Sepsis

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Description

The potentially life-threatening term of sepsis is defined as a systematic response to fight off the cause of an infection. It can be complicated by systemic inflammatory response syndrome (SIRS), resulting in a generalised inflammatory response, or in severe cases, septic shock. During septic shock, the reserve tissue capacity of tissue respiration is exhausted, resulting in the failure of the supply to meet the demand in terms of oxygenation. This results in hypotension not responding to fluid resuscitation. This can potentially lead to multiorgan failure where the body is unable to maintain haemostasis without medical intervention, a common cause of death in the ICU setting.

Clinically Relevant Anatomy

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Epidemiology and Etiology

Epidemiology

The incidence of sepsis is set at 50-95 per 100 000 with an suspected increase of 9% per year. This is further made up by:

• 2% of hospital admissions
• 9% of sepsis results in severe sepsis
• 3% septic shock
• 10% of ICU admissions per year
• Peak age around 60's

Risk factors:

• Cancer
• Immunodeficiency
• Chronic organ failure
• Male > female
• More common in non-white ethnic origin in North Americans
• Polymorphisms in genes that regulate immunity

Etiology

Sepsis is the result of gram-negative, gram-positive, polymicrobial bacteria, multidrug-resistant bacteria and fungi. 80% of sepsis cases is the result of the following infections.

• Chest (e.g. pneumonia)
• Abdomen
• Genitourinary system
• Primary bloodstream

Gram-positive bacteria 30–50% Meticillin-susceptible S aureus 14–24% Meticillin-resistant S aureus 5–11% Other Staphylococcus spp 1–3% Streptococcus pneumoniae 9–12% Other Streptococcus spp 6–11% Enterococcus spp 3–13% Anaerobes 1–2% Other gram-positive bacteria 1–5% Gram-negative bacteria 25–30% E coli 9–27% Pseudomonas aeruginosa 8–15% Klebsiella pneumoniae 2–7% Other Enterobacter spp 6–16% Haemophilus influenzae 2–10% Anaerobes 3–7% Other gram-negative bacteria 3–12% Fungus Candida albicans 1–3% Other Candida spp 1–2% Yeast 1% Parasites 1–3% Viruses 2–4% *From published clinical trials145,150 and epidemiological studies.5,6 Table 1: Main pathogens in septic shock

Mechanism of Injury / Pathological Process

Pathogens have the ability to trigger intercellular events in a variety of cells, including the neuroendocrine system, immune cells, epithelium and endothelium. Proinflammatory mediators attempt to eradicate the pathogens, a process that is controlled by anti-inflammatory mediators. This inflammatory process leads to tissue damage, changes in the leukocytes resulting in immune changes. When this natural control process fails, it leads to systemic inflammation and the infection is converted to sepsis or septic shock.

The hypothalamic thermostat is reset by the fever caused by sepsis. In an attempt to cool down, it results in peripheral vasodilatoation and subsequent depletion of the visceral perfusion. Excess nitric oxide production is stimulated by endotoxins and this leads to uncontrolled vasodilatation and a “functional haemorrhage”. Increased cardiac output is thus unsuccessful at maintaining an adequate blood pressure. This can lead to hypoxic tissue damage.

Shock in general normally runs the following course:

Insufficient tissue perfusion → anaerobic metabolism → lactic acidosis → metabolic acidosis → cellular damage → organ failure.

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. Lancet 2005; 365: 63–78 Service de Réanimation, Hôpital Raymond Poincaré, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Ile de France Ouest, Université de Versailles Saint Quentin en Yvelines, Garches, France (Prof Djillali Annane MD); Centre d’Investigation Clinique INSERM 0203, Unité de Pharmacologie Clinique, Hôpital de Pontchaillou, CHU de Rennes, Faculté de Médecine, Université de Rennes 1, Rennes, France (Prof E Bellissant MD); UP Cytokines & Inflammation, Institut Pasteur, Paris, France (J-M Cavaillon PhD) Correspondence to: Professor Djillali Annane, Service de Réanimation Médicale, Hôpital Raymond Poincaré, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris Ile de France Ouest, Université de Versailles Saint-Quentin en Yvelines, 104 Boulevard Raymond Poincaré, 92380 Garches, France [email protected] www.thelancet.com Vol 365 January 1, 2005 63 Septic shock Djillali Annane, Eric Bellissant, Jean-Marc Cavaillon 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. 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”, “lipopolysaccharide” variably combined with “incidence”, “prevalence”, “cause”, “origin”, “diagnosis”, “management”, “treatment”, “therapy”, “prognosis”, “morbidity”, and “mortality”. Studies were selected on the basis of relevance to septic shock. Seminar Patterns and receptors Matzinger10 redefined immunity by postulating that immune system activity stemmed from recognition of and reaction to internal danger signals, rather than from discrimination between self and non-self molecules. Danger signals also include recognition of exogenous molecules, pathogen-associated molecular patterns, which are surface molecules such as endotoxin (lipopolysaccharide), lipoproteins, outermembrane proteins, flagellin, fimbriae, peptidoglycan, peptidoglycan-associated lipoprotein, and lipoteichoic acid; and internal motifs released during bacterial lysis, such as heat-shock proteins and DNA fragments. These molecules are common to pathogenic, non-pathogenic, and commensal bacteria, making “microbial-associated molecular patterns” a better term. These patterns are recognised by specific pattern recognition receptors, which induce cytokine expression. These microbial patterns act synergistically with one another, with host mediators, and with hypoxia. Of pattern recognition receptors, the toll-like receptors are characterised by an extracellular leucinerich repeat domain and a cytoplasmic toll-interleukin-1 receptor (TIR) domain that shares considerable homology with the interleukin-1 receptor cytoplasmic domain. Currently, ten toll-like receptors have been described in humans, and the list of their specific microbial ligands is growing.11 Signal transduction after interaction between microbial-associated molecular patterns and these receptors results in activation of numerous adaptors, some with the TIR domain (myeloid differentiation protein [MyD] 88, TIR domaincontaining adaptor protein, TIR receptor domaincontaining adaptor protein inducing interferon � [TRIF], and TRIF-related adaptor molecule), and of kinase proteins. MyD88 interacts directly with most toll-like receptors and appears upstream from activation of the transcription nuclear factor-B. TRIF results in activation of nuclear factor interferon regulatory factor 3, promoting production of interferon � (figure 2).11 Additionally, molecules in the cytoplasm (MyD88s, interleukin-1 receptor-associated kinase-M, Tollip, suppressor of cytokine signalling 1) or at the cell surface (single immunoglobulin interleukin-1R-related molecule, ST2) negatively control the signalling cascade. Nod1 and Nod2 proteins are intracellular pattern recognition receptors.12 Nod1’s ligand is a peptidoglycan fragment that is almost exclusive to gram-negative bacteria. Nod2 detects a different such fragment and also recognises muramyl dipeptide, the smallest bioactive fragment common to all peptidoglycans. Four peptidoglycan recognition proteins (PGRPs), a third family of pattern recognition receptors, have been characterised in people.13 Three are membrane-bound proteins, PGRP-I, PGRP-I�, and PGRP-L. The fourth is the soluble molecule PGRP-S.

Clinical Presentation

Criteria

Two or more of the following:

• High grade (> 38˚C) or low grade (< 36˚C ) fevers
• Heart rate > 90/minute
• RR > 20/minute OR PaCO2 < 4.3kPa
• WCC > 12

Signs and symptoms

• Pyrexia
• Flushed presentation
• Tachypnea
• Hypotension
• Bounding pulse
• Restricted regional blood flow as the result of vasopressors
  

Diagnostic Procedures

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Outcome Measures

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Medical Management

Medical management is vital to prevent further inflammatory response by the cause of the sepsis. This is normally done by means of ventilatory and haemodynamic support. Treatment is aimed at controlling the cause of infection and restoring haemodynamic homeostasis.

Aims:

• Restoration of normal haemostasis
• Sustain tissue perfusion
• Avoid focussing on a single system
• Maintain oxygen delivery
• Keeping pH > 7.35

Strategies to improve oxygen delivery include:

• Respiratory support
• Inotropic support
• Vasodilators

Control of oxygen consumption is done by the following means:

• Respiratory support
• Sedation
• Paralysis
• Avoidance of pyrexia and stressors
• Supportive:
  • Blood transfusion (packed red blood cells)
  • Haemofiltration

Correction of metabolic acidosis (lactate-induced):

• Haemofiltration if pH < 7.2
• Changes to IPPV to improve PaCO2

Fluid management:

• Needs to be carefully administrated to avoid complications such as pulmonary oedema as a result of overload, as this will negatively affect oxygen delivery due to circulating volume problems.
• For optimal cardiac output:  PAWP = 18cmH2O and CVP = 10-12cmHO

Additional:

• Nutritional support is an important factor in the management of septic shock, as it can increase energy consumption up to 50%. It however negatively affects the utilization of nutrition, resulting in katabolism and subsequent muscle wasting.
• Antibiotics: Potential to exacerbate symptoms due to physiology described earlier
• Early initiated steroids, especially in cases with Gram-negativ septicaemia
  

Differential Diagnosis

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Physiotherapy management

Physiotherapy in the ICU

Physiotherapy interventions in the ICU setting normally consists of respiratory physiotherapy focussing on airway clearance technique and early mobilization. During acute sepsis or septic shock, patients are often too unstable for physiotherapy intervention, which only starts when the patient is haemodynamically stable.

A common result of these are critical illness neuropathy, and extensive rehabiltaiton should then be incorporated in the ICU, after discharge to the ward, as well as in the out-patient setting with the aim of getting the patient back to his baseline level of function and participation as per the ICF model.

Resources

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Case Studies / Key evidence

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References

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