Sepsis

Original Editors - Leana Louw

Top Contributors - Lucinda hampton, Leana Louw, Rachael Lowe, Kim Jackson, Aminat Abolade, Admin, Carina Therese Magtibay and Uchechukwu Chukwuemeka

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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, or in other words, an exacerbated immune response. 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 a variety of pathogens, mostly gram-positive. Common pathogens include the following:

• 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%)

80% of sepsis cases is the result of the following infections:

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

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.

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
• Signs of tissue hypoperfusion:
  • Areas of mottled skin
  • Oliguria
  • Mental confusion
  • Delayed capillary refill
  • Hyperlactacidaemia

The pathways leading to organ failures during sepsis can involve upregulation of inflammatory responses and neuroendocrine systems.70,88,89 Prompt recovery from organ failures in survivors and the normal anatomical appearance of the failed organs suggest that ischaemic and haemorrhagic damage are an uncommon mechanism. Alternatively, mediators such as TNF, interleukin 1, NO, and oxygen reactive species might inhibit the mitochondrial respiratory chain, inducing cellular dysoxia with reduced energy production, an effect aggravated by hormonal deficiencies.89 Inflammatory mediators might also alter modulation by the autonomic nervous system of biological oscillator functions,69 leading to disruption of communication between organs, which can precede the development of shock90 and multiorgan dysfunction.91 Lastly, excessive expression of tissue factor, decreased concentrations and activity of coagulation inhibitors (antithrombin III, activated protein C, and tissue factor pathway inhibitor), and insufficient fibrinolytic activity result in a procoagulant state that can interact with inflammatory mediators in a vicious circle, leading to organ failure.92

Diagnostic Procedures

Septic shock can only be diagnosed when it fits to the clinical criteria and a infection (and the pathogen if possible) is verified.

• Identification of infection:
  • Look for obvious signs - e.g. community-aquired pneumonia, prupura fulminans, cellulitis, wound discharge.
  • Blood tests / tissue biopsy or sample to determine pathogen
• Bloods:
  • PCR
  • Microarraybased rapid
• Assess for issue hypoperfusion
  • Glasgow coma scale to determine mental confusion (unable to do in sedated patients)
  • Input and output measures to determine oliguria
• Multi-organ failure

Outcome Measures

SOFA score

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.

Control infection source

• Antibiotics
• Removal of infected/necrotic tissue (where applicable)

Shock management

• Aim for restoration to the following values (if possible within 6 hours):
  • CVP: 8-12mmHg
  • MAP: 65-90
  • Sats > 70%
• Management strategies:
  • Fluids
  • Vasopressors (if hypotension still present after management with fluids)
  • Inotropes
  • Blood transfusions
  • Mechanical ventilation

Organ dysfunction management

• In cases of renal failure: Renal replacement treatement
• In ARDS/acute lung injury: Mechanical ventilation with tidal volumes of 6-7ml/kg ideal body weight

Enhancing or replacing host responses

• Endocrine response:
  • Low-dose corticosteroids
  • Low-dose vasopresssin (if corticosteroids are not able to be administrated or not working)
• Haemostasis response: Drotrecogin alfa

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
• ome patients with septic shock might benefit from drugs such as corticosteroids or activated protein C
  prophylactic antibiotics2 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 immunoglobulinEnteral nutritional supplementation

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.

mmune, neuroendocrine, and haemostasis responses. After discharge, appropriate rehabilitation and long-term follow-up are mandatory (figure 5).Fluid challenges can be repeated until cardiac output increases by more than 10% and as long as central venous pressure increases less than 3 mm Hg. Other monitoring tools include right-heart catheterisation, transpulmonary thermodilution techniques, echocardiography, and pulse pressure or vena cava variability,123 and physicians should use the method with which they are familiar. A trial of fluid replacement in 7000 critically ill patients showed no difference in mortality between crystalloids and albumin,124 and an ongoing trial (CRISTAL) is comparing synthetic colloids with crystalloids. For now, crystalloids and synthetic colloids can be used alone or in combination. Of the vasopressors, dopamine or norepinephrine is recommended as the first-line drug, although phase II trials have yielded conflicting results.123,125 Two large continuing trials in patients with septic shock are comparing epinephrine to combined dobutamine and norepinephrine (CATS) or dopamine to norepinephrine (DeBacker D, personal communication). At present, physicians should use their preferred drug (table 5). When hypotension results mainly from myocardial depression, inotropic agents can be used first. Vasopressors should be titrated to quickly restore systemic mean arterial pressure to 60–90 mm Hg, depending on whether the patient had pre-existing hypertension. Secondary endpoints that need monitoring include cardiac performance, tissue dysoxia (eg, lactate), and microcirculation as assessed by capillary refilling time or by sublingual capnography. Optimisation of haemodynamic status could require blood transfusion and, occasionally, vasodilators.108,109 Patients should be treated with oxygen, and when they have acute lung injury or acute respiratory distress syndrome, with invasive mechanical ventilation with a tidal volume of 6–7 mL/kg of ideal body weight.126 Daily haemodialysis127 or continuous venovenous haemofiltration with an ultrafiltration rate of 35–45 mL/kg per h128 should be used in patients with overt acute renal failure (table 5).88 The first attempts to combat inflammation in patients with septic shock relied on non-selective drugs—ie, highdose corticosteroids129 and non-steroidal anti-inflammatory drugs.130 These drugs failed to improve survival. Monoclonal antibodies (HA-1A, E5) targeting lipopolysaccharide131,132 were tested but proved ineffective because of their weak biological activity.133 By contrast, recombinant bactericidal permeability-increasing protein significantly improved functional outcome in children with severe meningococcal septicaemia (77% of 190 children recovered their preillness level of function compared with 66% of 203 placebo-treated controls, p=0·019).134 Other lipopolysaccharide-targeting drugs are being investigated, such as cationic antimicrobial protein 18 (which is also bactericidal),135 synthetic analogues of lipid A, E5564,136 human lipoproteins which also exert anti-inflammatory effects independently from binding tolipopolysaccharide,137 and recombinant monoclonal antibody to CD14.138 Second-generation drugs for septic shock blindly and massively block one factor in the inflammatory cascade, for instance, TNF, interleukin 1, platelet activating factor, adhesion molecules, arachidonic acid metabolites, oxygen free radicals, bradykinin, phosphodiesterase and C1 esterase, or NO synthase. They failed to improve survival.139 However, because they are biologically active, they might prove beneficial when used in specific strategies. A meta-analysis of 10 sepsis trials (6821 patients) showed an absolute reduction in mortality of 3·5% with antiTNF drugs.139 Carriers of the TNFB2 allele are at risk for lethal septic shock,9 indicating that antibodies to TNF should be reassessed in this population. Upregulation of inducible NO synthase contributes to hypotension and organ dysfunction during sepsis.123 However, constitutive NO synthase is essential for homoeostasis, and activity of inducible NO synthase is mainly confined to infected tissues.68 Thus, although non-selective inhibition of NO synthase was associated with increased mortality from septic shock,140 selective inhibition of inducible NO synthase deserves to be investigated. Future therapeutic targets could also include late mediators such as HMGB1 or macrophage migration inhibitory factor, complement C5a and its receptor, or apoptosis (table 6). Polyvalent intravenous immunoglobulins modulate the expression and function of Fc receptors, activation of complement and cytokine networks, production of idiotype antibodies, and activation, differentiation, and effector functions of T and B cells.141 A meta-analysis showed reduced mortality with polyclonal immunoglobulins (n=492; relative risk [RR] 0·64; 95% CI 0·51–0·80). However, a sensitivity analysis on highquality trials found no evidence that immunoglobulins were beneficial,142 highlighting the need for adequately powered trials of immunoglobulins in septic shock. Similarly, the clinical benefit from treatment with interferon � and granulocyte macrophage colony stimulating factor remains uncertain,139 although these drugs might correct a number of immune function variables.143,144 Recent approaches rely on replacement of hormones or coagulation inhibitors. A meta-analysis129 showed that hydrocortisone in doses from 200–300 mg for 5 days or more reduced duration of shock, systemic inflammation, and mortality (RR 0·80; 95% CI 0·67–0·95) without causing harm (table 5). Only patients with refractory septic shock and adrenal insufficiency benefit from hydrocortisone, and 50 �g/day oral fludrocortisone can be added.145 A continuing trial (CORTICUS) is investigating the risk to benefit ratio of hydrocortisone in non-refractory septic shock. Vasopressin replacement therapy in doses ranging from 0·01–0·04 IU/min improved haemodynamics and decreased catecholamine requirements (table 5).146–149 However, vasopressin might induce myocardial, cutaneous, or mesenteric vasoconstriction and should not be used until the results of the VAST trial are reported. Recombinant human activated protein C (drotrecogin alfa, 24 �g/kg per h for 96 h) provided a 6% reduction in 28-day mortality from sepsis with at least one recent (<48 h) organ dysfunction.150 A trial of this drug in 11 000 patients with sepsis inducing one organ dysfunction (ADDRESS) was stopped prematurely because of inefficacy. Drotrecogin alfa should be given for septic shock requiring respiratory or renal support, provided there is no risk of bleeding, as detailed in the PROWESS trial (table 5).150 Neither anti-thrombin III151 nor tissue factor pathway inhibitor54 have proved beneficial in patients with sepsis. Significant interactions were noted between heparin and activated protein C, anti-thrombin III, and tissue factor pathway inhibitor, masking treatment benefits and promoting bleeding. Continuing trials are reassessing these drugs in heparin-free patients. Meanwhile, anti-thrombin III and tissue factor pathway inhibitor should not be used, and heparin should be avoided during infusion of drotrecogin alfa. Whether heparin is beneficial in patients with sepsis remains unclear.

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