Sepsis can be defined as infection with evidence of systemic inflammation, whilst septic shock is sepsis with hypotension that persists despite intravenous fluid resuscitation. Together these sepsis syndromes represent major public healthcare issues, accounting for a third of admissions to UK intensive care units (ICUs) and causing significant morbidity and mortality. In the US sepsis is estimated to cost $17 billion per year, with over 750 000 people developing severe sepsis each year. Despite extensive research and recent advancements in supportive care, sepsis remains the most prevalent cause of death in non-coronary ICUs. Mortality rates vary between 30 and 70%, with over 37 000 deaths from sepsis in the UK each year.
A continuum of disease, sepsis syndromes can be classified into defined phases correlating with stepwise increases in mortality. The term ‘systemic inflammatory response syndrome’ (SIRS) was established by the Society of Critical Care and the American College of Chest Physicians in 1992 (see Table 1). By definition, SIRS does not require definable bacterial infection; it may be caused by various insults such as surgery, trauma, and pancreatitis. Infection is the inflammatory host response to microorganism invasion of normally sterile host tissue, and ‘sepsis’ is the systemic inflammatory response syndrome (SIRS) to such infection.
In over 80% of cases, infections of the chest, abdomen, genitourinary system or primary bloodstream are the cause of sepsis. Chest infections are the most prevalent cause, and are particularly associated with hospital-acquired sepsis.
Gram-negative bacteria is the causative microorganism in 25-30% of cases, with Gram-positive or polymicrobial infections accounting for 30-50% and 25% of cases respectively. The cause is not determined in about 20%, chiefly in patients with community-acquired sepsis who receive antibiotics prior to admission.
Neonates, the elderly, and those who are immuno-compromised i.e. cancer patients, are at increased risk of developing severe sepsis and septic shock. Genetic factors such as being male of non-white ethic origin and certain gene polymorphisms are also predisposing factors.
The pathophysiology of severe sepsis involves a complex host immune response to infection, involving activation of immune cells, release of inflammatory mediators, and activation of the coagulation cascade. It is the overwhelming host response or SIRS that underlies the clinical manifestations of severe sepsis, and which primarily affects patient outcome.
The initial pro-inflammatory phase is triggered by bacterial cell wall components (i.e. lipopolysaccharide or lipoteichoic acid from Gram-negative and Gram-positive bacteria respectively) and/or exotoxins (i.e. those produced by staphylococci or streptococci). These activate pattern recognition receptors on the surface of monocytes and macrophages, promoting the synthesis and release of pro-inflammatory cytokines including tumour-necrosis factor, interleukin-1, interleukin-6, and platelet-activating factor. In severe sepsis there is dysregulation of the initial response to the septic stimulus, and an excessive and inappropriate systemic pro-inflammatory reaction ensues leading to diffuse capillary injury. Characteristically, this initial exaggerated inflammatory response is followed by a compensatory anti-inflammatory response, with anti-inflammatory cytokines i.e. interleukin-10 released. Immune suppression in this latter phase may be profound, increasing the patients’ susceptibility to secondary infection.
The release of inflammatory mediators activates coagulation yet suppresses fibrinolysis, hence promoting widespread thrombosis. If unregulated this may progress to disseminated intravascular coagulation (DIC), whereby coagulation factors and platelets are consumed predisposing to bleeding tendency. Blood flow is impaired by vessel occlusion within the microcirculation, leading to tissue hypo-perfusion and organ dysfunction.
The endothelium is activated in sepsis both directly by bacterial components and by inflammatory mediators. The microcirculation is disrupted and endothelial dysfunction ensues, with capillary leakage contributing to the development of oedema and hypovolaemia. Cellular processes are also disturbed contributing to tissue hypoxia. In the macrocirculation, sepsis induces hypovolaemia, vaso-regulatory dysfunction and myocardial depression. In severe sepsis these pathophysiological processes reduce oxygen delivery to tissues, inducing global hypoxia and lactic acidosis. Ultimately, loss of homeostatic mechanisms in sepsis leads to multiple organ dysfunction and subsequent failure.
Infection must be recognised clinically and/or microbiologically for the definitive diagnosis of sepsis to be made. Infection may be clinically evident, such as pneumonia in a previously healthy person, organ perforation after abdominal surgery, or a purulent discharge from a wound. Otherwise diagnosis of infection relies on detection of pathogens in blood or tissue cultures, although these may be negative in 30% of cases.
The clinical manifestations of severe sepsis are the sequelae of the pathophysiological features described above:
Haemodynamic alterations in severe sepsis are variable and often dynamic. The septic patient may be hyperdynamic with bounding pulses, or hypotensive and vasoconstricted (peripherally ‘shut down’). Likewise not all sepsis patients will have pyrexia and some present with an abnormally low temperature. There is no ‘typical’ presentation of severe sepsis; hence it is important to consider the diagnosis as a differential on the wards.
The goal of critical care treatment strategies is to improve patient outcome. As for acute myocardial infarction and stroke, early recognition of sepsis with initiation of prompt and appropriate therapy improves survival. The Surviving Sepsis Campaign (SSC) was established with the aim to reduce sepsis mortality by 25% within 5 years through evidence-based guidelines to augment outcomes in severe sepsis and septic shock.
The aims of treatment in severe sepsis are to restore intravascular volume, to increase tissue perfusion, to maximise oxygen delivery to the tissues, to treat the causative infection, and ultimately to disrupt the pathophysiological changes that occur. The SSC guidelines for management of sepsis are summarised below:
Initial resuscitation and therapy
Early goal-directed fluid resuscitation is of survival benefit. Upon recognition of septic shock or sepsis-induced hypoperfusion (lactate >4 mmol/L) protocolized fluid resuscitation should be initiated immediately. The target of crystalloid (1L) or colloid (0.3-0.5L) fluid challenge over 30 mins is to achieve: CVP 8-12 mmHg, MAP ≥65 mmHg, urine output ≥0.5 ml.hg/hr, and central venous (ScvO2) or mixed venous oxygen saturation ≥70% or≥65% respectively. If the ScvO2 target is not achieved, consider transfusing packed red cells to a haemocrit > 30% or dobutamine infusion to increase oxygen delivery. If CVP increases without concurrent haemodynamic improvement reduce the rate of fluid administration. In general, a reduction of elevated pulse rate with fluid resuscitation indicates improved intravascular fluid levels.
2. Identification of causative agent
This is vital to inform therapy. At least two sets of blood cultures must be obtained prior to initiating antimicrobial therapy, with one drawn percutaneously and one through each intravascular device i.e. cannulae/lines. Other potential sources of infection must also be sampled and cultured i.e. urine, sputum, wounds and cerebrospinal fluid.
Intravenous antibiotics must be administered within the first hour of recognition of severe sepsis and septic shock. Initial empirical antimicrobial therapy should be broad-spectrum to cover all likely pathogens, taking into consideration local guidelines, primary site of infection, patient co-morbidities and drug intolerances. Neutropenic patients or those with suspected Pseudomonas infection should receive combination therapy. Consultation with the microbiology team may be necessary, and therapy tailored on the basis of the pathogen cultured and its antibiotic susceptibilities.
Haemodynamic support and adjunctive therapy
BP = CO x SVR. CO = HR x SV. Stroke volume is dependent upon preload, contractility and afterload.
Vasopressor therapy should be commenced if hypotension persists despite successive fluid boluses. The aim of vasopressor therapy is to maintain MAP >65 mmHg, which preserves circulatory autoregulation to maintain tissue perfusion. It is necessary to consider both regional and global perfusion, i.e. blood lactate as a surrogate marker of perfusion. Norepinephrine is the first-line agent to correct hypotension. It increases MAP to augment cardiac output, achieving this primarily through α-adrenoreceptor-mediated vasoconstriction. Although this would normally reduce splanchnic blood-flow, in severe sepsis it increases perfusion pressure to improve renal and gut circulation.
Dopamine is used as an alternative agent, and refractory cases may require epinephrine infusion. Low-dose dopamine is no longer indicated for renal protection.
In later stages of sepsis, toxic myocarditis may impair myocardial function (indicated by an elevated CVP and low cardiac output). Pulmonary oedema could be precipitated by aggressive fluid administration, whilst significant increase in SVR with vasopressors would be detrimental for cardiac output. An inotropic agent is required to increase myocardial contractility. Dobutamine infusion, often in combination with norepinephrine or dopamine, should be commenced. Dobutamine has predominantly β1-adrenoreceptor effects that increase heart rate and contractility, thus increasing cardiac output.
Severe sepsis affects the hypothalamic-pituitary-adrenal axis and may induce relative adrenocortical insufficiency. Thus in patients with vasopressor-unresponsive hypotension administration of low-dose corticosteroids (intravenous hydrocortisone 8 mg/h) can be of survival benefit and may even ameliorate shock.
2. Activated protein C
Recombinant activated protein C (APC) inactivates clotting factors Va and VIIIa to inhibit thrombin generation. Under SSC guidelines, APC should be given to all adult patients with sepsis-induced organ dysfunction who have at least two failing organs and an APACHE 2 (Acute Physiological and Chronic Health Evaluation) score >25. Although it reduces mortality in sepsis, APC increases the incidence of bleeding, hence it is contraindicated for patients with bleeding risk factors i.e. coagulopathy, recent major surgery, anticoagulant/thrombolytic therapy, chronic liver disease.
3. Blood products
After restoration of adequate tissue hypoperfusion, red blood cells should be transfused to increase oxygen delivery if haemoglobin decreases to <7.0 g/dL (to target Hb 7-9 g/dL). Contraindications to this include severe hypoxaemia, recent myocardial infarction, acute haemorrhage and lactic acidosis.
4. Supportive therapy of severe sepsis
Patients with severe sepsis should be mechanically ventilated under appropriate sedation. Hyperglycaemia results from relative insulin resistance in critical illness, hence intensive blood glucose control with intravenous glucose insulin decreases mortality. Unless contraindicated, patients should also receive deep vein thrombosis prophylaxis with heparin or low-molecular weight heparin.
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