Septic Shock

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Practice Essentials

Sepsis or septic shock is systemic inflammatory response syndrome (SIRS) secondary to a documented infection. This response is a state of acute circulatory failure characterized by persistent arterial hypotension despite adequate fluid resuscitation or by tissue hypoperfusion (manifested by a lactate concentration >4 mg/dL) unexplained by other causes.

Essential update: Septic shock study finds no significant difference in survival between 3 treatment approaches

In a randomized study of 1341 patients diagnosed with septic shock in 31 academic hospital emergency departments, survival did not differ between patients who received treatment based on specific protocols and those who received the usual high-level standard of care. Patients received treatment based on 1 of 3 approaches: protocol-based early goal-directed therapy (EGDT); protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or standard care.[1, 2]

At 60-day follow-up, 21% of the patients in the protocol-based EGDT group had died, compared with 18.2% of those in the protocol-based standard-therapy group and 18.9% of those in the standard-care group (P = .83). No significant differences between groups were found for 90-day mortality, 1-year mortality, or the need for organ support.[1, 2]

Signs and symptoms

Detrimental host responses to infection occupy a continuum that ranges from sepsis to severe sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific clinical features depend on where the patient falls on that continuum.

Signs and symptoms of sepsis are often nonspecific and include the following:

Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis, especially in elderly individuals.

It is important to identify any potential source of infection. Localizing signs and symptoms referable to organ systems may provide useful clues to the etiology of sepsis and are as follows:

See Clinical Presentation for more detail.

Diagnosis

Patients with sepsis may present in a myriad of ways, and a high index of clinical suspicion is necessary to identify subtle presentations. The hallmarks of severe sepsis and septic shock are changes that occur at the microvascular and cellular level and may not be clearly manifested in the vital signs or clinical examination. This process includes diffuse activation of inflammatory and coagulation cascades, vasodilation and vascular maldistribution, capillary endothelial leakage, and dysfunctional utilization of oxygen and nutrients at the cellular level.

Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are indicated in patients with septic shock.

Laboratory tests

The following are investigative studies to detect a clinically suspected focal infection, the presence of a clinically occult focal infection, and complications of sepsis and septic shock:

Imaging studies

The following radiologic studies, as indicated, may be used to evaluate patients with suspected severe sepsis and septic shock:

See Workup for more detail.

Management

Patients with sepsis, severe sepsis, and septic shock require admission to the hospital. Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion.

Treatment of patients with septic shock has the following major goals:

Management principles for septic shock include the following:

Pharmacotherapy

The following medications are used in the management of septic shock:

Surgery

Patients with focal infections should be sent for definitive surgical treatment after initial resuscitation and administration of antibiotics.[3] However, although urgent management is indicated for hemodynamically stable patients without evidence of acute organ failure, delay of invasive procedures for as long as 24 hours may be possible if the patient receives very close clinical monitoring and appropriate antimicrobial therapy.[3]

Certain conditions will not respond to standard treatment for septic shock until the source of infection is surgically removed (eg, intra-abdominal sepsis [perforation, abscesses], empyema, mediastinitis, cholangitis, pancreatic abscesses, pyelonephritis or renal abscess from ureteric obstruction, infective endocarditis, septic arthritis, infected prosthetic devices, deep cutaneous or perirectal abscess, and necrotizing fasciitis).

When possible, percutaneous drainage of abscesses and other well-localized fluid collections is preferred to surgical drainage.[3] However, any deep abscess or suspected necrotizing fasciitis should undergo drainage in the surgical suite.

See Treatment and Medication for more detail.

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A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrot....

Background

Over many years, the terms sepsis and septicemia have referred to several ill-defined clinical conditions present in a patient with bacteremia. Definitions have not changed greatly since 1914, when Schottmueller wrote, “Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes sign of illness.”

In practice, these 2 terms have often been used interchangeably; however, only about half of patients with signs and symptoms of sepsis have positive results on blood culture.[4, 5, 6] Furthermore, not all patients with bacteremia have signs of sepsis. It follows, therefore, that sepsis and septicemia are not in fact identical.

In the past few decades, the discovery of endogenous mediators of the host response has led to the recognition that the clinical syndrome of sepsis is the result of excessive activation of host defense mechanisms rather than the direct effect of microorganisms. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity.

Serious bacterial infections at any site in the body (see the image below), with or without bacteremia, are usually associated with important changes in the function of every organ system in the body. These changes are mediated mostly by elements of the host immune system against infection. Shock is deemed present when volume replacement fails to increase blood pressure to acceptable levels and when associated clinical evidence indicates inadequate perfusion of major organ systems, with progressive failure of organ system functions.


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Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologi....

Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of physiologic derangements in individual organs (ie, processes rather than events). Alteration in organ function can vary widely, ranging from a mild degree of organ dysfunction to frank organ failure. (See Multiple Organ Failure of Sepsis, Systemic Inflammatory Response Syndrome (SIRS), Toxic Shock Syndrome, and Septic Thrombophlebitis .)

This article does not cover sepsis of the neonate or infant. Special consideration must be given to neonates, infants, and small children with regard to fluid resuscitation, appropriate antibiotic coverage, intravenous (IV) access, and vasopressor therapy. (See Neonatal Sepsis, Pediatric Sepsis, Treatment of Sepsis and Septic Shock in Children, Shock in Pediatrics, and Shock and Hypotension in the Newborn.)

Shock Classification, Terminology, and Staging

Shock is identified in most patients by hypotension and inadequate organ perfusion, which may be caused by either low cardiac output or low systemic vascular resistance. Circulatory shock can be subdivided into 4 distinct classes on the basis of underlying mechanism and characteristic hemodynamics, as follows:

These classes of shock should be considered and systematically differentiated before a definitive diagnosis of septic shock is established.

Hypovolemic shock results from the loss of blood volume caused by such conditions as gastrointestinal (GI) bleeding, extravasation of plasma, major surgery, trauma, and severe burns. Patients suffering from hypovolemic shock demonstrate tachycardia, cool clammy extremities, hypotension, dry skin and mucous membranes, and poor turgor.

Obstructive shock results from an intrinsic or extrinsic obstruction of circulation. Pulmonary embolism and pericardial tamponade both result in obstructive shock.

Distributive shock is caused by excessive vasodilation and impaired distribution of blood flow (eg, direct arteriovenous shunting), and it is characterized by decreased resistance or increased venous capacity from the vasomotor dysfunction. Patients with this type of shock have high cardiac output, hypotension, a large pulse pressure, a low diastolic pressure, and warm extremities with good capillary refill. These findings on physical examination strongly suggest a working diagnosis of septic shock.

Cardiogenic shock is characterized by primary myocardial dysfunction, which renders the heart unable to maintain adequate cardiac output. Affected patients demonstrate clinical signs of low cardiac output while showing evidence of adequate intravascular volume. The patients have cool clammy extremities, poor capillary refill, tachycardia, a narrow pulse pressure, and low urine output.

Definitions of key terms

The basis of sepsis is the presence of infection associated with a systemic inflammatory response that results in physiologic alterations at the capillary endothelial level. The difficulty in diagnosis comes in knowing when a localized infection has become systemic and requires more aggressive hemodynamic support. No criterion standard exists for the diagnosis of endothelial dysfunction, and patients with sepsis may not initially present with frank hypotension and overt shock.

Clinicians often use the terms sepsis, severe sepsis, and septic shock without following commonly understood definitions. In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a consensus conference to establish definitions of these and related terms.[7, 8]

Systemic inflammatory response syndrome

The term systemic inflammatory response syndrome (SIRS) was developed in an attempt to describe the clinical manifestations that result from the systemic response to infection (fever or hypothermia, tachycardia, tachypnea, and hyperleukocytosis or leukopenia). Criteria for SIRS are considered to be met if at least 2 of the following 4 clinical findings are present:

Note that a patient can have a severe infection without meeting SIRS criteria; conversely, SIRS criteria may be present in the setting of many other illnesses not caused by an infectious process (see the image below).


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Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

In 2001, as a follow-up to the original ACCP/SCCM conference, an International Sepsis Definitions Conference was convened, with representation not only from the ACCP and the SCCM but also from the European Society of Intensive Care Medicine (ESICM), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The following definitions of sepsis syndromes were published to clarify the terminology used to describe the spectrum of disease that results from severe infection.[9]

Sepsis

Sepsis is defined as the presence of infection in association with SIRS, that is, a systemic immune response caused by an infection. The presence of SIRS is, of course, not limited to sepsis, but in the presence of infection, an increase in the number of SIRS criteria observed should alert the clinician to the possibility of endothelial dysfunction, developing organ dysfunction, and the need for aggressive therapy.

Certain biomarkers have been associated with the endothelial dysfunction of sepsis. However, although levels of biomarkers such as procalcitonin may be useful in differentiating between sepsis (generally >10 ng/mL) and SIRS (generally < 2 ng/mL),[10] the use of sepsis-specific biomarkers has not yet translated to establishing a clinical diagnosis of sepsis, particularly in the emergency department (ED) setting.

Two markers that may have potential roles in guiding the management of sepsis are the circulating apoptosis markers full-length and caspase-cleaved cytokeratin 18 (CK18) and nucleosomal DNA (nDNA), as suggested by the results of a small, noninterventional, multicenter study that made use of enzyme-linked immunosorbent assays (ELISAs).[11]

In septic patients who survived, levels of full-length and caspase-cleaved CK18 were decreased within 48 hours after treatment initiation; during the same period, levels were increased in septic patients who died within 28 days of admission.[11] Furthermore, when the investigators compared patients who required renal support with those who did not, significantly higher baseline levels of nDNA and total soluble CK18 levels were found in the group requiring renal support.[11] More data are needed to evaluate these findings.

At least 1 of the following manifestations of inadequate organ function or perfusion is typically included in sepsis:

Severe sepsis and septic shock

Severe sepsis is defined as sepsis that is complicated by end-organ dysfunction, as signaled by altered mental status, an episode of hypotension, elevated creatinine concentration, or evidence of disseminated intravascular coagulopathy (DIC).

Septic shock is defined as a state of acute circulatory failure characterized by persistent arterial hypotension despite adequate fluid resuscitation or by tissue hypoperfusion (manifested by a lactate concentration >4 mg/dL) that is unexplained by other causes. Patients receiving inotropic or vasopressor agents may not be hypotensive by the time that they manifest hypoperfusion abnormalities or organ dysfunction.

Bacteremia

Bacteremia is defined as the presence of viable bacteria within the liquid component of blood. It may be primary (without an identifiable focus of infection) or, more often, secondary (with an intravascular or extravascular focus of infection). Although sepsis is associated with bacterial infection, bacteremia is not a necessary ingredient in the activation of the inflammatory response that results in severe sepsis. In fact, septic shock is associated with culture-positive bacteremia in only 30-50% of cases.[4, 5, 6]

Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MODS) is defined as the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention. MODS may eventually lead to multiple organ failure syndrome (MOFS) and death. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common manifestations of MODS or MOFS. However, other conditions besides sepsis can cause MODS, including trauma, burns, and severe hemorrhagic shock.

Acute lung injury and acute respiratory distress syndrome

In 1994, the American-European Consensus Conference on ARDS agreed on standard definitions of ALI and ARDS.[12] However, these definitions were subsequently replaced by the following consensus, referred to as the Berlin Definition of ARDS, which essentially does away with the classification of ALI in favor of classifying ARDS as mild, moderate, or severe[13] :

MODS staging

Two well-defined forms of MODS exist. In either, the development of ALI or ARDS is of key importance to the natural history, though ARDS is the earliest manifestation in all cases.

In the more common form of MODS, the lungs are the predominant, and often the only, organ system affected until very late in the disease. Patients with this form of MODS most often present with a primary pulmonary disorder (eg, pneumonia, aspiration, lung contusion, near-drowning, chronic obstructive pulmonary disease [COPD] exacerbation, hemorrhage, or pulmonary embolism [PE]).

Progression of lung disease occurs to meet the ARDS criteria. Pulmonary dysfunction may be accompanied by encephalopathy or mild coagulopathy and persists for 2-3 weeks. At this time, the patient either begins to recover or progresses to develop fulminant dysfunction in other organ systems. Patients who develop another major organ dysfunction often do not survive.

In the second, less common, form of MODS, the presentation is quite different. Patients affected by this form often have an inciting source of sepsis in organs other than the lung; the most common sources are intra-abdominal sepsis, extensive blood loss, pancreatitis, and vascular catastrophes.

Not only does ALI or ARDS develop early, but dysfunction also develops in other organ systems, including the hepatic, hematologic, cardiovascular, and renal systems and central nervous system (CNS). Patients remain in a pattern of compensated dysfunction for several weeks, then either recover or deteriorate further.

Criteria for mild and severe organ dysfunction have been established by the 2012 Surviving Sepsis Guidelines (see Table 1, below).

Table 1. Surviving Sepsis Guidelines Criteria for Organ Dysfunction


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Pathophysiology

The pathophysiology of septic shock is not precisely understood but is considered to involve a complex interaction between the pathogen and the host’s immune system (see the image below). The normal physiologic response to localized infection includes activation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, release of inflammatory mediators, local vasodilation, increased endothelial permeability, and activation of coagulation pathways.


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Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.

These response mechanisms occur during septic shock, but on a systemic scale, leading to diffuse endothelial disruption, vascular permeability, vasodilation, and thrombosis of end-organ capillaries. Endothelial damage itself can further activate inflammatory and coagulation cascades, creating, in effect, a positive feedback loop and leading to further endothelial and end-organ damage.

Mediator-induced cellular injury

The evidence that sepsis results from an exaggerated systemic inflammatory response induced by infecting organisms is compelling. Inflammatory mediators are the key players in the pathogenesis of sepsis (see Table 2 below).

Table 2. Mediators of Sepsis


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Immunologic abnormalities

The following 3 families of pattern recognition receptors are involved in the initiation of the sepsis response:

These receptors trigger the innate immune response and modulate the adaptive immune response to infection.[16]

An initial step in the activation of innate immunity is the de novo synthesis of small polypeptides (cytokines) that induce protean manifestations on most cell types, from immune effector cells to vascular smooth muscle and parenchymal cells. Several cytokines are induced, including tumor necrosis factor (TNF) and interleukins (ILs), especially IL-1. These factors help keep infections localized; however, once the infection progresses, the effects can also be detrimental.

Circulating levels of IL-6 correlate have a strong correlation with outcome. High levels of IL-6 are associated with mortality, but the role of this cytokine in pathogenesis is not clear. IL-8 is an important regulator of neutrophil function, synthesized and released in significant amounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs.

Chemokines (eg, monocyte chemoattractant protein [MCP]-1) orchestrate the migration of leukocytes during endotoxemia and sepsis. Other cytokines thought to play a role in sepsis include the following:

In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.[17, 18, 19] (See Abnormalities of coagulation and fibrinolysis.)

Gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators, including the cytokines mentioned above, which play a pivotal role in initiating sepsis and shock. Various bacterial cell-wall components are known to release the cytokines, including lipopolysaccharide (LPS; gram-negative bacteria), peptidoglycan (gram-positive and gram-negative bacteria), and lipoteichoic acid (gram-positive bacteria).

Several of the harmful effects of bacteria are mediated by proinflammatory cytokines induced in host cells (macrophages/monocytes and neutrophils) by the bacterial cell-wall component. The most toxic component of gram-negative bacteria is the lipid A moiety of LPS, which leads to cytokine induction via lipoteichoic acid. Additionally, gram-positive bacteria may secrete superantigen cytotoxins that bind directly to the major histocompatibility complex (MHC) molecules and T-cell receptors, leading to massive cytokine production.

The complement system is activated and contributes to the clearance of the infecting microorganisms but probably also enhances the tissue damage. The contact systems become activated; consequently, bradykinin is generated.

Hypotension, the cardinal manifestation of sepsis, occurs via induction of nitric oxide (NO). NO plays a major role in the hemodynamic alterations of septic shock, which is a hyperdynamic form of shock.

In a study that evaluated the role of active nitrogen molecules in the progression of septic shock, investigators found not only that patients with sepsis and septic shock had elevated mean levels of nitrite (NO2)/nitrate (NO3) (sepsis, 78.92 µmol/L; septic shock, 97.20 µmol/L) as well as TNF-α (sepsis, 213.50 pg/mL; septic shock, 227.38 pg/mL) but also that levels of these 3 mediators increased with the severity of the sepsis.[20]

Another factor that contributes to the poor cellular oxygen utilization and tissue organ dysfunction during sepsis is mitochondrial dysfunction.[21] This is associated with excessive generation of peroxynitrates and reactive oxygen species (ROS) in combination with glutathione depletion.

A dual role exists for neutrophils: They are necessary for defense against microorganisms, but they may also become toxic inflammatory mediators, thereby contributing to tissue damage and organ dysfunction. Lipid mediators—eicosanoids, platelet-activating factor (PAF), and phospholipase A2—are generated during sepsis, but their contributions to the sepsis syndrome remain to be established.

Neutrophils are constitutively proapoptotic, a capacity that is essential for the resolution of inflammation and cell turnover. Poor apoptosis is associated with poor cell clearance and a proinflammatory state.

There is a growing body of evidence regarding sepsis-induced immunosuppression, which may culminate in a worse prognosis and a greater predisposition to other nosocomial infections.[22] In addition, there is evidence that patients with sepsis who have previously been infected with cytomegalovirus may have worse outcomes than those who have not.[23] That cytomegalovirus infection can also cause immunomodulation may be another factor contributing to sepsis-induced immunosuppression.

Abnormalities of coagulation and fibrinolysis

An imbalance of homeostatic mechanisms leads to disseminated intravascular coagulopathy (DIC) and microvascular thrombosis, causing organ dysfunction and death.[24] Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating thrombin production. Plasma levels of endothelial activation biomarkers are higher in patients with sepsis-induced hypotension than in patients with hypotension from other causes.[25]

The coagulation factors are activated as a result of endothelial damage. The process is initiated through binding of factor XII to the subendothelial surface, which activates factor XII. Subsequently, factor XI and, eventually, factor X are activated by a complex of factor IX, factor VIII, calcium, and phospholipid. The final product of the coagulation pathway is the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin, along with aggregated platelets, forms intravascular clots.

Inflammatory cytokines, such as IL-1α, IL-1β, and TNF-α, initiate coagulation by activating TF. TF interacts with factor VIIa to form factor VIIa-TF complex, which activates factors X and IX. Activation of coagulation in sepsis has been confirmed by marked increases in thrombin-antithrombin complexes and the presence of D-dimer in plasma, indicating activation of the clotting system and fibrinolysis.[26, 27] Tissue plasminogen activator (t-PA) facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.

Endotoxins increase the activity of inhibitors of fibrinolysis—namely, plasminogen activator inhibitor (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). levels of protein C and endogenous activated protein C (APC) are also decreased in sepsis. Endogenous APC is an important inhibitor of coagulation cofactors Va and VIIa. Thrombin, via thrombomodulin, activates protein C, which then acts as an antithrombotic in the microvasculature. Endogenous APC also enhances fibrinolysis by neutralizing PAI-1 and accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death. The insidious nature of sepsis is such that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal.[28]

Circulatory abnormalities

As noted (see Shock Classification, Terminology, and Staging), septic shock falls under the category of distributive shock, which is characterized by pathologic vasodilation and shunting of blood from vital organs to nonvital tissues (eg, skin, skeletal muscle, and fat). The endothelial dysfunction and vascular maldistribution characteristic of distributive shock result in global tissue hypoxia or inadequate delivery of oxygen to vital tissues. In addition, mitochondria can become dysfunctional, thus compromising oxygen utilization at the cellular level.

The predominant hemodynamic feature of septic shock is arterial vasodilation. The mechanisms implicated in this pathologic vasodilation are multifactorial, but the primary factors are thought to be (1) activation of adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle cells and (2) activation of NO synthase.

The potassium-ATP channels are directly activated by lactic acidosis. NO also activates potassium channels. Potassium efflux from cells results in hyperpolarization, inhibition of calcium influx, and vascular smooth muscle relaxation.[29] The resulting vasodilation can be refractory to endogenous vasoactive hormones (eg, norepinephrine and epinephrine) that are released during shock.

Diminished peripheral arterial vascular tone may cause blood pressure to be dependent on cardiac output, so that vasodilation results in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output is often limited by hypovolemia and a fall in preload because of low cardiac filling pressures. When intravascular volume is augmented, the cardiac output usually is elevated (hyperdynamic phase of sepsis and shock).

Although cardiac output is elevated, the performance of the heart, reflected by stroke work as calculated from stroke volume and blood pressure, is usually depressed. Factors responsible for myocardial depression of sepsis include myocardial depressant substances, coronary blood flow abnormalities, pulmonary hypertension, various cytokines, NO, and beta-receptor downregulation.

Although cardiac output is elevated, the arterial−mixed venous oxygen difference is usually narrow, and the blood lactate level is elevated. This implies that low global tissue oxygen extraction is the mechanism that may limit total body oxygen uptake in septic shock. The basic pathophysiologic problem seems to be a disparity between oxygen uptake and oxygen demand in the tissues, which may be more pronounced in some areas than in others.

This disparity is termed maldistribution of blood flow, either between or within organs, with a resultant defect in the capacity for local extraction of oxygen. During a fall in the oxygen supply, cardiac output becomes distributed so that the most vital organs, such as the heart and brain, remain relatively better perfused than nonvital organs are. However, sepsis leads to regional changes in oxygen demand and regional alteration in the blood flow of various organs.

The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activity of central mechanisms (eg, the autonomic nervous system). Regional regulation and the release of vasodilating substances (eg, NO and prostacyclin) and vasoconstricting substances (eg, endothelin) affect regional blood flow. Increased systemic microvascular permeability also develops, remote from the infectious focus, and contributes to edema of various organs (eg, the lung microcirculation) and to the development of ARDS.

In patients experiencing septic shock, oxygen delivery is relatively high, but the global oxygen extraction ratio is relatively low. Oxygen uptake increases with rising body temperature despite a fall in oxygen extraction.

In patients with sepsis who have low oxygen extraction and elevated arterial lactate levels, oxygen uptake depends on oxygen supply over a much wider range than normal. Therefore, oxygen extraction may be too low for tissue needs at a given oxygen supply, and oxygen uptake may increase with a boost in oxygen supply—a phenomenon termed oxygen uptake supply dependence or pathologic supply dependence. This concept is controversial, however; some investigators argue that supply dependence is an artifact rather than a real phenomenon.

Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathologic supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock.

Mechanisms of organ dysfunction

Sepsis is described as an autodestructive process that permits the extension of the normal pathophysiologic response to infection (involving otherwise normal tissues), resulting in MODS. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to the consequences of the inflammatory excesses of sepsis.

The precise mechanisms of cell injury and resulting organ dysfunction in patients with sepsis are not fully understood. MODS is associated with widespread endothelial and parenchymal cell injury occurring via the following proposed mechanisms:

Cardiovascular dysfunction

Significant derangement in the autoregulation of the circulatory system is typical in patients with sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection. NO plays a central role in the vasodilation of septic shock. Impaired secretion of vasopressin may also occur, which may permit the persistence of vasodilatation.

Changes in both systolic and diastolic ventricular performance occur in patients with sepsis. Through the Frank-Starling mechanism, cardiac output is often increased to maintain blood pressure in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately.

Because sepsis interferes with the normal distribution of systemic blood flow to organ systems, core organs may not receive appropriate oxygen delivery. The microcirculation is the key target organ for injury in patients with sepsis. A decrease in the number of functional capillaries leads to an inability to extract oxygen maximally; this inability is caused by intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells. Increased endothelial permeability leads to widespread tissue edema involving protein-rich fluid.

Hypotension is caused by the redistribution of intravascular fluid volume that results from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances.

Pulmonary dysfunction

The pathogenesis of sepsis-induced ARDS is a pulmonary manifestation of SIRS. A complex interaction between humoral and cellular mediators, inflammatory cytokines and chemokines, is involved in this process. A direct or indirect injury to the endothelial and epithelial cells of the lung increases alveolar capillary permeability, causing ensuing alveolar edema. The edema fluid is protein-rich; the ratio of alveolar fluid edema to plasma is 0.75-1.0, whereas in patients with hydrostatic cardiogenic pulmonary edema, the ratio is less than 0.65.

Injury to type II pneumocytes decreases surfactant production; furthermore, the plasma proteins in alveolar fluid inactivate the surfactant previously manufactured. These enhance the surface tension at the air-fluid interfaces, producing diffuse microatelectasis.

Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membrane. ARDS is a frequent manifestation of these effects.

ALI (mild ARDS in the Berlin Definition) is a type of pulmonary dysfunction secondary to parenchymal cellular damage that is characterized by endothelial cell injury and destruction, deposition of platelet and leukocyte aggregates, destruction of type I alveolar pneumocytes, an acute inflammatory response through all injury phases, and repair and hyperplasia of type II pneumocytes. Migration of macrophages and neutrophils into the interstitium and alveoli produces various mediators that contribute to the alveolar and epithelial cell damage.

If addressed at an early stage, ALI may be reversible, but in many cases, the host response is uncontrolled, and ALI progresses to more severe ARDS. Continued infiltration occurs with neutrophils and mononuclear cells, lymphocytes, and fibroblasts. An alveolar inflammatory exudate persists, and type II pneumocyte proliferation is evident. If this process can be halted, complete resolution may occur. In other patients, progressive respiratory failure and pulmonary fibrosis develop.

The central pathologic finding in ARDS is severe injury to the alveolocapillary unit. After initial extravasation of intravascular fluid, inflammation and fibrosis of pulmonary parenchyma develop into a morphologic picture termed diffuse alveolar damage (DAD). The clinical and pathologic evolution can be categorized into the following 3 overlapping phases[30] :

The exudative phase of DAD occurs in the first week and is dominated by alveolar edema and hemorrhage (see the images below). Other histologic features include dense eosinophilic hyaline membranes and disruption of the capillary membranes. Necrosis of endothelial cells and type I pneumocytes occur, along with leukoagglutination and deposition of platelet fibrin thrombi.


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Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diff....


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Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diff....

The proliferative phase is prominent in the second and third week after the onset of ARDS, but it may begin as early as day 3. Organization of the intra-alveolar and interstitial exudate, infiltration with chronic inflammatory cells, parenchymal necrosis, and interstitial myofibroblast reaction occur. Proliferation of type II cells and fibroblasts, which convert the exudate to cellular granulation tissue, is noted, as is excessive collagen deposition, transforming into fibrous tissue (see the images below).


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Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has o....


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Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, w....

The fibrotic phase occurs by the third or fourth week after the onset of ARDS, though it may begin as early as the first week. The collagenous fibrosis completely remodels the lung, the air spaces are irregularly enlarged, and alveolar duct fibrosis is apparent. Lung collagen deposition increases, and microcystic honeycomb formation and traction bronchiectasis follow.

Gastrointestinal dysfunction

The gastrointestinal (GI) tract may help to propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may be aspirated into the lungs and produce nosocomial pneumonia. The gut’s normal barrier function may be affected, thereby allowing translocation of bacteria and endotoxin into the systemic circulation and extending the septic response.

Septic shock usually causes ileus, and the use of narcotics and sedatives delays the institution of enteral feeding. This interferes with optimal nutritional intake, in the face of high protein and energy requirements.

Glutamine is necessary for normal enterocyte functioning. Its absence in commercial formulations of total parenteral nutrition (TPN) leads to breakdown of the intestinal barrier and translocation of the gut flora into the circulation. This may be one of the factors driving sepsis. In addition to inadequate glutamine levels, this may lessen the immune response by decreasing leukocyte and natural killer (NK) cell counts, as well as total B-cell and T-cell counts.[31]

Hepatic and renal dysfunction

By virtue of the liver’s role in host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and the progression of sepsis. The hepatic reticuloendothelial system acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into the systemic circulation.

Acute kidney injury (AKI)—previously termed acute renal failure (ARF)—caused by acute tubular necrosis often accompanies sepsis. The mechanism involves systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activation of neutrophils by endotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction

Central nervous system (CNS) involvement in sepsis produces encephalopathy (septic encephalitis) and peripheral neuropathy. The pathogenesis is poorly defined, but it may involve systemic inflammation from either infectious or noninfectious causes,[32] as well as a combination of the effects of hypoxemia, hypotension, hemorrhage, and medications such as sedatives and analgesics.[32, 33]

Etiology

Most patients who develop sepsis and septic shock have underlying circumstances that interfere with local or systemic host defense mechanisms. Sepsis is seen most frequently in elderly persons and in those with comorbid conditions that predispose to infection, such as diabetes or any immunocompromising disease. Patients may also have genetic susceptibility, making them more prone to developing septic shock from infections that are well tolerated in the general population.[34, 35, 36, 37, 38]

The most common disease states predisposing to sepsis are malignancies, diabetes mellitus, chronic liver disease, and chronic kidney disease. The use of immunosuppressive agents is also a common predisposing factor. In addition, sepsis is a common complication after major surgery, trauma, and extensive burns. Patients with indwelling catheters or devices are also at high risk.

In most patients with sepsis, a source of infection can be identified. The exceptions are patients who are immunocompromised with neutropenia, in whom an obvious source often is not found.

Causative microorganisms

Before the introduction of antibiotics, gram-positive bacteria were the principal organisms that caused sepsis. Subsequently, gram-negative bacteria became the key pathogens causing severe sepsis and septic shock. Currently, however, the rates of severe sepsis and septic shock due to gram-positive organisms are rising again because of the more frequent use of invasive procedures and lines in critically ill patients. As a result, gram-positive and gram-negative microorganisms are now about equally likely to be causative pathogens in septic shock.[39, 40, 41, 42]

Respiratory tract and abdominal infections are the most frequent causes of sepsis, followed by urinary tract and soft-tissue infections.[39, 40, 41, 42] Each organ system tends to be infected by a particular set of pathogens (see below).

Lower respiratory tract infections cause septic shock in 35-50% of patients.[39, 40, 41, 42] The following are the common pathogens:

Abdominal and GI tract infections cause septic shock in 20-40% of patients.[39, 40, 41, 42] The following are the common pathogens:

Urinary tract infections cause septic shock in 10-30% of patients.[39, 40, 41, 42] The following are the common pathogens:

Infections of the male and female reproductive systems cause septic shock in 1-5% of patients.[39, 40, 41, 42] The following are the common pathogens:

Soft-tissue infections cause septic shock in 5-10% of patients.[39, 40, 41, 42] The following are the common pathogens:

Infections due to foreign bodies cause septic shock in 1-5% of patients.[39, 40, 41, 42] S aureus, S epidermidis, and fungi (eg, Candida species) are the common pathogens.

Miscellaneous infections, such as CNS infections, also cause septic shock in 1-5% of patients.[39, 40, 41, 42] Neisseria meningitidis is a common cause of such infections (see the image below).


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Gram stain of blood showing the presence of Neisseria meningitidis.

Risk factors

Risk factors for severe sepsis and septic shock include the following:

Epidemiology

United States statistics

The incidence of sepsis has been growing in recent decades, for reasons that likely include the following:

An analysis of a large sample from major US medical centers reported the incidence of severe sepsis as 3 cases per 1000 population and 2.26 cases per 100 hospital discharges.[43] Of these patients, 51.1% were admitted to an intensive care unit (ICU), and an additional 17.3% were cared for in an intermediate care or coronary care unit. When analyzed in relation to age, the incidence of severe sepsis ranged from 0.2 cases per 1000 admissions in children to 26.2 per 1000 in individuals older than 85 years.

In this analysis, mortality was 28.6% overall, ranging from 10% in children to 38.4% in elderly people.[43] Hospital billing codes were used to identify patients with infection and organ dysfunction consistent with the definition of severe sepsis. Severe sepsis resulted in an average cost of $22,100 per case, with an annual total cost of $16.7 billion nationally.

In a large retrospective analysis, the National Center for Health Statistics used the National Hospital Discharge Survey of 500 nonfederal US hospitals (which included more than 10 million cases of sepsis over a 22-year period) to report that septicemia accounted for 1.3% of all hospitalizations.[44] The incidence of sepsis increased 3-fold between 1979 and 2000, from 83 cases per 100,000 population per year to 240 per 100,000.

A subsequent large survey of emergency department (ED) visits showed that severe sepsis accounted for more than 500,000 such visits annually (0.7% of total visits), that the majority of patients presented to EDs without an academic affiliation, and that the mean length of stay in the ED was approximately 5 hours.[45]

In a later report, the US Centers for Disease Control and Prevention (CDC) determined that the inflation-adjusted aggregate cost for the treatment of hospital patients with sepsis increased by 12% per year from 1997 to 2008.[46]

In a 2013 report, Gaieski et al showed that in a large population database, the use of different epidemiologic methodologies affects the average annual incidence of severe sepsis, which can vary as much as 3.5-fold, depending on the method utilized.[47] The investigators found that when the codes for sepsis in the International Classification of Diseases, Ninth Revision (ICD-9), were used, the incidence of severe sepsis doubled over a 6-year period (2004-2009).

It is possible that the higher incidence rates in this study, relative to those cited in previous studies, may be attributable to the growing awareness of sepsis, the increased use of its code classification, and the inclusion of both ICU and non-ICU patients.

Age-, sex-, and race-related demographics

Sepsis and septic shock occur at all ages. However, a strong correlation exists between advanced age and the incidence of septic shock, with a sharp increase in the number of cases in patients older than 50 years.[43, 48] At present, most sepsis episodes are observed in patients older than 60 years. Advanced age is a risk factor for acquiring nosocomial bloodstream infection (BSI) in the development of severe forms of sepsis.

Overall, compared with younger patients, elderly patients are more susceptible to sepsis, have less physiologic reserve to tolerate the insult from infection, and are more likely to have underlying diseases; all of these factors adversely affect survival. In addition, elderly patients are more likely to have atypical or nonspecific presentations with sepsis.

Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock are consistently greater in men; the percentage of affected male patients ranges from 52% to 66%. However, it is not clear whether this difference can be attributed to an underlying higher prevalence of comorbid conditions or to a higher incidence of lung infection in men, or whether women are inherently protected against the inflammatory injury that occurs in severe sepsis.[43, 44]

With regard to ethnicity, one large epidemiologic study showed that the risk of septicemia in the nonwhite population is almost twice that in the white population, with the highest risk accruing to black men.[44] Potential reasons for this difference include issues relating to decreased access to health care and increased prevalence of underlying medical conditions.

Another large epidemiologic study tied the increased incidence of septic shock in the black population to increased rates of infection necessitating hospitalization and increased development of organ dysfunction.[49] In this study, black patients with septic shock had a higher incidence of underlying diabetes and renal disease, which may explain the higher rates of infection. However, development of acute organ dysfunction was independent of comorbidities.[49]

Prognosis

Mortality figures for severe sepsis and septic shock have commonly been quoted as ranging from 20% to 50%. Clinical trials from the past decade have found the mortality associated with septic shock to range from 24% to 41%.[39, 40, 41, 42] Although one report noted that crude hospital mortality for severe sepsis was significantly lower in the United States (28%) than in Europe (41%), the difference ceased to be significant when adjusted by disease severity.[41]

Mortality has been found to vary according to the degree of illness, which may range along a spectrum extending from sepsis to severe sepsis to septic shock. The following clinical characteristics are related to the severity of sepsis:

Factors consistently associated with increased mortality in sepsis include advanced age, comorbid conditions, and clinical evidence of organ dysfunction.[43, 48] One study found that in the setting of suspected infection, simply meeting SIRS criteria, without evidence of organ dysfunction, did not predict increased mortality; this finding suggests that organ dysfunction is a better predictor than SIRS criteria alone.[48] However, there is evidence that meeting greater numbers of SIRS criteria is associated with increased mortality.[50]

Notably, tachypnea is the SIRS criterion that best predicts an adverse outcome. This is likely because tachypnea is also an indicator of pulmonary organ dysfunction and a feature commonly associated with pneumonia and ARDS, both of which are associated with increased mortality in sepsis. Altered mental status is considered a sign of organ dysfunction and is also associated with increased mortality.

In one epidemiologic study, reported mortality figures were 7% for SIRS, 16% for sepsis, 20% for severe sepsis, and 46% for septic shock.[51] Poor prognostic factors included the following:

A link between impaired adrenal function and higher septic shock mortality has been suggested. The adrenal gland is enlarged in patients with septic shock as compared with control subjects. A study by Jung et al found that the absence of this enlargement, indicated by total adrenal volume of less than 10 cm3, was associated with increased 28-day mortality in patients with septic shock.[52]

A multicenter prospective study published by Brun-Buisson reported a mortality of 56% during ICU stays and 59% during hospital stays,[4] with 27% of all deaths occurring within 2 days of the onset of severe sepsis and 77% occurring within the first 14 days. The risk factors for early mortality in this study were as follows:

Studies have shown that appropriate selection and early administration of antibiotics (ie, antibiotics that are effective against the organism that is ultimately identified) lead to a significant reduction in mortality.[53] For this reason, it is important to initiate broad-spectrum coverage until the specific organism is cultured and antibiotic sensitivities are determined.

Although mortality is known to be high, the effect of sepsis on survivors’ quality of life of survivors has not been well characterized until comparatively recently. It is increasingly evident that septic shock is often a major sentinel event that has lasting effects on the patient’s independence, reliance on family support, and need for long-term nursing home or institutionalized care.[54]

Prolonged tissue hypoperfusion can lead to long-term neurologic and cognitive sequelae.[17] Newer evidence shows that septic shock in elderly persons leads to significant long-term cognitive and functional disability in comparison with hospitalized individuals who have nonsepsis conditions.

History

Sepsis or septic shock is systemic inflammatory response syndrome (SIRS) secondary to a documented infection (see Shock Classification, Terminology, and Staging). Detrimental host responses to infection occupy a continuum that ranges from sepsis to severe sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific clinical features depend on where the patient falls on that continuum. Symptoms of sepsis are often nonspecific and include the following:

These symptoms are not pathognomonic for sepsis syndromes and may be present in a wide variety of other conditions. Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis, especially in elderly individuals.

Fever is a common symptom, though it may be absent in elderly or immunosuppressed patients. The hypothalamus resets in sepsis, so that heat production and heat loss are balanced in favor of a higher temperature. An inquiry should be made about fever onset (abrupt or gradual), duration, and maximal temperature. These features have been associated with increased infectious burden and severity of illness. However, fever alone is an insensitive indicator of sepsis; in fact, hypothermia is more predictive of illness severity and death.

Chills are a secondary symptom associated with fever, developing as a consequence of increased muscular activity that produces heat and raises the body temperature. Sweating occurs when the hypothalamus returns to its normal set point and senses the higher body temperature, stimulating perspiration to evaporate excess body heat.

Mental function is often altered. Mild disorientation or confusion is especially common in elderly individuals. Apprehension, anxiety, agitation, and, eventually, coma are manifestations of severe sepsis. The exact cause of metabolic encephalopathy is not known; altered amino acid metabolism may play a role.

Hyperventilation with respiratory alkalosis is a common feature of patients with sepsis. This feature results from stimulation of the medullary respiratory center by endotoxins and other inflammatory mediators.

Localizing symptoms referable to organ systems may provide useful clues to the etiology of sepsis. Such symptoms include the following:

Physical Examination

The hallmarks of severe sepsis and septic shock are changes that occur at the microvascular and cellular level with diffuse activation of inflammatory and coagulation cascades, vasodilation and vascular maldistribution, capillary endothelial leakage, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for clinicians is to recognize that this process is under way when it may not be clearly manifested in the vital signs or clinical examination.

The physical examination should first involve assessment of the patient’s general condition, including an assessment of airway, breathing, and circulation (ie, the ABCs), as well as mental status. An acutely ill, flushed, and toxic appearance is observed universally in patients with serious infections.

Examine vital signs, and observe for signs of hypoperfusion. Carefully examine the patient for evidence of localized infection. Ensure that the patient’s body temperature is measured accurately. Rectal temperatures should be obtained, as oral and tympanic temperatures are not always reliable. Fever may be absent, but patients generally have tachypnea and tachycardia.

Pay attention to the patient’s skin color and temperature. Pallor or grayish or mottled skin are signs of poor tissue perfusion seen in septic shock. In the early stages of sepsis, cardiac output is well maintained or even increased. The vasodilation may result in warm skin, warm extremities, and normal capillary refill (warm shock). As sepsis progresses, stroke volume and cardiac output fall. The patients begin to manifest the signs of poor perfusion, including cool skin, cool extremities, and delayed capillary refill (cold shock).

Petechiae or purpura (see the image below) can be associated with disseminated intravascular coagulation (DIC). These findings are an ominous sign.


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A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the prese....

Tachycardia is a common feature of sepsis and indicative of a systemic response to stress; it is the physiologic mechanism by which cardiac output, and thus oxygen delivery to tissues, is increased. Tachycardia indicates hypovolemia and the need for intravascular fluid repletion; however, an increased heart rate often persists in sepsis despite adequate fluid repletion. Narrow pulse pressure and tachycardia are considered the earliest signs of shock. Tachycardia may also be a result of fever itself.

Tachypnea is a common and often underappreciated feature of sepsis. It is an indicator of pulmonary dysfunction and is commonly found in pneumonia and acute respiratory distress syndrome (ARDS), both of which are associated with increased mortality in sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators is a possible cause. As tissue hypoperfusion ensues, the respiratory rate also rises to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious.

Altered mental status is another common feature of sepsis. It is considered a sign of organ dysfunction and is associated with increased mortality. Mild disorientation or confusion is especially common in elderly individuals. Other manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtundation or comatose states. The cause of these mental status abnormalities is not entirely understood, but in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a causative factor.

In septic shock, it is important to identify any potential source of infection. This is particularly important in cases where a site of infection can be removed or drained, as in certain intra-abdominal infections, soft-tissue abscesses and fasciitis, or perirectal abscesses. The following physical signs help localize the source of an infection:

Complications

End-organ failure is a major contributor to mortality in sepsis and septic shock. The complications with the greatest adverse effect on survival are ARDS, DIC, and acute kidney injury (AKI; previously termed acute renal failure [ARF]).

Acute respiratory distress syndrome

Acute lung injury (ALI)—mild ARDS, by the Berlin Definition[13] —leading to moderate or severe ARDS is a major complication of severe sepsis and septic shock. The incidence of ARDS is approximately 18% in patients with septic shock, and mortality approaches 50%. ARDS also leads to prolonged intensive care unit (ICU) stays and an increased incidence of ventilator-associated pneumonia.

ARDS secondary to severe sepsis demonstrates the manifestations of underlying sepsis and the associated multiple organ dysfunction. Pulmonary manifestations include acute respiratory distress and acute respiratory failure resulting from severe hypoxemia caused by intrapulmonary shunting. Fever and leukocytosis may be present secondary to the lung inflammation.

The severity of ARDS may range from mild lung injury to severe respiratory failure. The onset of ARDS usually is within 12-48 hours of the inciting event. The patients demonstrate severe dyspnea at rest, tachypnea, and hypoxemia; anxiety and agitation are also present.

The frequency of ARDS in sepsis has been reported to range from 18% to 38% (with gram-negative sepsis, 18-25%). Sepsis and multiorgan failure are the most common cause of death in ARDS patients. Approximately 16% of patients with ARDS die of irreversible respiratory failure. Most patients who show improvement achieve maximal recovery by 6 months, with lung function improving to 80-90% of predicted values.

Acute kidney injury

Sepsis is the most common cause of AKI (ARF), which affects 40-70% of all critically ill patients, depending on how AKI is defined (eg, according to the RIFLE [risk, injury, failure, loss, and end stage] or AKIN [Acute Kidney Injury Network] classifications]).[46] AKI complicates therapy and worsens the overall outcome.[55] There is an increased risk of mortality when urosepsis is present with severe sepsis and septic shock[56] ; however, the global prognosis for patients with urosepsis is better than that for those with sepsis from other infectious sites.

Other complications

Other complications of septic shock include the following:

Approach Considerations

Early recognition and management are key in patients with severe sepsis or septic shock. Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are indicated in patients with septic shock. These measures are necessary because these patients often require admission to an intensive care unit (ICU) for invasive monitoring and support. Once patients are stabilized, clinicians can determine their approach to the diagnostic workup.

Investigative studies include laboratory tests and imaging modalities to detect a clinically suspected focal infection, the presence of a clinically occult focal infection, and complications of sepsis and septic shock.

Initial Laboratory Studies

Complete blood count with differential

The white blood cell (WBC) count and the WBC differential can be somewhat helpful in predicting bacterial infection, though an elevated WBC count is not specific to infection. In the setting of fever without localizing signs of infection, a WBC count higher than 15,000/µL or a neutrophil band count higher than 1500/µL has about a 50% correlation with bacterial infection. WBC counts higher than 50,000/µL or lower than 300/µL are associated with significantly decreased survival rates.

Hemoglobin concentration dictates oxygen-carrying capacity in blood, which is crucial in shock to maintain adequate tissue perfusion. The goal is to keep the hematocrit above 30% and the hemoglobin concentration above 10 g/dL.

Platelets, as acute-phase reactants, usually increase at the onset of any serious stress and are typically elevated in the setting of inflammation. However, the platelet count will fall with persistent sepsis, and disseminated intravascular coagulation (DIC) may develop.

Coagulation studies

Coagulation status should be assessed by measuring the prothrombin time (PT) and the activated partial thromboplastin time (aPTT). Patients with clinical evidence of a coagulopathy require additional tests to detect the presence of DIC. The PT and the aPTT are elevated in DIC, fibrinogen levels are decreased, and fibrin split products are increased.

Blood chemistries

At regular intervals, metabolic assessment should be carried out by measuring serum levels of electrolytes, including magnesium, calcium, phosphate, and glucose. Sodium and chloride levels are abnormal in severe dehydration. Decreased bicarbonate can point to acute acidosis—however, sodium bicarbonate therapy is not recommended to improve hemodynamics or replace vasopressor requirements in patients with lactic acidemia from hypoperfusion whose pH level is 7.15 or greater.[14, 59]

Glucose control is important in the management of sepsis: Hyperglycemia is associated with higher mortality.

Serum lactate is perhaps the best serum marker for tissue perfusion, in that it is elevated under conditions of anaerobic metabolism, which occurs when tissue oxygen demand exceeds supply. This can result from decreased arterial oxygen content (hypoxemia), decreased perfusion pressure (hypotension), maldistribution of flow, and decreased diffusion of oxygen across capillary membranes to target tissues, as well as decreased oxygen utilization on a cellular level.

There is also evidence that lactate can be elevated in sepsis in the absence of tissue hypoxia, as a consequence of mitochondrial dysfunction and downregulation of pyruvate dehydrogenase, which is the first step in oxidative phosphorylation.[60]

Lactate levels higher than 2.5 mmol/L are associated with an increase in mortality. The higher the serum lactate, the worse the degree of shock and the higher the mortality. Lactate levels higher than 4 mmol/L in patients with suspected infection have been shown to yield a 5-fold increase in the risk of death and are associated with a mortality approaching 30%.[61] It has been hypothesized that lactate clearance is a measure of tissue reperfusion and an indication of adequate therapy.[62, 63]

Renal and hepatic function should be assessed with the following chemistry studies:

Liver function tests (LFTs) and levels of bilirubin, ALP, and lipase are important in evaluating multiorgan dysfunction or a potential causative source (eg, biliary disease, pancreatitis, or hepatitis). Increased BUN and creatinine levels can point to severe dehydration or renal failure.

In severely ill patients suspected of having adrenal insufficiency, a delta cortisol level below 9 µg/dL (after administration of 250 µg of cosyntropin) or a random total cortisol level below 10 µg/dL is diagnostic.[64] It should be kept in mind that the adrenocorticotropic hormone (ACTH) stimulation test is not recommended for identifying the subset of patients with septic shock or acute respiratory distress syndrome (ARDS) who should receive corticosteroid therapy.[64]

The American College of Critical Care Medicine (ACCCM) does not recommend the routine use of free cortisol measurements in critically ill patients.[64] There are no clear parameters for the normal range of free cortisol in such patients, and the free cortisol assay is not widely available, despite its advantages over the total serum cortisol assay.[64]

Microbiology Studies

Blood cultures

Blood cultures should be obtained in patients with suspected sepsis to facilitate isolation of a specific organism and tailoring of antibiotic therapy. These cultures are the primary means of diagnosing intravascular infections (eg, endocarditis) and infections of indwelling intravascular devices. Individuals at high risk for endocarditis are intravenous (IV) drug abusers and patients with prosthetic heart valves.

Patients at risk for bacteremia include adults who are febrile with an elevated WBC or neutrophil band count, elderly patients who are febrile, and neutropenic patients who are febrile. These populations have a 20-30% incidence of bacteremia. The incidence of bacteremia increases to at least 50% in patients with sepsis and evidence of end-organ dysfunction.

The Surviving Sepsis Campaign recommends obtaining at least 2 blood cultures before antibiotics are administered, with 1 percutaneously drawn and the other(s) obtained through each vascular access (unless the device was inserted < 48 hours beforehand).[14, 59] Again, however, it must be remembered that blood cultures are positive in fewer than 50% of cases of sepsis.[4, 5, 6]

To optimize recovery of aerobic bacteria from patients with suspected intra-abdominal infection, 1-10 mL of fluid can be directly inoculated into an aerobic blood culture; an additional 0.5 mL of fluid should be sent for Gram staining and, if indicated, fungal cultures.[3] For anaerobic bacteria, 1-10 mL of fluid can also be directly inoculated into an anaerobic blood culture bottle.

Susceptibility testing for organisms that have a high risk for resistance (eg, Pseudomonas, Proteus, Acinetobacter, Staphylococcus aureus, and predominant [moderate to heavy growth] Enterobacteriaceae) should be performed.[3] Unfortunately, in patients with community-acquired intra-abdominal infection, blood cultures are not of much clinical utility; Gram staining of the infected material also is not generally useful in such cases.

Urinalysis and urine culture

Urinalysis and urine culture are indicated for every patient who is in a septic state. Urinary tract infection (UTI) is a common source for sepsis, especially in elderly individuals. Adults who are febrile without localizing symptoms or signs have a 10-15% incidence of occult UTI. Obtaining a culture is important for isolating a specified organism and tailoring antibiotic therapy.

Gram stain and culture of secretions and tissue

The Gram stain is the only immediately available test that can document the presence of bacterial infection and guide the choice of initial antibiotic therapy. Secretions or tissue for Gram stain and culture from the sites of potential infection (eg, cerebrospinal fluid [CSF], wounds, respiratory secretions, or other body fluids) may be are obtained as they are identified, preferably before administering antibiotic therapy.[14, 59]

At least 1 mL of fluid or tissue is needed for cultures.[3] For aerobic or anaerobic cultures, 0.5 mL of fluid or 0.5 g of tissue should be transported to the laboratory in the appropriate aerobic or anaerobic transport medium.[3]

If pneumonia is suspected, a sputum specimen should be obtained for Gram stain and culture, provided that the patient has a productive cough and that a good-quality specimen can be obtained.[65] Any abscess should be drained promptly and purulent material sent to the microbiology laboratory for analysis. If meningitis is suspected, a CSF specimen should be obtained.

Routine culture and susceptibility studies should be obtained in the following cases[3] :

Although Gram staining may be helpful for identifying healthcare-related infections (eg, presence of yeast), it has not proved to be of clinical value in community-acquired intra-abdominal infections.[3] Anaerobic cultures are not necessary for community-acquired intra-abdominal infections if empiric antimicrobial therapy against common anaerobic pathogens is administered.

Plain Radiography

Chest

Because most patients who present with sepsis have pneumonia, and because the clinical examination is unreliable for the detection of pneumonia (especially in elderly patients), a chest radiograph is warranted. Chest radiography detects infiltrates in about 5% of febrile adults without localizing signs of infection; accordingly, it should be routine in adults who are febrile without localizing symptoms or signs and in patients who are febrile with neutropenia and without pulmonary symptoms.

Chest radiography is useful in detecting radiographic evidence of ARDS (see the images below), which carries a high mortality. The discovery of such evidence on a chest radiograph should prompt consideration of early intubation and mechanical ventilation, even if the patient has not yet shown signs of overt respiratory distress.


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Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.


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Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.


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A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed....

In early ARDS, the chest radiograph may appear normal. The typical findings of noncardiogenic pulmonary edema are bilateral hazy, symmetric homogeneous opacities, which may demonstrate air bronchograms. The margins of pulmonary vessels become indistinct and obscured with disease progression.

The usual findings of metastatic pulmonary edema, such as Kerley A or B lines, are not usually observed; a perihilar distribution of opacities is also absent. Furthermore, other findings of cardiogenic pulmonary edema, such as cardiomegaly, vascular redistribution, and pleural effusions, are absent as well.

With disease progression, the ground-glass opacities change into heterogeneous linear or reticular infiltrates. Days to weeks later, either persistent chronic fibrosis may develop or the chest radiograph appearance becomes more normal. Periodic chest radiographs during the management of ARDS are particularly important for diagnosing barotrauma, confirming adequate positioning of an endotracheal tube or intravascular catheters, and detecting nosocomial pneumonia.

Abdomen

Supine and upright or lateral decubitus abdominal radiographs should be obtained; these may be useful when an intra-abdominal source of sepsis is suspected. Abdominal plain films should be obtained if clinical evidence of bowel obstruction or perforation exists. However, if obvious signs of diffuse peritonitis are present and immediate surgical intervention is planned, further diagnostic imaging is not required.[3]

In adult patients with suspected intra-abdominal infection who are not undergoing immediate laparotomy, computed tomography (CT) of the abdomen is preferable to abdominal radiography.[3]

Extremities

Plain radiographs of the extremities may be helpful when deep soft-tissue infection is suspected. These films can show evidence of soft-tissue gas formation; however, it is important to emphasize that necrotizing fasciitis is a clinical diagnosis (signaled, for example, by extreme pain, crepitus, bullae, hemorrhage, and foul-smelling exudates).

If clinical suspicion of necrotizing fasciitis is high, a surgical consultation should be obtained immediately, and the patient should be taken promptly to the operating room for intervention, often without the need for any imaging. CT and magnetic resonance imaging (MRI) cannot be relied on to make this diagnosis.

Plain radiographs can also show evidence of osteomyelitis. However, MRI is much more sensitive for making this diagnosis.

Ultrasonography

Abdominal ultrasonography is indicated when patients have evidence of acute cholecystitis or ascending cholangitis exists[3] (eg, right upper quadrant abdominal tenderness, fever, vomiting, elevated LFT results, elevated bilirubin level, or elevated alkaline phosphatase level). Surgery or endoscopic retrograde cholangiopancreatography (ERCP) may be urgently necessary in the setting of sepsis with acute cholecystitis or ascending cholangitis.

Echocardiography has a number of uses in assessing patients with septic shock and may be considered.[66] This imaging modality can provide a comprehensive cardiac evaluation in patients with hemodynamic instability and can be helpful for guiding fluid therapy and monitoring treatment effects. Other conditions that can be assessed include sepsis-induced myocardial dysfunction, right heart failure, dynamic left ventricular obstruction, and tamponade.[66]

CT and MRI

CT is the imaging modality of choice for excluding an intra-abdominal abscess or a retroperitoneal source of infection. Obesity or the presence of excessive intestinal gas markedly interferes with abdominal imaging by ultrasonography; therefore, CT is preferred in this setting.

Obtain an abdominal CT scan if the patient has abdominal or flank tenderness in the setting of sepsis. Certain abdominal processes (eg, diverticular abscess, ischemic bowel, appendicitis, perinephric abscess) may necessitate urgent operative intervention.

When clinical evidence of a deep soft tissue infection exists, such as crepitus, bullae, hemorrhage, or foul-smelling exudate, obtain a plain radiograph. The presence of soft-tissue gas often dictates surgical exploration.

Although either CT or MRI may reveal evidence of subcutaneous and deep-tissue inflammation, neither modality is sensitive or specific in the setting of necrotizing deep-tissue infection, and neither should be relied upon to make this diagnosis. MRI is much more sensitive for osteomyelitis than plain radiography is.

If there is evidence of increased intracranial pressure (eg, papilledema) or focal mass lesions (focal defects, preceding sinusitis or otitis, or recent intracranial surgery), antibiotic therapy should be initiated, and a head CT scan should be obtained. Antibiotics will not begin to affect CSF cultures for at least several hours; therefore, proper antibiotic administration should not be delayed by the procedure if there is a high suspicion for meningitis.

If bacterial meningitis is strongly suspected, a lumbar puncture (LP) should be performed promptly, without any delay to obtain a CT scan.

Lumbar Puncture

An LP is indicated when there is clinical evidence or suspicion of meningitis or encephalitis. If the opening pressure is elevated, only as much CSF as is needed for culture should be obtained. Broad-spectrum antibiotics to cover meningitis should be administered before the start of the procedure. In patients with an acute fulminant presentation, rapid onset of septic shock, and severely impaired mental status, this procedure is used to rule out bacterial meningitis.

Approach Considerations

Patients with sepsis, severe sepsis, and septic shock require hospital admission. Patients with sepsis who respond to early goal-directed resuscitation therapy (EGDT) in the emergency department (ED) and show no evidence of end-organ hypoperfusion may be admitted to a general hospital unit, optimally one that has close nursing observation and monitoring. Such patients do not require invasive hemodynamic monitoring and usually do not require admission to an intensive care unit (ICU).

Patients who do not respond to initial ED treatment (ie, have recurrent hypotension despite adequate fluid challenges) and those who are in septic shock require admission to an ICU for continuous monitoring and continued goal-directed therapy. If an appropriate ICU bed or physician is not available, the patient should be transferred with advanced life support monitoring to another hospital with the available resources.

There is some controversy surrounding EGDT in the management of severe sepsis and septic shock. EGDT was previously evaluated in a single randomized trial at a single institution.[67] Three new randomized trials are in currently progress in Australia (ARISE [Australasian Resuscitation In Sepsis Evaluation]), the United Kingdom (ProMISE [Protocolised Management In Sepsis]), and the United States (ProCESS [Protocolized Care for Early Septic Shock]).

Goals and principles of treatment

The treatment of patients with septic shock has the following major goals:

Management principles, based on the current literature, include the following:

Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes antimicrobial therapy targeting the most likely pathogen, removal or drainage of the infected foci, treatment of complications, and interventions to prevent and treat effects of harmful host responses. Source control is an essential component of sepsis management.

Venous access

In all cases of septic shock, adequate venous access must be ensured for volume resuscitation. When sepsis is suspected, 2 large-bore (16-gauge) intravenous (IV) lines should be placed if possible to allow administration of aggressive fluid resuscitation and broad-spectrum antibiotics.

If the hypotension does not respond to a crystalloid fluid bolus of 30 mL/kg (1-2 L) over 30-60 minutes or if fluids cannot be infused rapidly enough, a central venous catheter should be placed in the internal jugular or subclavian vein. This catheter allows administration of medication centrally and provides multiple ports for rapid fluid administration, antibiotics, and vasopressors if needed. It also allows measurement of central venous pressure (CVP), a surrogate for volume status, if CVP measurement capability is available.

If an intravascular access device is suspected as the source of severe sepsis or septic shock, alternative vascular access must be obtained, and the suspect device must then be removed.

Urinary catheterization

An indwelling urinary catheter should be placed. In all patients with sepsis, urine output (UOP), a marker for adequate renal perfusion and cardiac output, should be closely monitored, as should renal function; mortality is greatly increased in patients with urosepsis and severe sepsis or septic shock. Normal UOP in an adult is 0.5 mL/kg/hr or more,[14, 59] equivalent to about 30-50 mL/hr for most adults.

Any abnormalities in UOP should prompt assessment of the adequacy of circulating blood volume, cardiac output, and blood pressure; these should be corrected if inadequate. As with sepsis in other sites, early and appropriate initiation of antimicrobial therapy—as well as identification and management of any urinary tract disorders—is essential.[56]

Intubation and mechanical ventilation

Most patients with sepsis develop respiratory distress as a manifestation of severe sepsis or septic shock. The lung injury is characterized pathologically as diffuse alveolar damage (DAD) and ranges from acute lung injury (ALI)—or mild ARDS, by the Berlin Definition[13] —to moderate or severe ARDS (see Background). These patients need intubation and mechanical ventilation for optimal respiratory support. Intubation should be considered early in the course of progressing severe sepsis and septic shock.

Direct delivery of oxygen into the trachea at a fraction of inspired oxygen (FIO2) of 1 is far superior to delivery via a nonrebreather oxygen mask. Mechanical ventilation, with appropriate sedation, also eliminates the work of breathing as well as decreases the metabolic demands of breathing, which accounts for about 30% of total metabolic demand at baseline.

Alveolar overdistention and repetitive opening and closing of alveoli during mechanical ventilation have been associated with an increased incidence of ARDS. Low−tidal volume ventilatory strategies have been used to minimize this type of alveolar injury. The recommended tidal volume is 6 mL/kg, with plateau pressures kept at or below 30 mL H2 O.[14, 59] Positive end-expiratory pressure (PEEP) is required to prevent alveolar collapse at end-expiration.[68]

General Treatment Guidelines

The major focus of resuscitation from septic shock is on supporting cardiac and respiratory functions. The other organ systems may also require attention and support during this critical period. Patients in septic shock generally require intubation and assisted ventilation because respiratory failure either is present at the onset of illness or may develop during its course. Correction of the shock state and abnormal tissue perfusion is the next step in the treatment of patients with septic shock.

In 2004, the first set of formal treatment guidelines for septic shock were published.[69] These guidelines, known as the Surviving Sepsis Campaign, were formulated by an international consensus group that was composed of experts from 11 organizations, including the Society of Critical Care Medicine (SCCM), the American College of Chest Physicians (ACCP), the European Society of Intensive Care Medicine (ESICM), and the American College of Emergency Physicians (ACEP).

The Surviving Sepsis Campaign guidelines were updated in 2012, and the current versions reflect the most modern opinion on the treatment of septic shock.[14] The reader is encouraged to check the Sepsis Campaign’s Website periodically for new information.

The first 6 hours of resuscitation of a critically ill patient with sepsis or septic shock are critical.[14] The following should be completed within 3 hours:

The following should be completed within 6 hours:

The Royal College of Obstetricians and Gynaecologists (RCOG) recommends following the Surviving Sepsis Campaign guidelines for managing pregnant women with sepsis or septic shock.[70] Treatment strategies include early recognition and resuscitation measures, supportive care, removal of the septic focus, administration of blood products as needed, and thromboprophylaxis, as well as the involvement of a multidisciplinary team.[14, 70] (See Shock and Pregnancy.)

Respiratory support

An initial assessment of airway and breathing is vital in a patient with septic shock. Supplemental oxygen should be administered to all patients with suspected sepsis. Early intubation and mechanical ventilation should be strongly considered for patients with any of the following:

Circulatory support

Patients with suspected septic shock require an initial crystalloid fluid challenge of 30 mL/kg (1-2 L) over 30-60 minutes, with additional fluid challenges. (A fluid challenge consists of rapid administration of volume over a particular period, followed by assessment of the response.) (See Fluid Resuscitation.)

Administration of crystalloid solution is titrated to a CVP goal of 8-12 mm Hg or signs of volume overload (dyspnea, pulmonary rales, or pulmonary edema on the chest radiograph). Patients with septic shock often require a total of 4-6 L or more of crystalloid solution. However, CVP measurement should not be entirely relied upon, because there is some debate as to how accurately it correlates with intravascular volume status and cardiac volume responsiveness, especially in fluid-resuscitated patients.[71]

Some studies have used noninvasive means of estimating CVP—for example, ultrasonography to measure inferior vena cava diameter as a surrogate for volume status. Nagdev et al used the difference between inspiratory and expiratory caval diameter (the caval index) to predict CVP and found that a 50% difference predicted a CVP lower than 8 mm Hg with both a sensitivity and a specificity greater than 90%.[72]

UOP should also be monitored as a measure of dehydration. UOP lower than 30-50 mL/hr should prompt further fluid resuscitation.

Given that third-spacing of intravascular fluid is a hallmark of septic shock, it makes sense that administration of colloid solution might be beneficial. However, although colloid resuscitation with albumin has not been shown in many meta-analyses to have any advantage over isotonic crystalloid resuscitation (isotonic sodium chloride solution or lactated Ringer solution) in this setting,[73] Delaney et al found adjunctive albumin resuscitation to provide a statistically significant mortality benefit in relation to other regimens.[74]

In the Saline versus Albumin Fluid Evaluation (SAFE) trial, in which about 1200 of 7000 ICU patients who required fluid resuscitation had severe sepsis, no overall difference between the 2 treatment groups was seen.[75] However, the investigators noted a trend toward improved outcome in patients with severe sepsis who received 4% albumin rather than normal saline. The data are inconclusive, especially with regard to the initial resuscitation phase for septic shock in the ED; therefore, crystalloid fluid resuscitation is recommended.

The current Surviving Sepsis guidelines recommend rapid administration of an initial fluid challenge with 30 mL/kg of crystalloid solution.[14] Albumin should be used only when substantial amounts of crystalloid solution are required. Hydroxyethyl starch solutions are not recommended.[14] (See Goals of Hemodynamic Support.)

Correction of anemia and coagulopathy

Hemoglobin levels as low as 8 g/dL are well tolerated by patients, and transfusion is not required unless the patient has poor cardiac reserve or demonstrates evidence of myocardial ischemia. Thrombocytopenia and coagulopathy are common in patients with sepsis; these patients do not require replacement with platelets or fresh frozen plasma (FFP) unless they develop active clinical bleeding.

If hemoglobin levels fall below 7 g/dL, red blood cell (RBC) transfusion is recommended to a target hemoglobin range of 7-9 g/dL.[14] Even in the absence of apparent bleeding, patients with severe sepsis should receive platelet transfusion if platelet counts fall below 10 × 109/L (10,000/µL). Platelet transfusion may also be considered when bleeding risk is increased and platelet counts are below 20 × 109/L (20,000/µL).[14] Patients who are to undergo surgery or other invasive procedures may require higher platelet counts (eg, ≥50 × 109/L [50,000/µL]).

Other points to consider with respect to the administration of blood products include the following[14, 59] :

Antimicrobial therapy

IV antibiotic therapy should be initiated within the first hour after the recognition of septic shock or severe sepsis; delays in administration are associated with increased mortality.[6, 14, 59] Selection of antibiotic agents is empiric, based on an assessment of the patient’s underlying host defenses, the potential source of infection, and the most likely responsible organisms. (See Empiric Antimicrobial Therapy.)

When the source is unknown, the antibiotic chosen must be a broad-spectrum agent that covers gram-positive, gram-negative, and anaerobic bacteria. In addition, consideration must be given to pathogens with antibiotic resistance, such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas species, and gram-negative organisms with extended-spectrum beta-lactamase (ESBL) activity.

Patients who are at risk for these types of infection are those with recent, prolonged, or multiple hospitalizations. The 2012 Surviving Sepsis Campaign guidelines recommend combination empiric therapy for neutropenic patients as well as for those with difficult-to-treat, multidrug-resistant microorganisms, such as Acinetobacter and Pseudomonas.[14]

Temperature control

Fever generally requires no treatment, except in patients who have limited cardiovascular reserve as a consequence of increased metabolic requirements. Antipyretic drugs and physical cooling methods, such as sponging or cooling blankets, may be used to lower the patient’s temperature.

External cooling is another method of fever control that has been reported to be safe and to decrease vasopressor requirements and early mortality in patients with septic shock. In a multicenter, randomized, controlled study comprising febrile patients with septic shock who required vasopressors, mechanical ventilation, and sedation, the group that received external cooling, as compared with the group that did not, exhibited the following[76] :

Although a 50% decrease in the vasopressor dose was significantly more common after 12 hours of external cooling treatment, the same result was not found after 48 hours of this therapy.[76]

Metabolic and nutritional support

Patients with septic shock develop electrolyte abnormalities. Potassium, magnesium, and phosphate levels should be measured and corrected if deficient.

Patients with septic shock generally have high protein and energy requirements. Although a brief period (several days) without nutrition does not cause deleterious effects, prolonged starvation must be avoided.

Early nutritional support is of critical importance in patients with septic shock. The oral or enteral route is preferred, unless the patient has an ileus or other intestinal abnormality. Gastroparesis is commonly observed and can be treated by administering motility agents or placing a small-bowel feeding tube.

Diminished bowel sounds are not a contraindication to a trial of enteral nutrition, though motility agents or a small-bowel feeding tube may be necessary. The benefits of enteral nutrition are as follows:

The 2012 Surviving Sepsis Campaign guidelines recommend using nutritional support without specific immunomodulating supplementation.[14]

Goals of Hemodynamic Support

Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation, which ultimately causes cellular, and then organ system, dysfunction. Therefore, the goals of hemodynamic therapy are restoration and maintenance of adequate tissue perfusion so as to prevent multiple organ dysfunction.

Careful clinical and invasive monitoring is required for assessment of global and regional perfusion. Shock at the bedside is defined by an MAP lower than 60 mm Hg or a decrease in MAP of 40 mm Hg from baseline.

Elevation of the blood lactate level on serial measurements of lactate can indicate inadequate tissue perfusion. In addition, mixed venous oxyhemoglobin saturation serves as an indicator of the balance between oxygen delivery and consumption. A decrease in maximal venous oxygen (MVO2) can be secondary to decreased cardiac output; however, maldistribution of blood flow in patients experiencing septic shock may artificially elevate the MVO2 levels. An MVO2 of less than 65% generally indicates decreased tissue perfusion.

Regional perfusion in patients with septic shock is evaluated by assessing the adequacy of organ function. Indications of inadequate perfusion may include any of the following:

Hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if necessary, optimizing perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.

Fluid Resuscitation

Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients with sepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of the patient’s volume and cardiovascular status.

Monitor patients for signs of volume overload, such as dyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chest radiograph. Improvements in mental status, heart rate, MAP, capillary refill, and UOP indicate adequate volume resuscitation.

Volume resuscitation can be achieved with either crystalloid or colloid solutions. The crystalloid solutions are 0.9% sodium chloride and lactated Ringer solution; the colloid solutions are albumin, dextrans, and pentastarch. Although most clinical trials have not shown either type of resuscitation fluid to be superior in septic shock, a meta-analysis by Delaney et al found a significant reduction in mortality associated with albumin-containing solutions as compared with other fluid resuscitation regimens.[74]

It should be kept in mind, however, that crystalloid fluids not only must be given in considerably (2-4 times) greater volumes than colloid fluids but also take longer to achieve the same end points. On the other hand, colloid solutions are much more expensive than crystalloid solutions.

The 2012 Surviving Sepsis Campaign guidelines recommend rapid administration of an initial fluid challenge with 30 mL/kg of crystalloid solution.[14] Albumin infusion should be used only when substantial amounts of crystalloid solution are required. Hydroxyethyl starch solutions are not recommended.

In some patients, clinical assessment of the response to volume infusion may be difficult. In such cases, it may be facilitated by monitoring the response of CVP or pulmonary artery occlusion pressure (PAOP) to fluid boluses. Fluid administration should be continued as long as hemodynamic improvement continues.[14, 59]

A sustained rise of more than 5 mm Hg in cardiac filling pressure after a fluid volume is infused indicates that the compliance of the vascular system is decreasing as further fluid is being infused. Such patients are susceptible to volume overload, and further fluid should be administered with care.

Data from several studies suggest that the incidence of pulmonary edema is essentially the same with crystalloid solutions as with colloid solutions when cardiac filling pressures are maintained at a lower level. However, if higher filling pressures are required for maintenance of optimal hemodynamics, crystalloid solutions may increase extravascular fluid fluxes through a decrease in plasma oncotic pressure.

EGDT may be considered for severe sepsis and septic shock[67] ; however, this approach remains controversial, and further studies are under way. One of these studies was just completed and published in 2014, the ProCESS trial,[77] which was a randomized trial of protocol-based care for early septic shock. This trial enrolled 1341 patients and compared a protocol-based EGDT (N=439) to two other arms: protocol-based standard therapy (N=446) and usual care (N=456). The results showed no significant 60-day mortality differences among the three arms, 21%, 18.2%, and 18.9%, respectively. Because these mortality rates were lower than the original EGDT study,[67] the authors performed a subgroup analysis including the sickest third of patients based on lactate levels and APACHE II scores, which showed similar or higher mortality than that from the original study,[67] but no benefit from EGDT was detected in this high-disease-severity population.

Another study recently published, the OPTIMISE study,[78] was a pragmatic, randomized, observer-blinded trial that compared a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid/inotrope (dopexamine) (N=368) with usual care within 6 hours following major gastrointestinal surgery (N=366). The outcome measured was a composite of 30-day mortality plus moderate or major complications; no composite outcome differences were observed between the two groups. The authors also performed an updated meta-analysis with the addition of their new data and found a potential reduction in complication rates, but not in mortality.

However, at the same time, a French study showed that in previously nonhypertensive patients, targeting a mean arterial pressure of 65-75 mm Hg was as good, if not better, than targeting a mean arterial pressure 80-85 mm Hg.[79]

Further, the large retrospective study of all of Australia and New Zealand ICU care from 2000-2012 demonstrated a clear progressive decline in septic shock mortality rates from 35% to 18% over this period, with equal trends across all age groups and treatment settings.[80]

Vasopressor Therapy

If the patient does not respond to resuscitation with several liters (usually ≥4 L) of isotonic crystalloid solution or if evidence of volume overload is present, the depressed cardiovascular system can be stimulated by means of vasopressor therapy.

Vasopressor administration is required for persistent hypotension once adequate intravascular volume expansion has been achieved. Persistent hypotension is typically defined as systolic blood pressure lower than 90 mm Hg or MAP lower than 65 mm Hg with altered tissue perfusion. The mean blood pressure required for adequate splanchnic and renal perfusion (MAP, 60 or 65 mm Hg) is based on clinical indices of organ function.

The goal of vasopressor therapy is to reverse the pathologic vasodilation and altered blood flow distribution that occur as a result of the activation of adenosine triphosphate (ATP)-dependent potassium channels in vascular smooth muscle cells and the synthesis of the vasodilator nitric oxide (NO).

First-line agents: norepinephrine vs dopamine

The recommended first-line agent for septic shock is norepinephrine, preferably administered through a central catheter.[14, 59] Norepinephrine has predominant alpha-receptor agonist effects and results in potent peripheral arterial vasoconstriction without significantly increasing heart rate or cardiac output. The dosage range for norepinephrine is 5-20 µg/min, and it is not based on the weight of the patient.

Norepinephrine is preferred to dopamine for managing septic shock because dopamine is known to cause unfavorable flow distribution (more arrhythmias). In this setting, norepinephrine has been shown to be both significantly safer and somewhat more effective.

In a systematic review of randomized controlled trials, norepinephrine was significantly superior to dopamine in improving both in-hospital and 28-day mortality in septic shock patients.[81] In a meta-analysis that evaluated these 2 agents in the setting of septic shock, the investigators determined that in comparison with dopamine, epinephrine was associated with a decreased risk of death and a lower incidence of arrhythmic events.[82]

In theory, norepinephrine is the ideal vasopressor in the setting of warm shock, wherein peripheral vasodilation exists in association with normal or increased cardiac output. The typical patient with warm shock has warm extremities but exhibits systemic hypotension and tachycardia, the results of decreased systemic vascular resistance.

Dopamine should be used only in certain highly specific situations, such as when there is a low risk of tachyarrhythmias and bradycardia. Treatment usually begins at 5-10 µg/kg/min IV, and the infusion is adjusted according to the blood pressure and other hemodynamic parameters. Often, patients may require high dosages of dopamine (up to 20 µg/kg/min). Low-dose dopamine is not recommended for renal protection.[14, 59]

Second-line agents

Second-line vasopressors appropriate for patients who have persistent hypotension despite maximal doses of norepinephrine or dopamine are epinephrine, phenylephrine, and vasopressin.

Epinephrine clearly increases MAP in patients unresponsive to other vasopressors, mainly by virtue of its potent inotropic effects on the heart; thus, it should probably be the first alternative agent considered in patients with septic shock who show a poor clinical response to norepinephrine or dopamine.[14, 59] Adverse effects include tachyarrhythmias, myocardial and splanchnic ischemia, and increased systemic lactate concentrations.

Phenylephrine exerts a pure alpha-receptor agonist effect, which results in potent vasoconstriction, albeit at the expense of depressed myocardial contractility and heart rate. Phenylephrine may be considered a first-line agent in patients with extreme tachycardia; its pure alpha-receptor activity will not result in increased chronotropy.[83]

Vasopressin, or antidiuretic hormone (ADH), has been proposed for use in septic shock because it is an endogenous peptide with potent vasoactive effects and its circulating levels are depressed in septic shock. According to the 2012 Surviving Sepsis Campaign guidelines, vasopressin should not be the single initial vasopressor but should be reserved for salvage therapy.[14] After first-line treatment, 0.03 U/min of vasopressin may be added to norepinephrine, with an anticipated effect equivalent to that of norepinephrine alone.[14, 59]

Characteristics of the vasopressors

Norepinephrine

Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. It can increase blood pressure successfully in patients with sepsis who remain hypotensive after fluid resuscitation and dopamine. The dosage may range from 0.2 to 1.5 µg/kg/min, and dosages as high as 3.3 µg/kg/min have been used because of the alpha-receptor downregulation in sepsis.

In patients with sepsis, indices of regional perfusion (eg, urine flow) and lactate concentration have improved after norepinephrine infusion. Several studies have found that a significantly greater percentage of patients treated with norepinephrine were resuscitated successfully, in comparison with patients treated with dopamine.[81, 82] Therefore, norepinephrine should be used early and should not be withheld as a last resort in patients with severe sepsis who are in shock.

Concerns about compromising splanchnic tissue oxygenation have not been borne out by the data; the studies have confirmed no deleterious effects on splanchnic oxygen consumption and hepatic glucose production, provided that adequate cardiac output is maintained.

Dopamine

A precursor of norepinephrine and epinephrine, dopamine has varying effects, according to the doses infused. At lower doses, it has a much greater effect on beta receptors; at higher doses, it has more alpha-receptor effects and increases peripheral vasoconstriction.

Dosages range from 2 to 20 µg/kg/min. A dosage lower than 5 µg/kg/min results in vasodilation of renal, mesenteric, and coronary beds.[14] At a dosage of 5-10 µg/kg/min, beta1 -adrenergic effects induce an increase in cardiac contractility and heart rate. At dosages of about 10 µg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and elevation in blood pressure.[14]

Dopamine is effective for optimizing MAP in patients with septic shock who remain hypotensive after volume resuscitation. The blood pressure increases primarily as a result of the drug’s inotropic effect, which is useful in patients who have concomitant reductions in cardiac function.

Dopamine may be particularly useful in the setting of cold shock, where peripheral vasoconstriction exists (cold extremities) and cardiac output is too low to maintain tissue perfusion. Undesirable effects include tachycardia, increased pulmonary shunting, the potential to decrease splanchnic perfusion, and an increase in pulmonary arterial wedge pressure (PAWP).

Low-dose (renal-dose) dopamine has been studied. Dopamine at a dosage of 2-3 µg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers; however, several well-designed clinical trials have not found such regimens to have any beneficial effects on renal blood flow and function in the setting of circulatory shock of any etiology.

Multiple studies also have not shown prophylactic or therapeutic low-dose dopamine administration to have any beneficial effect in patients with sepsis who are critically ill. In view of the real side effects of dopamine infusion, the use of renal-dose dopamine should be abandoned.

Epinephrine

Epinephrine can increase MAP by increasing cardiac index and stroke volume, as well as by increasing systemic vascular resistance and heart rate. This agent may increase oxygen delivery and oxygen consumption. The use of epinephrine is recommended only in patients who are unresponsive to traditional agents. The undesirable effects of epinephrine include the following:

Phenylephrine

Phenylephrine is a selective alpha1 -adrenergic receptor agonist that is used primarily in anesthesia to increase blood pressure. Although the data are limited, studies have found phenylephrine to increase MAP in patients who were septic and hypotensive with increased oxygen consumption. However, concern remains about this agent’s potential to reduce cardiac output and lower heart rate in patients with sepsis. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other agents.

Vasopressin

Vasopressin is synthesized in the hypothalamus and excreted by the posterior pituitary. In contrast to endogenous catecholamines (eg, norepinephrine), whose serum levels are universally high in septic shock, vasopressin stores are limited and its levels are low.[84] Furthermore, catecholamine effectiveness on vascular smooth muscle cells is inhibited by the activation of ATP-dependent potassium channels and NO.

Exogenous administration of vasopressin results in vasoconstriction via activation of V1 receptors on vascular smooth muscle cells that have the effect of inhibiting ATP-dependent potassium channels and, in theory, restoring the effectiveness of catecholamines. Vasopressin is also thought to inhibit NO synthase and therefore counteract the vasodilatory effect of NO. In addition, vasopressin increases renal perfusion by causing vasodilation of afferent renal arterioles, in contrast to the renal vasoconstriction caused by catecholamines.

Several small clinical trials have shown that low-dose vasopressin increases MAP and decreases the requirement for catecholamines while maintaining mesenteric and renal perfusion.[84] However, a large, randomized trial (the Vasopressin and Septic Shock Trial [VASST]) did not find mortality to be significantly lower in patients who received vasopressin in addition to norepinephrine than in those who received norepinephrine alone, even though vasopressin reduced the requirement for norepinephrine.[85]

Overall, the major adverse effects attributed to vasopressin (myocardial ischemia, cardiac arrest, mesenteric, and digital ischemia) were not significantly increased in the trial; however, patients with known coronary artery disease or congestive heart failure were excluded from the study.[85] The incidence of digital ischemia was higher with vasopressin use. Because the mean time to receiving the drug in VASST was 12 hours, this study does not address the use of vasopressin in early sepsis resuscitation.

Inotropic Therapy and Augmented Oxygen Delivery

Although myocardial performance is altered during sepsis and septic shock, cardiac output generally is maintained in patients with volume-resuscitated sepsis. Data from the 1980s and 1990s suggested a linear relation between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that the oxygen delivery likely was insufficient to meet the metabolic needs of the patient.

However, subsequent investigations challenged the concept of pathologic supply dependency, suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation) was not associated with improved patient outcome. Therefore, the role of inotropic therapy is uncertain, unless the patient has inadequate cardiac index, MAP, mixed venous oxygen saturation (SmvO2), and UOP despite adequate volume resuscitation and vasopressor therapy.

Patients with severe sepsis or septic shock have hypermetabolism, maldistribution of blood flow, and, possibly, suboptimal oxygen delivery; therefore, attempts at detecting and correcting tissue hypoxia must be made. Lactic acidosis is an indication of either global ischemia (inadequate oxygen delivery) or regional (organ-specific) ischemia. Calculation of pH in the gastric mucosa via gastric tonometry may detect tissue hypoxia in the splanchnic circulation; however, this technique has not been validated extensively and is not widely available.

Dobutamine is an inotropic agent that stimulates beta receptors and results in increased cardiac output. In theory, it can enhance tissue oxygen delivery in patients with septic shock who have received adequate fluid resuscitation and vasopressor support. In EGDT, dobutamine is recommended if there is evidence of tissue hypoperfusion (central venous oxygen saturation [ScvO2] < 70 mm Hg) after CVP, MAP, and hematocrit goals have been met.

The 2012 Surviving Sepsis Campaign guidelines recommend administration of dobutamine dosages up to 20 µg/kg/min only in the presence of myocardial dysfunction or persistent hypoperfusion despite adequate fluid resuscitation and adequate MAP.[14]

Although initial aggressive resuscitation to maximize oxygen delivery improves outcome, manipulation of oxygen delivery to deliver supraphysiologic oxygen to tissues via blood transfusion, fluid boluses, or inotropic therapy once organ dysfunction has developed has not improved outcome in critically ill patients. Hayes et al reported a higher mortality in patients with sepsis who were maintained on high levels of oxygen delivery.[86] Thus, inotropic therapy is not recommended for increasing the cardiac index to supranormal levels.[14, 59]

In patients with septic shock, the inability to increase oxygen consumption and to decrease lactate levels most likely is a consequence of impaired oxygen extraction or inability to reverse anaerobic metabolism. Boosting oxygen delivery to supranormal levels does not reverse these pathophysiologic mechanisms after the development of organ injury.

Empiric Antimicrobial Therapy

Empiric antimicrobial therapy should be initiated early in patients experiencing septic shock (within 1 hour of recognition of septic shock) and severe sepsis without septic shock, if possible.[14, 59]

The Surviving Sepsis Campaign guidelines recommend including 1 or more agents that are not only active against the likely organisms but also capable of penetrating “in adequate concentrations into the presumed source of sepsis,” with daily reevaluation of the anti-infective therapy for potential deescalation.[14, 59]

Generally, a 7- to 10-day treatment course is followed. Longer treatment regimens may be warranted in the presence of a slow clinical response, undrainable foci of infection, and immunologic deficiencies (eg, neutropenia). The use of procalcitonin or similar biomarkers may facilitate discontinuance of antibiotics in patients with clinical improvement and no further evidence of infection.[14]

Combination empiric therapy is recommended for patients with the following[14] :

However, combination therapy should be limited to 3-5 days, after which period treatment should switch to the most appropriate monotherapy once the results of the susceptibility profile are available.[14, 59]

The following points must always be considered:

Antibiotic selection

The selection of appropriate agents is based on the patient’s underlying host defenses, the potential sources of infection, and the most likely culprit organisms. Antibiotics must be broad-spectrum agents and must cover gram-positive, gram-negative, and anaerobic bacteria because organisms from any of these different classes can produce the same clinical picture of distributive shock.

If the patient is “antibiotic-experienced,” strong consideration should be given to using an aminoglycoside rather than a quinolone or cephalosporin for gram-negative coverage. Knowing the antibiotic resistance patterns of both the hospital itself and its referral base (ie, nursing homes) is very important.

Antibiotics should be administered parenterally, in doses adequate to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than with the number of antibiotics given.

In the selection of empiric antibiotics, the increasing prevalence of MRSA must be taken into account, and an agent such as vancomycin or linezolid should be included. This is especially true in patients with a history of IV drug use, those with indwelling vascular catheters or devices, or those with recent hospitalizations. Antianaerobic coverage is indicated in patients with intra-abdominal or perineal infections.

Certain organisms, chiefly Enterobacteriaceae (eg, Escherichia coli and Klebsiella pneumoniae), contain a beta-lactamase enzyme that hydrolyzes the beta-lactam ring of penicillins and cephalosporins and thus inactivates these antibiotics (ESBL-producing bacteria). This phenomenon has become an increasing concern as its prevalence has increased. Beta-lactam antibiotics that have remained effective against ESBL-producing organisms include cephamycins (eg, cefotetan) and carbapenems (eg, imipenem, meropenem, and ertapenem).[87]

In immunocompetent patients, monotherapy with carbapenems (eg, imipenem and meropenem), third- or fourth-generation cephalosporins (eg, cefotaxime, cefoperazone, ceftazidime, and cefepime), or extended-spectrum penicillins (eg, ticarcillin and piperacillin) is usually adequate, without the need for a nephrotoxic aminoglycoside.[88] Patients who are immunocompromised or at high risk for multidrug-resistant organisms typically require dual broad-spectrum antibiotics with overlapping coverage.

Within these general guidelines, no single combination of antibiotics is clearly superior to any other.

The FDA recently approved 3 new antibiotics, oritavancin (Orbactiv), dalbavancin (Dalvance), and tedizolid (Sivextro), for the treatment of acute bacterial skin and skin structure infections. These agents are active against Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S aureus [MSSA, MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), among others. For complete drug information, including dosing, see the following monographs:

Community-acquired pneumonia

For inpatients with pneumonia who are not admitted to the ICU, the guidelines formulated by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recommend administering the following[65] :

For inpatients with pneumonia who are admitted to the ICU, the IDSA/ATS guidelines offer the following minimal recommendations[65] :

Other IDSA/ATS recommendations include the following[3] :

Intra-abdominal infections

For community-acquired abdominal infections, the IDSA and the Surgical Infection Society (SIS) indicate that empiric antibiotic therapies should be active against enteric gram-negative aerobic and facultative bacilli as well as enteric gram-positive streptococci.[3]

Empiric coverage is not needed for Enterococcus, nor is empiric antifungal therapy needed for Candida, unless these infections are severe. Antibiotics with activity against E faecalis include ampicillin, piperacillin-tazobactam, and vancomycin. Fluconazole is used for isolated C albicans; an echinocandin (eg, caspofungin, micafungin, or anidulafungin) is used for fluconazole-resistant Candida.[3] In critically ill patients, an echinocandin is recommended over a triazole (eg, fluconazole or itraconazole).[3]

Agents that cause healthcare-associated intra-abdominal infections include Candida, Enterococcus, and MRSA. Empiric antibiotic therapy for those infections should be based on local susceptibility results.

In adults with community-acquired infection or hospital-associated intra-abdominal infection of high severity (eg, Acute Physiology And Chronic Health Evaluation [APACHE] II score >15), broad-spectrum agents are used against gram-negative activity (eg, metronidazole plus meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, ciprofloxacin, or levofloxacin; alternatively, metronidazole plus ceftazidime or cefepime).[3]

Antibiotics that are not recommended for treating intra-abdominal infections, because of the greater prevalence of resistance, include ampicillin-sulbactam and quinolones (high resistance in community-acquired E coli), as well as cefotetan and clindamycin (high resistance in Bacteroides fragilis).[3] In addition, aminoglycosides, because of their toxicity and the availability of other agents, are not recommended for routine use in community-acquired abdominal infections.

Corticosteroid Therapy

Corticosteroid insufficiency has been associated with severe illness.[89] The American College of Critical Care Medicine (ACCCM) uses the term “critical illness-related corticosteroid insufficiency” (CIRCI) to describe hypothalamic-pituitary-adrenal (HPA) axis dysfunction in critically ill patients and recommends avoiding use of the terms “absolute” or “relative” adrenal insufficiency in such patients.[64]

Although there is theoretical and experimental animal evidence favoring the use of large doses of corticosteroids (eg, methylprednisolone, hydrocortisone, and dexamethasone) in patients with severe sepsis and septic shock, the clinical medical literature does not support the routine use of such doses in these patients.

High-dose corticosteroids should not be used in patients with severe sepsis or septic shock. A meta-analysis of prospective, randomized, controlled trials of glucocorticoid use did not find any benefit from corticosteroids and suggested that their use could be harmful.[90] A review of 3 meta-analyses found that use of low-dose corticosteroids did not improve survival in septic shock and severe sepsis and that they were associated with side effects that included superinfections, bleeding, and hyperglycemia.[91]

Some trials have documented positive results from stress-dose administration of corticosteroids in patients with severe and refractory shock.[92] Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.

Other studies have shown that lower-dose steroids may be beneficial for patients with relative adrenal insufficiency. In a study by Annane et al that included 299 patients with septic shock who were randomly assigned to receive low-dose steroids (hydrocortisone, 50 mg q6hr, and fludrocortisone, 50 µg/day) or placebo, 77% were nonresponders; for nonresponders who received steroids, there was a 10% absolute benefit with respect to mortality (63% vs 53%).[93]

In this study, all patients had been intubated, had been persistently hypotensive despite crystalloid resuscitation and vasopressor administration, and had had evidence of end-organ failure.[93] Nonresponders were defined as those whose cortisol level increased by less than 10 µg/dL in a cortisol stimulation test and thus were considered adrenally insufficient. This test involves measuring cortisol levels before and 30 minutes after IV administration of 0.25 mg of cosyntropin (ie, adrenocorticotropic hormone [ACTH]).

Although performing the cortisol stimulation test in the ED setting may not be practical, given time and resource constraints, it is worth noting that more than 75% of patients with vasopressor-refractory hypotension were adrenally insufficient.[93] This finding suggested that the majority of patients with vasopressor-refractory shock would benefit from steroid administration, regardless of the results of the cortisol stimulation test. A common choice is hydrocortisone 100 mg IV; a good alternative is dexamethasone 10 mg IV.

In a subsequent study, Annane et al published a systematic review of corticosteroid use for severe sepsis and septic shock, the pooled results of which showed that the subgroup of studies using prolonged, low-dose corticosteroid therapy demonstrated a beneficial effect on short-term mortality.[94] However, no clear benefit was shown with the use of high-dose corticosteroids for severe sepsis or septic shock.[94]

In the CORTICUS (Corticosteroid Therapy of Septic Shock) study, a large randomized trial of hydrocortisone versus placebo in patients with septic shock, no difference in mortality was noted between the groups, even though the patients who received steroids had a more rapid resolution of shock, as measured by a shorter duration of vasopressor therapy[95] and a faster improvement in Sequential Organ Failure Assessment (SOFA) scores.[96] However, the incidence of superinfection and recurrent sepsis was higher in those who received steroids.

Additionally, the result of the cortisol stimulation test had no bearing on outcome in the CORTICUS trial,[95] which raises questions about the value of this test in determining who will benefit from steroid treatment. However, the CORTICUS study enrolled all patients with septic shock, regardless of vasopressor response. Consequently, patients in this study had a lower mortality than those in the Annane study.

Guidelines recommendations and summary of key points regarding steroids

The 2012 Surviving Sepsis Campaign guidelines emphasize that steroids should not be administered to patients with septic shock unless hemodynamic stability cannot be achieved with fluid resuscitation and vasopressor agents.[14] In addition, these guidelines[14, 59] and those of the ACCCM[64] recommend the following:

The ACCCM also has the following treatment recommendations[64] :

The following key points summarize use of corticosteroids in septic shock:

Glycemic Control

A Belgian study of critically ill surgical ICU (SICU) patients found a 10% mortality benefit in those with tighter glycemic control—when the glucose levels were maintained between 80 and 110 mg/dL through intensive insulin therapy.[97] However, subsequent large, randomized studies did not replicate the results from the Belgian study[98, 99, 100] In fact, intensive insulin treatment has been shown to lead to increased episodes of hypoglycemia and increased mortality in ICU patients.[100, 101, 102, 103]

On the basis of the current evidence, the Surviving Sepsis Campaign guidelines recommend maintaining a glucose level below 180 mg/dL.[14]

DVT Prophylaxis and Management of DIC

Deep vein thrombosis

The Severe Sepsis Campaign guidelines have the following recommendations or suggestions regarding prophylaxis of deep vein thrombosis (DVT) in patients with severe sepsis[14, 59] :

(See Deep Venous Thrombosis, Thromboembolism, and General Principles of Anticoagulation in Deep Venous Thrombosis.)

Disseminated intravascular coagulation

DIC, a condition in which bleeding and thrombosis occur, can contribute to multiorgan system failure and carries a high mortality. Although controversy exists regarding DIC treatment, the overall management strategy is to treat the underlying cause and provide supportive care (see Correction of anemia and coagulopathy under General Treatment Guidelines).

In 2009, the British Committee for Standards in Haematology (BCSH) published their guidelines recommendations, in which they state that treating the underlying etiology is “the cornerstone” of DIC therapy.[104] The BSCH guidelines regarding adjunctive treatment (eg, plasma and platelet transfusion, anticoagulation, use of anticoagulant factor concentrates, and antifibrinolytic therapy) are discussed below.

Plasma and platelet transfusion

In general, the BSCH recommends reserving transfusion of platelets or plasma (components) for patients with DIC who are bleeding (rather than administering this therapy on the basis of laboratory findings). Thus, platelet transfusion should be considered in patients with DIC and bleeding (or a high risk of bleeding) who have a platelet count below 50 × 109/L (50,000/µL).[104] The Surviving Sepsis Campaign suggests considering platelet transfusion in such patients when platelet counts are below 20 × 109/L (20,000/µL).[14]

Other BSCH plasma/platelet transfusion guidelines include the following[104] :

Anticoagulation

Therapeutic doses of heparin should be considered in the following clinical situations of DIC[104] :

Continuous infusion of UFH should be considered in patients with DIC who are at high risk of bleeding; for example, weight-adjusted doses (eg, 10 U/kg/hr) “may be used without the intention to prolong the aPTT ratio to 1.5-2.5 times the control.”[104] Close monitoring of these patients is required for signs of bleeding and for their aPTT measurements.

DVT prophylaxis with prophylactic doses of heparin or LMWH is recommended for critically ill patients with DIC who are not actively bleeding.[104]

Antifibrinolytic therapy

In general, the BSCH does not recommend administering antifibrinolytic agents to patients with DIC.[104] In patients who have DIC that is characterized by a primary hyperfibrinolytic state and who present with severe bleeding, administration of lysine analogues (eg, tranexamic acid 1 g q8hr) may be considered.

Management of Acute Respiratory Distress Syndrome

ARDS and ALI (now often referred to as mild ARDS, in accordance with the Berlin Definition[13] ) are major complications of sepsis and septic shock. The incidence of ARDS in septic shock ranges from 20% to 40% and is higher when a pulmonary source of infection exists. (See Acute Respiratory Distress Syndrome and Pediatric Acute Respiratory Distress Syndrome.)

ARDS can be associated with clinical disorders causing direct lung injury, such as gastric acid aspiration, thoracic trauma, pneumonia, and near drowning; or indirect lung injury, including severe sepsis, acute pancreatitis, drug overdose, reperfusion injury, and severe nonthoracic trauma. Sepsis-associated ARDS carries an abysmal prognosis and carries the highest mortality.

Management of ARDS is primarily supportive; pharmacologic and other innovative therapies have not proved especially beneficial. General supportive care includes adequate treatment of underlying sepsis with appropriate antibiotics and surgical management if indicated. Appropriate fluid management to lower intravascular volume without affecting cardiac output and organ perfusion may be beneficial. The fluid manipulation often requires invasive hemodynamic monitoring.

The goals of mechanical ventilation include the following:

A lung-protective and pressure-limited ventilatory strategy has been shown to improve survival rates and lower rates of barotrauma. Current recommendations are to use a tidal volume of 5-8 mL/kg, to employ a longer inspiratory time, and not to exceed a transpulmonary pressure of 30 cm H2 O. Permissive hypercapnia may ensue may occur with the use of lesser tidal volumes, but it is tolerated.

The use of PEEP may reduce or prevent ventilator-induced lung injury. Sufficient PEEP to recruit atelectatic alveolar units and to increase lung volumes so that respiration happens on the most compliant part of the pressure volume curve is recommended. In clinical practice, this can be achieved by measuring plateau pressures and calculating lung compliance at different levels of PEEP. The use of prone positioning and NO may prove to be beneficial in the short term; these interventions have not been shown to improve survival rates.

High-dose corticosteroids, though not useful in early management, can improve survival in patients whose ARDS is not resolving. In a study by Meduri et al, prolonged administration of methylprednisolone in patients with nonresolving ARDS was associated with improvement and reduced mortality.[105] Mortality was 0/16 (0%) for the treatment group and 5/8 (62%) for the placebo group in the ICU. The rate of infections, including pneumonia, was similar in the 2 groups. More evidence is needed regarding steroid use and ARDS.

Surgical Treatment

Patients with focal infections should be sent for definitive surgical treatment after initial resuscitation and antibiotic therapy.[3] Little is gained by spending hours stabilizing the patient while an infected focus persists. However, even though urgent management is warranted for hemodynamically stable patients without evidence of acute organ failure, it may be possible to delay invasive procedures up to 24 hours—provided that very close clinical monitoring is instituted and appropriate antimicrobial therapy administered.[3]

Any soft-tissue abscess should be drained promptly. Certain conditions will not respond to standard treatment for septic shock until the source of infection is surgically removed. Some of these common foci of infection include intra-abdominal sepsis (perforation or abscess), empyema, mediastinitis, cholangitis, pancreatic abscess, pyelonephritis or renal abscess from ureteric obstruction, infective endocarditis, septic arthritis, infected prosthetic devices, deep cutaneous or perirectal abscess, and necrotizing fasciitis.

Whenever possible, percutaneous drainage of abscesses and other well-localized fluid collections is preferred to surgical drainage.[3] For example, a superficial abscess can be drained in the ED. However, any deep abscess or suspected necrotizing fasciitis should be drained in the surgical suite. Other examples of emergency conditions that call for rapid management are diffuse peritonitis, cholangitis, and intestinal infarction.[14, 59]

In cases of sepsis of unclear etiology, a thorough search for abscesses should be performed, with particular attention paid to the rectal and perianal area.

Prevention

Patients with impaired host defense mechanisms are at greatly increased risk for sepsis. The main causes of impaired host defense are as follows:

Ventilatory support and invasive catheters further increase the risk of infection. Avoiding the use of catheters or removing them as soon as possible may prevent severe sepsis.

Prophylactic antibiotics in the perioperative phase, particularly after GI surgery, may be beneficial. The use of topical antibiotics around invasive catheters and as part of dressings for patients with burns is helpful. Other preventive measures include maintenance of adequate nutrition, administration of pneumococcal vaccine in patients who have undergone splenectomy, and early enteral feeding.

Prevention of sepsis with topical or systemic antibiotics is suggested for high-risk patients. Use of nonabsorbable antibiotics in the stomach to prevent translocation of bacteria and occurrence of bacteremia is a controversial issue.

Numerous trials have been performed, using either topical antibiotics alone or a combination of topical and systemic antibiotics. A systemic review by Nathens found no benefit in medical patients but documented a reduced mortality in surgical trauma patients.[106] The beneficial effect was achieved with a combination of systemic and topical antibiotics, predominantly by reducing lower respiratory tract infections in treated patients.

Progression from infection with systemic inflammatory response syndrome (ie, sepsis) to severe sepsis with organ dysfunction to septic shock with refractory hypotension can often be reversed with early identification, aggressive crystalloid fluid resuscitation, broad-spectrum antibiotic administration, and removal of the infectious source if possible.

Basic measures to prevent nosocomial infections include the following[56] :

Medication Summary

The most important aspects of medical therapy for patients with sepsis include adequate oxygen delivery, crystalloid fluid administration, and broad-spectrum antibiotics. Although colloid solution is mentioned, a mortality benefit of colloid over crystalloid solution has not been proved. Blood transfusion may also be beneficial for patients with low hemoglobin concentrations.

Vasopressors are important for patients whose conditions are refractory to adequate fluid resuscitation. Steroid administration should be considered in patients whose conditions are refractory to both fluids and vasopressors.

Norepinephrine (Levophed)

Clinical Context:  Norepinephrine is used in protracted hypotension after adequate fluid replacement. It stimulates beta1- and alpha-adrenergic receptors, thereby in turn increasing cardiac muscle contractility and heart rate as well as vasoconstriction. As a result, it increases systemic blood pressure and cardiac output. Adjust and maintain the infusion to stabilize the blood pressure (eg, 80-100 mm Hg systolic blood pressure) sufficiently to perfuse vital organs.

Dopamine (Intropin)

Clinical Context:  Dopamine stimulates both adrenergic and dopaminergic receptors. Its hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Higher doses produce cardiac stimulation and renal vasodilation. After therapy is initiated the dosage may be increased by 1-4 µg/kg/min every 10-30 minutes until a satisfactory response is attained. Maintenance dosages lower than 20 µg/kg/min are usually satisfactory for 50% of the patients treated.

Dobutamine

Clinical Context:  Dobutamine is a sympathomimetic amine with stronger beta than alpha effects. It produces systemic vasodilation and increases the inotropic state. Vasopressors augment the coronary and cerebral blood flow during the low-flow state associated with shock. Sympathomimetic amines with both alpha- and beta-adrenergic effects are indicated in cardiogenic shock.

Dobutamine is used in early goal-directed therapy if there is evidence that tissue hypoperfusion and myocardial dysfunction is related to sepsis. Dopamine and dobutamine are the drugs of choice for improving cardiac contractility, with dopamine the preferred agent in hypotensive patients. Higher dosages of dobutamine may cause an increase in heart rate, exacerbating myocardial ischemia.

Epinephrine (Adrenalin)

Clinical Context:  Epinephrine is used for hypotension that is refractory to dopamine or norepinephrine. It stimulates alpha- and beta-adrenergic receptors, resulting in relaxation of bronchial smooth muscle, increased cardiac output, and increased blood pressure.

Vasopressin (Pitressin)

Clinical Context:  Vasopressin (Pitressin)

Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. It increases water resorption at the distal renal tubular epithelium (ADH effect). Vasopressin promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.

Phenylephrine

Clinical Context:  Phenylephrine is a strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity. It produces vasoconstriction of arterioles and increased peripheral vascular resistance. This agent causes reflex myocardial depression and decreased heart rate; therefore, it must be used with caution. Phenylephrine is a first-line agent in patients with hypotension and extreme tachycardia. It can be used as an adjunct to norepinephrine or dopamine to augment peripheral vasoconstriction.

Class Summary

In cardiovascular disorders, vasopressors are used for their alpha1 and beta1 properties. They induce vasoconstriction and elevate mean arterial pressure, as well as provide hemodynamic support in acute heart failure and shock.

Vasopressors are used as second-line agents in the treatment of septic shock. There is no evidence that one vasopressor is superior compared to the other.

Normal saline (NS, 0.9% NaCl)

Clinical Context:  Normal saline restores interstitial and intravascular volume. It is used in initial volume resuscitation.

Lactated Ringer

Clinical Context:  LR solution restores interstitial and intravascular volume. It is used in initial volume resuscitation.

Class Summary

Isotonic sodium chloride solution (normal saline [NS]) and lactated Ringer (LR) solution are isotonic crystalloid fluids, the standard intravenous (IV) fluids used for initial volume resuscitation. These solutions expand the intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays in the intravascular space; therefore, large quantities may be required to maintain adequate circulating volume.

NS and LR solution are isotonic and have equivalent volume-restoring properties. Although some differences exist in the metabolic changes observed with the administration of large quantities of the 2 fluids, for practical purposes and in most situations, the differences are clinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation with NS and resuscitation with LR solution.

Albumin (Buminate, Albuminar)

Clinical Context:  Albumin is given for certain types of shock or impending shock. It is useful for plasma volume expansion and maintenance of cardiac output. A solution of NS and 5% albumin is available for volume resuscitation. The 5% solutions are indicated for expanding plasma volume, whereas the 25% solutions are indicated for raising oncotic pressure.

Class Summary

Colloids are used to provide oncotic expansion of plasma volume. They expand plasma volume to a greater degree than isotonic crystalloids and reduce the tendency toward pulmonary and cerebral edema. About 50% of the administered colloid stays intravascular.

Cefotaxime (Claforan)

Clinical Context:  Cefotaxime is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Cefotaxime is used to treat against an increasing prevalence of penicillinase-producing microorganisms. This agent inhibits bacterial cell-wall synthesis by binding to 1 or more penicillin-binding proteins. Cell-wall autolytic enzymes lyse bacteria, and cell-wall assembly is arrested.

Ticarcillin-clavulanate (Timentin)

Clinical Context:  Ticarcillin-clavulanate consists of an antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positive organisms (except for variable coverage against Staphylococcus epidermidis and no coverage against methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative organisms, and anaerobes.

Piperacillin-tazobactam (Zosyn)

Clinical Context:  Piperacillin-tazobactam inhibits the biosynthesis of cell-wall mucopeptide and is effective during the stage of active multiplication. It has antipseudomonal activity.

Imipenem-cilastatin (Primaxin)

Clinical Context:  Imipenem-cilastatin is a carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. It is used for treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of their potential for toxicity.

Meropenem (Merrem)

Clinical Context:  Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci relative to imipenem. Compared with imipenem, it is less likely to cause seizures and better able to penetrate the blood-brain barrier.

Clindamycin (Cleocin)

Clinical Context:  Clindamycin is primarily used for its activity against anaerobes. It has some activity against Streptococcus species and methicillin-sensitive S aureus (MSSA).

Metronidazole (Flagyl)

Clinical Context:  Metronidazole is an imidazole ring-based antibiotic that is active against various anaerobic bacteria and protozoa. It is usually combined with other antimicrobial agents, except when used for Clostridium difficile enterocolitis, in which monotherapy is appropriate.

Ceftriaxone (Rocephin)

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell-wall synthesis by binding to 1 or more penicillin-binding proteins. Cell-wall autolytic enzymes lyse bacteria, and cell-wall assembly is arrested.

Ciprofloxacin (Cipro)

Clinical Context:  Ciprofloxacin is a fluoroquinolone with variable activity against Streptococcus species, activity against methicillin-sensitive S aureus and Staphylococcus epidermidis, activity against most gram-negative organisms, and no activity against anaerobes. It is a synthetic broad-spectrum antibacterial compounds with a novel mechanism of action, targeting bacterial topoisomerase II and IV, thus leading to a sudden cessation of DNA replication. Oral bioavailability is near 100%.

Cefepime (Maxipime)

Clinical Context:  Cefepime is a fourth-generation cephalosporin. It has gram-negative coverage comparable to that of ceftazidime but has better gram-positive coverage (comparable to that of ceftriaxone). Cefepime is active against Pseudomonas species. It has increased effectiveness against extended-spectrum beta lactamase (ESBL)-producing organisms. Its poor capacity to cross the blood-brain barrier precludes its use for treatment of meningitis.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin is a fluoroquinolone with excellent gram-positive and gram-negative coverage. It is an excellent agent for pneumonia and has excellent abdominal coverage as well. Its high urine concentration necessitates reduced dosing in urinary tract infection.

Vancomycin

Clinical Context:  Vancomycin provides gram-positive coverage and good hospital-acquired MRSA coverage. It is being used increasingly often because of the high incidence of MRSA. Vancomycin should be given to all septic patients with indwelling catheters or devices. It is advisable for skin and soft-tissue infections.

Class Summary

Early empiric antibiotic therapy is the only other proven medical treatment in septic shock. Use of broad-spectrum or multiple antibiotics provides the necessary wide coverage. In children who are immunocompetent, monotherapy with a third-generation cephalosporin (eg, cefotaxime, ceftriaxone, or ceftazidime) is possible. In immunocompetent adults, an antipseudomonal penicillin or carbapenem is used as monotherapy.

Penicillinase-resistant synthetic penicillins and a third-generation cephalosporin are used for combination therapy in children. Combination therapy in adults involves a third-generation cephalosporin plus anaerobic coverage (ie, clindamycin or metronidazole) or a fluoroquinolone plus clindamycin. All antibiotics should initially be administered IV.

Hydrocortisone (A-Hydrocort, Solu-Cortef)

Clinical Context:  Endogenous cortisol is a stress hormone that acts in part to maintain vascular tone in states of shock. Some evidence suggests that exogenous hydrocortisone administration may increase mean arterial pressure and improve outcomes in patients with septic shock who have persistent hypotension despite adequate crystalloid resuscitation and vasopressor support.

Dexamethasone

Clinical Context:  Dexamethasone has many pharmacologic benefits, but it also has significant adverse effects. This agent stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-2, and interferon gamma). The inhibition of chemotactic factors and factors that increase capillary permeability hinders recruitment of inflammatory cells into affected areas.

Dexamethasone suppresses lymphocyte proliferation through direct cytolysis, and it inhibits mitosis. It breaks down granulocyte aggregates and improves pulmonary microcirculation. Adverse effects include hyperglycemia, hypertension, weight loss, gastrointestinal (GI) bleeding or perforation, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose- or duration-dependent.

Dexamethasone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. It lacks the salt-retaining property of hydrocortisone. Patients can be switched from an IV to PO regimen in a 1:1 ratio.

Class Summary

Corticosteroids are powerful anti-inflammatory agents. They may maintain vascular tone in states of shock. These agents are most likely to be beneficial if therapy is initiated within 8 hours of the onset of severe septic shock.

Author

Andre Kalil, MD, MPH, Professor of Medicine, Department of Medicine, Section of Infectious Diseases; Director, Transplant ID Program, University of Nebraska Medical Center

Disclosure: Spectral Diagnostics Grant/research funds None; Asahi Kasei Grant/research funds Other

Coauthor(s)

Kristina L Bailey, MD, Assistant Professor, Department of Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr hc, FCCP, MCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting

Additional Contributors

Fatima Al Faresi, MD Dermatologist, Tawam Hospital, Al Ain, UAE

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy ofSciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Ismail Cinel, MD, PhD Visiting Associate Professor, Division of Critical Care Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey

Disclosure: Nothing to disclose.

Clara-Dina Cokonis, MD Staff Physician, Department of Medicine, Division of Dermatology, Cooper Hospital University Medical Center

Disclosure: Nothing to disclose.

R Phillip Dellinger, MD Professor of Medicine, Program Director, Critical Care Medicine Fellowship Program, Robert Wood Johnson School of Medicine, University of Medicine and Dentistry of New Jersey; Head, Division of Critical Care Medicine, Medical Director, Medical/Surgical/Cardiovascular Surgical Intensive Care Unit, Cooper University Hospital

Disclosure: Wyeth Consulting fee Consulting; BRAHMS Grant/research funds Other Clinical Trial; Artisan Grant/research funds Other Clinical Trial; Agenix Grant/research funds Other Clinical Trial

Daniel J Dire, MD, FACEP, FAAP, FAAEM Clinical Professor, Department of Emergency Medicine, University of Texas Medical School at Houston; Clinical Professor, Department of Pediatrics, University of Texas Health Sciences Center San Antonio

Daniel J Dire, MD, FACEP, FAAP, FAAEM is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American Academy of Pediatrics, American College of Emergency Physicians, and Association of Military Surgeons of the US

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Michael R Filbin, MD Clinical Instructor, Department of Emergency Medicine, Massachusetts General Hospital

Michael R Filbin, MD is a member of the following medical societies: American College of Emergency Physicians, Massachusetts Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Franklin Flowers, MD Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, Affiliate Associate Professor of Pediatrics and Pathology, University of Florida College of Medicine

Franklin Flowers, MD, is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology

Disclosure: Nothing to disclose.

Cory Franklin, MD Professor, Department of Medicine, Rosalind Franklin University of Medicine and Science; Director, Division of Critical Care Medicine, Cook County Hospital

Cory Franklin, MD is a member of the following medical societies: New York Academy of Sciences and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, Weill Cornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program, Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Department of Emergency Medicine, St George's University School of Medicine

Theodore J Gaeta, DO, MPH, FACEP is a member of the following medical societies: Alliance for Clinical Education, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council of Emergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Hassan I Galadari, MD Assistant Professor of Dermatology, Faculty of Medicine and Health Sciences, United Arab Emirates University

Hassan I Galadari, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, and American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

Paul Krusinski, MD Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Steven M Manders, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania; Associate Professor, Department of Internal Medicine, Division of Dermatology, University of Medicine and Dentistry of New Jersey

Disclosure: Nothing to disclose.

Steven Mink, MD Head, Section of Pulmonary Medicine, Department of Internal Medicine, St Boniface Hospital; Professor of Medicine, University of Manitoba, Canada

Steven Mink, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Mark L Plaster, MD, JD Executive Editor, Emergency Physicians Monthly

Mark L Plaster, MD, JD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: M L Plaster Publishing Co LLC Ownership interest Management position

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Vicken Y Totten, MD, MS, FACEP, FAAFP Assistant Professor, Case Western Reserve University School of Medicine; Director of Research, Department of Emergency Medicine, University Hospitals, Case Medical Center

Vicken Y Totten, MD, MS, FACEP, FAAFP is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Eric L Weiss, MD, DTM&H Medical Director, Office of Service Continuity and Disaster Planning, Fellowship Director, Stanford University Medical Center Disaster Medicine Fellowship, Chairman, SUMC and LPCH Bioterrorism and Emergency Preparedness Task Force, Clinical Associate Progressor, Department of Surgery (Emergency Medicine), Stanford University Medical Center

Eric L Weiss, MD, DTM&H is a member of the following medical societies: American College of Emergency Physicians, American College of Occupational and Environmental Medicine, American Medical Association, American Society of Tropical Medicine and Hygiene, Physicians for Social Responsibility, Southeastern Surgical Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

References

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A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). Computed tomography (CT) scanning helped to evaluate the extent of the infection and to exclude other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).

Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.

Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This photomicrograph shows early stage (exudative stage) DAD.

Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of early stage (exudative stage) DAD.

Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has occurred; hyaline membranes as well as collagen and fibroblasts are present.

Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, which may develop into fibrotic stage of DAD.

An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.

Gram stain of blood showing the presence of Neisseria meningitidis.

A 28-year-old woman who was a former intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to bilateral pneumococcal pneumonia.

A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the presence of Neisseria meningitidis. The skin manifestation seen in this image is characteristic of severe meningococcal infection and is called purpura fulminans.

Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.

Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.

A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.

Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the presence of Neisseria meningitidis. The skin manifestation seen in this image is characteristic of severe meningococcal infection and is called purpura fulminans.

Gram stain of blood showing the presence of Neisseria meningitidis.

Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This photomicrograph shows early stage (exudative stage) DAD.

Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of early stage (exudative stage) DAD.

Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has occurred; hyaline membranes as well as collagen and fibroblasts are present.

Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, which may develop into fibrotic stage of DAD.

Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.

Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.

A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.

An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.

A 28-year-old woman who was a former intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to bilateral pneumococcal pneumonia.

Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.

Soft-tissue infection secondary to group A streptococci, leading to toxic shock syndrome.

Necrotizing cellulitis of toxic shock syndrome.

Necrosis of the little toe of the right foot and cellulitis of the foot secondary to group A streptococcal infection.

Group A streptococci cause beta hemolysis on blood agar.

Gram stain of blood showing group A streptococci that was isolated from a patient who developed toxic shock syndrome. Image courtesy of T. Matthews.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The leg was incised to exclude underlying necrotizing infection. Image courtesy of Rob Green, MD.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). This patient also had streptococcal pharyngitis. Image courtesy of Rob Green, MD.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. Image courtesy of Rob Green, MD.

A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. He improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over his palms and soles. Image courtesy of Rob Green, MD.

Progression of soft-tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Image courtesy of S. Manocha.

Necrotizing fasciitis of the foot. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Extensive debridement of necrotizing fasciitis of the hand.

Healing of the hand after aggressive surgical debridement of necrotizing fasciitis (same patient as in previous image).

A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). Computed tomography (CT) scanning helped to evaluate the extent of the infection and to exclude other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).

Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).

Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).

Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema.

Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema (same lesion as shown in previous computed tomography image).

Organ System Sepsis Criteria Severe Sepsis Criteria
PulmonaryArterial hypoxemia: PaO2/FIO2 < 300Arterial hypoxemia: PaO2/FIO2 < 250 in absence of pneumonia and < 200 in presence of pneumonia
HepaticHyperbilirubinemia: Plasma total bilirubin >4 mg/dL or 70 µmol/LHyperbilirubinemia: Plasma total bilirubin >2 mg/dL or 34.2 µmol/L
RenalCreatinine increase >0.5 mg/dL or 44.2 µmol/L

Acute oliguria: Urine output < 0.5 mL/kg/hr for ≥2 hr despite adequate fluid resuscitation

Creatinine >2 mg/dL or 176.8 µmol/L

Acute oliguria: Urine output < 0.5mL/kg/hr for ≥2 hr despite adequate fluid resuscitation

GastrointestinalIleus: Absent bowel sounds
HematologicINR >1.5, aPTT >60 s, or platelets < 100,000/µLINR >1.5 or platelets < 100,000/µL
CardiovascularHyperlactatemia >1 mmol/L; decreased capillary refill or mottling

Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg

Hyperlactatemia: Above upper limits of laboratory normal

Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg

Central nervous systemConfusion, lethargy, coma
aPTT = activated partial thromboplastin time; FIO2 = fraction of inspired oxygen; INR = international normalized ratio; MAP = mean arterial pressure; PaO2 = partial pressure of oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time; SBP = systolic blood pressure.

Source: Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.[14]

Type Mediator Activity
Cellular mediatorsLPSActivation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators
Lipoteichoic acid
Peptidoglycan
Superantigens
Endotoxin
Humoral mediatorsCytokinesActivate inflammatory pathways
  • TNF-α and IL-1β
Potent proinflammatory effect
  • IL-6
Acts as pyrogen, stimulates B- and T-cell proliferation
  • IL-8
Neutrophil chemotactic factor, activation and degranulation of neutrophils
  • IL-10
Inhibits cytokine production, induces immunosuppression
  • MIF
Activates macrophages and T cells
  • G-CSF
Promotes neutrophil and macrophage, platelet activation
ComplementPromotes neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects
Nitric oxideInvolved in hemodynamic alterations of septic shock; cytotoxic, augments vascular permeability, contributes to shock
Lipid mediatorsEnhance vascular permeability and contribute to lung injury
  • Phospholipase A2
  • PAF
  • Eicosanoids
Arachidonic acid metabolitesAugment vascular permeability
Adhesion moleculesEnhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis; increased levels of VAP-1 activity and anchor protein SDC-1 content have been found in critically ill patients with septic shock[15]
  • Selectins
  • Leukocyte integrins
  • High mobility box–1
Late mediator of endotoxin-induced lethality and tissue repair
G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPS = lipopolysaccharide; MIF = macrophage inhibitory factor; PAF = platelet-activating factor; SDC-1 = syndecan-1; TNF = tumor necrosis factor; VAP-1 = vascular adhesion protein–1.

Source: Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304.[16]