a tertiary health care center.  In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy ; September 29-October 2, 1991;; Chicago, Ill. Abstract 800:232.
Murray JF, Matthay MA, Luce JM, Flick MR.  An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis . 1988;;138:720-723.
Teasdale G, Jennett B.  Assessment of coma and impaired consciousness: a practical scale. Lancet . 1974;;2:81-84.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE.  APACHE II: a severity of disease classification system. Crit Care Med . 1985;;13:818-829.
McCabe WR, Jackson GG.  Gram-negative bacteremia, II: clinical, laboratory, and therapeutic observations. Arch Intern Med . 1962;;110:856-864.
Owens WD, Felts JA, Spitznagel EL Jr.  ASA physical status classifications: a study of consistency of ratings. Anesthesiology . 1978;;49:239-243.
Woolson R. Statistical Methods for the Analysis of Biomedical Data . New York, NY: John Wiley & Sons Inc; 1987;:252-260.
Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data . New York, NY: John Wiley & Sons Inc; 1980;:10-20.
SAS Institute. SAS/STAT User's Guide: Version 6 .4th ed. Vol 2. Cary, NC: SAS Institute; 1990;.
Freeman J, Hutchinson GB.  Prevalence, incidence, and duration. Am J Epidemiol . 1980;;112: 707-723.
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