Elsevier

The Lancet

Volume 365, Issue 9453, 1 January 2005, Pages 63-78
The Lancet

Seminar
Septic shock

https://doi.org/10.1016/S0140-6736(04)17667-8Get rights and content

Summary

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

Section snippets

Epidemiology

The yearly incidence of sepsis is 50–95 cases per 100 000, and has been increasing by 9% each year.3 This disease accounts for 2% of hospital admissions; roughly 9% of patients with sepsis progress to severe sepsis, and 3% of those with severe sepsis experience septic shock,4 which accounts for 10% of admissions to intensive care units.5

The occurrence of septic shock peaks in the sixth decade of life.5 Factors that can predispose people to septic shock include cancer, immunodeficiency, chronic

Cause

Infections of the chest, abdomen, genitourinary system, and primary bloodstream cause more than 80% of cases of sepsis.3, 5, 6 Rates of pneumonia, bacteraemia, and multiple-site infection have increased steadily over time, whereas abdominal infections have remained unchanged and genitourinary infections have decreased.3, 5

The occurrence of gram-negative sepsis has diminished over the years to 25–30% in 2000. Gram-positive and polymicrobial infections accounted for 30–50% and 25% of cases,

Pathomechanisms

The definition of sepsis is often over-simplified as being the result of exacerbated inflammatory responses. However, pathogenesis involves several factors that interact in a long chain of events from pathogen recognition to overwhelming of host responses.

Diagnosis

Diagnosis of septic shock in patients with systemic inflammatory response syndrome means that the infection must be recognised and proof obtained of a causal link between infection and organ failure and shock (table 3, figure 4).

There may be a clinically obvious infection, such as purpura fulminans, cellulitis, toxic shock syndrome, community-acquired pneumonia in a previously healthy individual, or a purulent discharge from a wound or normally sterile cavity (eg, bladder, peritoneal or pleural

Treatment

Interventions that can prevent septic shock in some populations include prophylactic antibiotics,111, 112 maintenance of blood glucose concentrations between 4 and 6 mmol/L,113 selective digestive-tract decontamination,114 strategies for prevention of iatrogenic infections,115 and immune therapies such as vaccines116, 117 and intravenous immunoglobulin (table 4).118, 119 Enteral nutritional supplementation, especially with L-arginine, can reduce infection rate after elective surgery and in

Mortality

Short-term mortality from septic shock has decreased significantly in recent years. In one study, mortality fell from 62% in the early 1990s to 56% in 2000.5 Mortality varies from 35% to 70%, depending on factors such as age, sex, ethnic origin, comorbidities, presence of acute lung injury or acute respiratory distress syndrome or renal failure, whether the infection is nosocomial or polymicrobial, and whether a fungus is the causative agent.3, 4, 5, 6 Comparisons with matched patients without

The future

Septic shock remains a major source of short-term and long-term morbidity and mortality, and places a large burden on the healthcare system. The recent identification in people of molecules that sense microbial determinants has been an important step in understanding the molecular and cellular basis of sepsis. Characterisation of the links between inflammation, coagulation, and the immune and neuroendocrine systems have led to international guidelines recommending the use of drotrecogin alfa

Search strategy and selection criteria

We attempted to identify all relevant studies irrespective of language or publication status (published, unpublished, in press, and in progress). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004) using the terms “sepsis” and “septic shock”, and MEDLINE (1966 to June 2004), EMBASE (1974 to June 2004), and LILACS (www.bireme.br; accessed Aug 1, 2003) databases using the terms “septic shock”, “sepsis”, “septicaemia”, “endotoxin”,

References (153)

  • M Levi et al.

    Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice

    Blood

    (2003)
  • SB Yan et al.

    Low levels of protein C are associated with poor outcome in severe sepsis

    Chest

    (2001)
  • T Nakamura et al.

    Efficacy of a selective histamine H-2 receptor agonist, dimaprit, in experimental models of endotoxin shock and hepatitis in mice

    Eur J Pharmacol

    (1997)
  • K Hanasaki et al.

    Resistance to endotoxic shock in phospholipase A2 receptor-deficient mice

    J Biol Chem

    (1997)
  • D Annane et al.

    Compartmentalised inducible nitric-oxide synthase activity in septic shock

    Lancet

    (2000)
  • T Sharshar et al.

    Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

    Lancet

    (2003)
  • N Pathan et al.

    Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock

    Lancet

    (2004)
  • BL Jaber et al.

    Cytokine gene promoter polymorphisms and mortality in acute renal failure

    Cytokine

    (2004)
  • M Singer et al.

    Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation

    Lancet

    (2004)
  • DJ Gattas et al.

    Procalcitonin as a diagnostic test for sepsis: health technology assessment in the ICU

    J Crit Care

    (2003)
  • M Christ-Crain et al.

    Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial

    Lancet

    (2004)
  • Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis

    Crit Care Med

    (1992)
  • MM Levy et al.

    2001 SCCM/ESICM/ACCP/ ATS/SIS International Sepsis Definitions Conference

    Crit Care Med

    (2003)
  • GS Martin et al.

    The epidemiology of sepsis in the United States from 1979 through 2000

    N Engl J Med

    (2003)
  • MS Rangel-Frausto et al.

    The dynamics of disease progression in sepsis: Markov modeling describing the natural history and the likely impact of effective antisepsis agents

    Clin Infec Dis

    (1998)
  • D Annane et al.

    Current epidemiology of septic shock: the CUB-Rea Network

    Am J Respir Crit Care Med

    (2003)
  • C Alberti et al.

    Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study

    Intensive Care Med

    (2002)
  • TI Sorensen et al.

    Genetic and environmental influences on premature death in adult adoptees

    N Engl J Med

    (1988)
  • JA Hubacek et al.

    Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis

    Crit Care Med

    (2001)
  • MT Lin et al.

    Genomic polymophisms in sepsis

    Crit Care Med

    (2004)
  • P Matzinger

    Tolerance, danger, and the extended family

    Annu Rev Immunol

    (1994)
  • SE Girardin et al.

    The role of peptidoglycan recognition in innate immunity

    Eur J Immunol

    (2004)
  • G Monneret et al.

    Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis

    Crit Care Med

    (2003)
  • S Weijer et al.

    Diminished interferon-g production and responsiveness after endotoxin administration to healhy humans

    J Infec Dis

    (2002)
  • T Fumeaux et al.

    Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock

    Am J Respir Crit Care Med

    (2002)
  • Y Le Tulzo et al.

    Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock

    Am J Respir Crit Care Med

    (2004)
  • K Tschaikowsky et al.

    Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients

    Crit Care Med

    (2002)
  • A Belaaouaj et al.

    Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis

    Nat Med

    (1998)
  • H Tanaka et al.

    Role of granulocyte elastase in tissue injury in patients with septic shock complicated by multiple-organ failure

    Ann Surg

    (1991)
  • A Murata et al.

    Protective effect of recombinant neutrophil elastase inhibitor (R-020) on sepsis-induced organ injury in rat

    Inflammation

    (1994)
  • J Mallen-St Clair et al.

    Mast cell dipeptidyl peptidase I mediates survival from sepsis

    J Clin Invest

    (2004)
  • A Nakamura et al.

    Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice

    J Exp Med

    (2003)
  • RS Hotchkiss et al.

    Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans

    J Immunol

    (2001)
  • A Ayala et al.

    The induction of accelerated thymic programmed cell death during polymicrobial sepsis: control by corticosteroids but not tumor necrosis factor

    Shock

    (1995)
  • I Bogdan et al.

    Tumor necrosis factor-alpha contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis

    J Infect Dis

    (1997)
  • J Wood et al.

    Inadequate interleukin 2 production. A fundamental immunological deficiency in patients with major burns

    Ann Surg

    (1984)
  • J Muret et al.

    Ex vivo T-lymphocyte derived cytokine production in SIRS patients is influenced by experimental procedures

    Shock

    (2000)
  • CE McCall et al.

    Tolerance to endotoxin-induced expression of the interleukin-1β gene in blood neutrophils of humans with the sepsis syndrome

    J Clin Invest

    (1993)
  • C Mu-oz et al.

    Dissociation between plasma and monocyte-associated cytokines during sepsis

    Eur J Immunol

    (1991)
  • EV Granowitz et al.

    Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans

    J Immunol

    (1993)
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