Septic shock e-Medicine Article

Author: Michael R Pinsky, MD, CM, FCCP, FCCM; Chief Editor: Michael R Pinsky, MD, CM, FCCP, FCCM more...

Updated: Aug 25, 2011

Background

In 1914, Schottmueller wrote, “Septicemia is a state of microbial invasion from a portal of entry into the blood streamwhich causes sign of illness.” The definition did not change much over the years, because the terms sepsis andsepticemia referred to several ill-defined clinical conditions present in a patient with bacteremia. In practice, the termsoften were used interchangeably; however, fewer than half the patients with signs and symptoms of sepsis havepositive results on blood culture.

Furthermore, not all patients with bacteremia have signs of sepsis; therefore, sepsis and septicemia are not identical.In the past few decades, the discovery of endogenous mediators of the host response has led to the recognition thatthe clinical syndrome of sepsis is the result of excessive activation of host defense mechanisms rather than the directeffect of microorganisms. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity.

Serious bacterial infections at any body site, with or without bacteremia, are usually associated with important changesin the function of every organ system in the body. These changes are mediated mostly by elements of the hostimmune system against infection. Shock is deemed present when volume replacement fails to increase bloodpressure to acceptable levels and associated clinical evidence indicates inadequate perfusion of major organsystems, with progressive failure of organ system functions.

Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of physiologic derangementsin individual organs (ie, processes rather than events). Alteration in organ function can vary widely from a mild degreeof organ dysfunction to frank organ failure.

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, andvasopressor therapy. See Neonatal Sepsis for complete information on this topic.

Classification of shock

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

Hypovolemic shockObstructive shockDistributive shockCardiogenic shock

These classes of shock should be considered and systemically differentiated before establishing a definitivediagnosis of septic shock.

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. The patient demonstrates tachycardia, cool clammyextremities, hypotension, dry skin and mucus membranes, and poor turgor.

Obstructive shock results from impedance of circulation by an intrinsic or extrinsic obstruction. Pulmonary embolismand pericardial tamponade both result in obstructive shock.

Distributive shock is caused by such conditions as direct arteriovenous shunting and is characterized by decreasedresistance or increased venous capacity from the vasomotor dysfunction. These patients have high cardiac output,

Septic Shock http://emedicine.medscape.com/article/168402-overview

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hypotension, large pulse pressure, a low diastolic pressure, and warm extremities with a good capillary refill. Thesefindings on physical examination strongly suggest a working diagnosis of septic shock.

Cardiogenic shock is characterized by primary myocardial dysfunction, resulting in the inability of the heart to maintainadequate cardiac output. These patients demonstrate clinical signs of low cardiac output, while evidence exists ofadequate intravascular volume. The patients have cool clammy extremities, poor capillary refill, tachycardia, narrowpulse pressure, and a low urine output.

Definitions of key terms

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

Clinicians often use the terms sepsis, severe sepsis, and septic shock without a commonly understood definition. In1991, 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.[1, 2]

Systemic inflammatory response syndrome (SIRS) is a term that was developed in an attempt to describe the clinicalmanifestations that result from the systemic response to infection. Criteria for SIRS are considered to be met if atleast 2 of the following 4 clinical findings are present:

Temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F)Heart rate (HR) greater than 90 beats per minute (bpm)Respiratory rate (RR) greater than 20 breaths per minute or arterial carbon dioxide tension (PaCO2) lower than32 mm HgWhite blood cell (WBC) count higher than 12,000/µL or lower than 4000/µL, or 10% immature (band) forms

Of course, a patient can have either severe sepsis or septic shock without meeting SIRS criteria, and conversely,SIRS criteria may be present in the setting of many other illnesses (see the image below).

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

In 2001, as a follow-up to the original ACCP/SCCM conference, an International Sepsis Definitions Conference wasconvened, with representation not only from the ACCP and the SCCM but also from the European Society of IntensiveCare Medicine (ESICM), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The followingdefinitions of sepsis syndromes were published in order to clarify the terminology used to describe the spectrum of

disease that results from severe infection.[3]

Sepsis is defined as the presence of infection in association with SIRS. The presence of SIRS is, of course, notlimited to sepsis, but in the presence of infection, an increase in the number of SIRS criteria observed should alert theclinician to the possibility of endothelial dysfunction, developing organ dysfunction, and the need for aggressivetherapy. Certain biomarkers have been associated with the endothelial dysfunction of sepsis; however, the use ofsepsis-specific biomarkers has not yet translated to establishing a clinical diagnosis of sepsis in the emergencydepartment (ED).

With sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion is typically included:

Alteration in mental stateHypoxemia (arterial oxygen tension [PaO2] < 72 mm Hg at fraction of inspired oxygen [FiO2] 0.21; overtpulmonary disease not the direct cause of hypoxemia)


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Elevated plasma lactate levelOliguria (urine output < 30 mL or 0.5 mL/kg for at least 1 h)

Severe sepsis is defined as sepsis complicated by end-organ dysfunction, as signaled by altered mental status, anepisode 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 despiteadequate fluid resuscitation or by tissue hypoperfusion (manifested by a lactate concentration greater than 4 mg/dL)unexplained by other causes. Patients receiving inotropic or vasopressor agents may not be hypotensive by the timethat they manifest hypoperfusion abnormalities or organ dysfunction.

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 ofinfection). Although sepsis is commonly associated with bacterial infection, bacteremia is not a necessary ingredient inthe 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, 7]

Multiple organ dysfunction syndrome (MODS) is defined as the presence of altered organ function in a patient who isacutely ill and in whom homeostasis cannot be maintained without intervention.

The American-European Consensus Conference on ARDS agreed upon the following definitions of acute lung injury

(ALI) and acute respiratory distress syndrome (ARDS).[8] The criteria for ALI include the following:

An oxygenation abnormality with a PaO2/FiO2 ratio less than 300Bilateral opacities on chest radiograph compatible with pulmonary edemaPulmonary artery occlusion pressure less than 18 mm Hg or no clinical evidence of left atrial hypertension ifPaO2 is not available

ARDS is a more severe form of ALI and is defined similarly, except that the PaO2/FiO2 ratio is 200 or less.

See the following articles for more information:

Pediatric SepsisBacterial SepsisToxic Shock SyndromePediatric Toxic Shock Syndrome

Pathophysiology

The pathophysiology of septic shock is not precisely understood, but it involves a complex interaction between thepathogen and the host’s immune system. The normal physiologic response to localized infection includes theactivation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, the release ofinflammatory mediators, local vasodilation, increased endothelial permeability, and activation of coagulation pathways.

These mechanisms are in play 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 furtheractivate inflammatory and coagulation cascades, creating in effect a positive feedback loop, and leading to furtherendothelial and end-organ damage.

Mediator-induced cellular injury

The evidence that sepsis results from an exaggerated systemic inflammatory response induced by infectingorganisms is compelling; inflammatory mediators are the key players in the pathogenesis (see the table below).

Table 1. Mediators of Sepsis (Open Table in a new window)

Type Mediator Activity

Cellularmediators

Lipopolysaccharide Activation of macrophages, neutrophils, platelets, and endothelium releasesvarious cytokines and other mediatorsLipoteichoic acid


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Peptidoglycan

Superantigens

Endotoxin

Humoralmediators

Cytokines Potent proinflammatory effect

Neutrophil chemotactic factor

Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibitscytokine production, induces immunosuppression

Activation and degranulation of neutrophils

Cytotoxic, augments vascular permeability, contributes to shock

Involved in hemodynamic alterations of septic shock

Promote neutrophil and macrophage, platelet activation and chemotaxis,other proinflammatory effects

Enhance vascular permeability and contributes to lung injury

Enhance neutrophil-endothelial cell interaction, regulate leukocyte migrationand adhesion, and play a role in pathogenesis of sepsis

TNF-alpha and IL-1β

IL-8

IL-6

IL-10

MIF

G-CSF

Complement

Nitric oxide

Lipid mediators

Phospholipase A2

PAF

Eicosanoids

Arachidonic acidmetabolites

Adhesion molecules

Selectins

Leukocyte integrins


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G-CSF = Granulocyte colony-stimulating factor; IL = interleukin; MIF = macrophage inhibitory factor; PAF = platelet-activating factor; TNF = tumor necrosis factor.

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

Circulating levels of IL-6 correlate well with outcome. High levels of IL-6 are associated with mortality, but its role inpathogenesis is not clear. IL-8 is an important regulator of neutrophil function, synthesized and released in significantamounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs.

The chemokines (monocyte chemoattractant protein–1) orchestrate the migration of leukocytes during endotoxemiaand sepsis. The other cytokines that have a supposed role in sepsis are IL-10, interferon gamma, IL-12, macrophagemigration inhibition factor, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF).

In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.[9, 10,

11] (See Abnormalities of coagulation and fibrinolysis.)

Gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators, including the cytokines justmentioned, which play a pivotal role in initiating sepsis and shock. Various bacterial cell wall components are known torelease the cytokines, including lipopolysaccharide (gram-negative bacteria), peptidoglycan (gram-positive andgram-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 thegram-negative bacteria is the lipid A moiety of lipopolysaccharide. The gram-positive bacteria cell wall leads tocytokine induction via lipoteichoic acid.

Additionally, gram-positive bacteria may secrete the superantigen cytotoxins that bind directly to the majorhistocompatibility 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 probablyalso 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 thehemodynamic alterations of septic shock, which is a hyperdynamic form of shock.

A dual role exists for neutrophils; they are necessary for defense against microorganisms but also may become toxicinflammatory mediators contributing to tissue damage and organ dysfunction.

The 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.

Abnormalities of coagulation and fibrinolysis

An imbalance of homeostatic mechanisms leads to disseminated intravascular coagulopathy (DIC) and microvascular

thrombosis, causing organ dysfunction and death.[12] Inflammatory mediators instigate direct injury to the vascularendothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade andaccelerating production of thrombin. Plasma levels of endothelial activation biomarkers are higher in patients whose

hypotension is the result of sepsis than in patients with hypotension of other causes.[13]

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


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Inflammatory cytokines, such as IL-1α, IL-1β, and TNF-alpha, initiate coagulation by activating TF. TF interacts withfactor VIIa to form factor VIIa-TF complex, which activates factors X and IX. Activation of coagulation in sepsis hasbeen confirmed by marked increases in thrombin-antithrombin complex and the presence of D-dimer in plasma,

indicating activation of the clotting system and fibrinolysis.[14, 15] Tissue plasminogen activator (t-PA) facilitatesconversion of plasminogen to plasmin, a natural fibrinolytic.

Endotoxins increase the activity of inhibitors of fibrinolysis—namely, plasminogen activator inhibitor (PAI-1) andthrombin activatable fibrinolysis inhibitor (TAFI).

The levels of protein C and endogenous activated protein C (APC) are also decreased in sepsis. Endogenous APC isan important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin, via thrombomodulin, activates proteinC, which then functions as an antithrombotic in the microvasculature. Endogenous APC also enhances fibrinolysis byneutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy andmicrovascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death. Theinsidious nature of sepsis is such that microcirculatory dysfunction can occur while global hemodynamic parameters

such as blood pressure may remain normal.[16]

Circulatory abnormalities

As noted (see Background), septic shock falls under the category of distributive shock, which is characterized bypathologic vasodilation and shunting of blood from vital organ to nonvital tissues such as skin, skeletal muscle, andadipose. The endothelial dysfunction and vascular maldistribution characteristic of distributive shock result in globaltissue hypoxia or inadequate delivery of oxygen to vital tissues. In addition, mitochondria can become dysfunctional,thus compromising oxygen utilization at the tissue level.

The predominant hemodynamic feature of septic shock is arterial vasodilation. The mechanisms implicated in thispathologic vasodilation are multifactorial, but the primary factors are thought to be (1) activation of adenosinetriphosphate (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.[17] The resulting vasodilation can be refractory to endogenous vasoactive hormones (eg, norepinephrineand epinephrine) that are released during shock.

Diminished peripheral arterial vascular tone may result in dependency of blood pressure on cardiac output, causingvasodilation to result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septicshock, the rise in cardiac output often is limited by hypovolemia and a fall in preload because of low cardiac fillingpressures. When intravascular volume is augmented, the cardiac output usually is elevated (the hyperdynamic phaseof sepsis and shock).

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

Although an elevation of cardiac output occurs, the arterial-mixed venous oxygen difference usually is narrow, and theblood lactate level is elevated. This implies that low global tissue oxygen extraction is the mechanism that may limittotal body oxygen uptake in septic shock. The basic pathophysiologic problem seems to be a disparity between theuptake 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 capacityto extract oxygen locally. During a fall in oxygen supply, cardiac output becomes distributed so that most vital organs,such as the heart and brain, remain relatively better perfused than nonvital organs are. However, sepsis leads toregional changes in oxygen demand and regional alteration in blood flow of various organs.

The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activityof central mechanisms (eg, the autonomic nervous system). The regional regulation and the release of vasodilatingsubstances (eg, NO, prostacyclin) and vasoconstricting substances (eg, endothelin) affect regional blood flow.

Increased systemic microvascular permeability also develops, remote from the infectious focus, and contributes toedema of various organs, particularly the lung microcirculation, and to the development of ARDS.


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

In patients with sepsis who have low oxygen extraction and elevated arterial blood lactate levels, oxygen uptakedepends on oxygen supply over a much wider range than normal. Therefore, oxygen extraction may be too low fortissue needs at a given oxygen supply, and oxygen uptake may increase with a boost in oxygen supply—aphenomenon termed oxygen uptake supply dependence or pathologic supply dependence. However, this concept iscontroversial, because other investigators argue that supply dependence is artifactual rather than a real phenomenon.

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

Mechanisms of organ dysfunction

Sepsis is described as an autodestructive process that permits the extension of the normal pathophysiologicresponse to infection (involving otherwise normal tissues), resulting in multiple organ dysfunction syndrome. Organdysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to theconsequences 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 because of the following proposedmechanisms:

Hypoxic hypoxia - The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation oftissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalitiescontribute to the septic microcirculatory defect in sepsis. Reactive oxygen species, lytic enzymes, vasoactivesubstances (eg, NO), and endothelial growth factors lead to microcirculatory injury, which is compounded by theinability of the erythrocytes to navigate the septic microcirculation.Direct cytotoxicity - Endotoxin, TNF-alpha, and NO may cause damage to mitochondrial electron transport,leading to disordered energy metabolism. This is called cytopathic or histotoxic anoxia—that is, an inability touse oxygen even when it is present.Apoptosis (programmed cell death) - This is the principal mechanism by which dysfunctional cells normally areeliminated. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, butother tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement ofapoptosis plays a critical role in tissue injury in patients with sepsis.Immunosuppression - The interaction between proinflammatory and anti-inflammatory mediators may lead to animbalance and an inflammatory reaction, or immunodeficiency may predominate, or both may occur.Coagulopathy - Subclinical coagulopathy signified by mild elevation of the thrombin time or activated partialthromboplastin time or by a moderate reduction in platelet count is extremely common, but overt DIC is rare.Coagulopathy is caused by deficiencies of coagulation system proteins, including protein C, antithrombin III,and TF inhibitors.

Cardiovascular dysfunction

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

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

Sepsis interferes with the normal distribution of systemic blood flow to organ systems; therefore, core organs may notreceive appropriate oxygen delivery.

The microcirculation is the key target organ for injury in patients with sepsis syndrome. A decrease in the number offunctional capillaries leads to an inability to extract oxygen maximally; this inability is caused by intrinsic and extrinsiccompression of capillaries and plugging of the capillary lumen by blood cells. Increased endothelial permeability leadsto widespread tissue edema involving protein-rich fluid.

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


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Pulmonary dysfunction

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

Injury to type II pneumocytes decreases surfactant production; furthermore, the plasma proteins in alveolar fluidinactivate 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 capillarymembrane. ARDS is a frequent manifestation of these effects. As many as 40% of patients with severe sepsisdevelop ALI.

ALI is a type of pulmonary dysfunction secondary to parenchymal cellular damage that is characterized by endothelialcell injury and destruction, deposition of platelet and leukocyte aggregates, destruction of type I alveolar pneumocytes,an acute inflammatory response through all the phases of injury, and repair and hyperplasia of type II pneumocytes.Migration of macrophages and neutrophils into the interstitium and alveoli produces many different mediators, whichcontribute 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 ALIprogresses to ARDS. Continued infiltration occurs with neutrophils and mononuclear cells, lymphocytes, andfibroblasts. An alveolar inflammatory exudate persists, and type II pneumocyte proliferation is evident. If this processcan be halted, complete resolution may occur. In other patients, a progressive respiratory failure and pulmonaryfibrosis develop.

The central pathologic finding in ARDS is severe injury to the alveolocapillary unit. Following initial extravasation ofintravascular fluid, inflammation and fibrosis of pulmonary parenchyma develops into a morphologic picture, termeddiffuse alveolar damage (DAD). The clinical and pathological evolution can be categorized into the following 3overlapping phases (Katzenstein, 1986): (1) the exudative phase of edema and hemorrhage, (2) the proliferativephase of organization and repair, and (3) the fibrotic phase of end stage fibrosis.

The exudative phase occurs in the first week and is dominated by alveolar edema and hemorrhage. The otherhistological 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 plateletfibrin thrombi.

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

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


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The proliferative phase is prominent in the second and third week following onset of ARDS but may begin as early asthe third day. 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, whichconvert the exudate to cellular granulation tissue, occurs; excessive collagen deposition, transforming into fibroustissue, occurs.

This photomicrograph shows a delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type IIpneumocytes has occurred, hyaline membranes are present, and collagen and fibroblasts are present.

This photomicrograph shows a delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). This is fibrin stainshowing collagenous tissue, which may develop into the fibrotic stage of DAD.

The fibrotic phase occurs by the third or fourth week of the onset, though the process may begin in the first week. Thecollagenous fibrosis completely remodels the lung, the air spaces are irregularly enlarged, and alveolar duct fibrosis isapparent. Lung collagen deposition increases, microcystic honeycomb formation, and traction bronchiectasis follows.

Gastrointestinal dysfunction

The GI tract may help to propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may aspirate intothe lungs and produce nosocomial pneumonia. The gut’s normal barrier function may be affected, thereby allowingtranslocation 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. Theoptimal level of nutritional intake is interfered with in the face of high protein and energy requirements.

Glutamine is necessary for normal enterocyte functioning. Its absence in commercial total parenteral nutrition (TPN)formulations leads to a breakdown of the intestinal barrier and to translocation of the gut flora into the circulation. Thismay be one of the factors that drives sepsis. In addition to inadequate glutamine levels, this may lessen the immune

response by decreasing leukocyte and natural killer cell counts, as well as total B-cell and T-cell counts.[18]

Hepatic dysfunction

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

Renal dysfunction

Acute renal failure (ARF) caused by acute tubular necrosis often accompanies sepsis. The mechanism involvessystemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activation of neutrophils byendotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction


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Central nervous system (CNS) involvement in sepsis produces encephalopathy and peripheral neuropathy. Thepathogenesis is poorly defined.

Etiology

Most patients who develop sepsis and septic shock have underlying circumstances that interfere with the local orsystemic host defense mechanisms. Sepsis is seen most frequently in elderly persons and in those with comorbidconditions that predispose to infection, such as diabetes or any immunocompromising disease.

The most common disease states predisposing to sepsis are malignancies, diabetes mellitus, chronic liver disease,chronic renal failure, and the use of immunosuppressive agents. In addition, sepsis also is a common complicationafter 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, with the exception of patients who areimmunocompromised with neutropenia, where an obvious source often is not found. Multiple sites of infection mayoccur in 6-15% of patients.

Causative microorganisms

Before the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causingsepsis. More recently, gram-negative bacteria have become the key pathogens causing severe sepsis and septicshock.

Anaerobic pathogens are becoming less important as a cause of sepsis. In one institution, the incidence of anaerobicbacteremia declined by 45% over a 15-year period. Fungal infections are the cause of sepsis in 0.8-10.2% of patientswith sepsis, and their incidence appears to be increasing (see the image below).

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

Respiratory tract infection and urinary tract infection are the most frequent causes of sepsis, followed by abdominaland soft tissue infections. Each organ system tends to be infected by a particular set of pathogens (see below).

Lower respiratory tract infections are the cause of septic shock in 25% of patients, and the following are the commonpathogens:

Streptococcus pneumoniaeKlebsiella pneumoniaeStaphylococcus aureusEscherichia coliLegionella speciesHaemophilus speciesAnaerobesGram-negative bacteriaFungi

Urinary tract infections are the cause of septic shock in 25% of patients, and the following are the common pathogens:

E coliProteus speciesKlebsiella species


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Pseudomonas speciesEnterobacter speciesSerratia species

Soft tissue infections are the cause of septic shock in 15% of patients, and the following are the common pathogens:

S aureusStaphylococcus epidermidisStreptococciClostridiaGram-negative bacteriaAnaerobes

GI tract infections are the cause of septic shock in 15% all patients, and the following are the common pathogens:

E coliStreptococcus faecalisBacteroides fragilisAcinetobacter speciesPseudomonas speciesEnterobacter speciesSalmonella species

Infections of the male and female reproductive systems are the cause of septic shock in 10% of patients, and thefollowing are the common pathogens:

Neisseria gonorrhoeaeGram-negative bacteriaStreptococciAnaerobes

Foreign bodies leading to infections are the cause of septic shock in 5% of patients, and S aureus, S epidermidis,and fungi/yeasts (eg, Candida species) are the common pathogens.

Miscellaneous infections are the cause of septic shock in 5% of patients, and Neisseria meningitidis is the mostcommon cause of such infections (see the image below).

Gram stain of blood showing presence of Neisseria meningitidis.

Risk factors

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

Extremes of age ( < 10 y and >70 y)Primary diseases (eg, liver cirrhosis, alcoholism, diabetes mellitus, cardiopulmonary diseases, solidmalignancy, hematologic malignancy)Immunosuppression (eg, neutropenia, immunosuppressive therapy, corticosteroid therapy, IV drug abuse [seethe image below], complement deficiencies, asplenia)Major surgery, trauma, burnsInvasive procedures (eg, catheters, intravascular devices, prosthetic devices, hemodialysis and peritonealdialysis catheters, endotracheal tubes)Previous antibiotic treatmentProlonged hospitalizationOther factors, such as childbirth, abortion, and malnutrition


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A 28-year-old woman who is a previous intravenous drug user (HIV-negative status) developed septic shock secondary tobilateral pneumococcal pneumonia.

Epidemiology

United States statistics

Since the 1930s, studies have shown an increasing incidence of sepsis. In the United States, 200,000 cases of septicshock and 100,000 deaths per year occur from this disease.

In 1 study, the incidence of bacteremic sepsis (both gram-positive and gram-negative) increased from 3.8 cases per1000 admissions in 1970 to 8.7 per 1000 in 1987. Between 1980 and 1992, the incidence of nosocomial bloodstream infection in 1 institution increased from 6.7 cases per 1000 discharges to 18.4 per 1000. The increase in thenumber of patients who are immunocompromised and an increasing use of invasive diagnostic and therapeuticdevices predisposing to infection are major reasons for the increase in incidences of sepsis.

A 2001 article reported the incidence, cost, and outcome of severe sepsis in the United States.[19] Analysis of a largesample from the major centers reported the incidence of severe sepsis as 3 cases per 1000 population and 2.26cases per 100 hospital discharges. Out of these cases, 51.1% were admitted to an intensive care unit (ICU), and anadditional 17.3% were cared for in an intermediate care or coronary care unit.

Incidence ranged from 0.2 cases per 1000 admissions in children to 26.2 per 1000 in individuals older than 85 years.The mortality rate was 28.6% and ranged from 10% in children to 38.4% in elderly people. Severe sepsis resulted in

an average cost of $2200 per case, with an annual total cost of $16.7 billion nationally.[19]

The National Center for Health Statistics published a large retrospective analysis using the National Hospital DischargeSurvey of 500 nonfederal US hospitals, which included more than 10 million cases of sepsis over a 22-year period.Septicemia accounted for 1.3% of all hospitalizations, and 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.[20]

The reasons for this growing incidence likely include an increasingly elderly population, increased recognition ofdisease, increased performance of invasive procedures and organ transplantation, increased use ofimmunosuppressive agents and chemotherapy, increased use of indwelling lines and devices, and increase in chronicdiseases such as end-stage renal disease and HIV. Of note, in 1987, gram-positive organisms surpassed

gram-negative organisms as the most common cause of sepsis, a position they still hold today.[20]

Angus et al published linked data from several sources related to hospital discharge from all hospitals from 7 large

states.[19] Hospital billing codes were used to identify patients with infection and organ dysfunction consistent with thedefinition of severe sepsis. This method yielded 300 annual cases per 100,000 population, 2.3% of hospital

discharges, or an estimated 750,000 cases annually in the United States.[19]

A more recent large survey of ED visits showed that severe sepsis accounts for more than 500,000 such visitsannually (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 is approximately 5 hours.[21]

ARDS has a reported incidence ranging from 1.5-8.4 cases per 100,000 population per year.[22] Subsequent studiesreport a higher incidence: 12.6 cases per 100,000 population per year for ARDS and 18.9 cases per 100,000population per year for acute lung injury. The mortality rate from ARDS has been documented at approximately 50% inmost studies.


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International statistics

A Dutch surveillance study examined the incidence, causes, and outcome of sepsis in patients admitted to a universityhospital. The investigators reported that the incidences of sepsis syndrome and septic shock were, respectively, 13.6

and 4.6 cases per 1000 persons.[23]

Age distribution for septic shock

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.[19, 24] Atpresent, most sepsis episodes are observed in patients older than 60 years. Advanced age is a risk factor foracquiring nosocomial blood stream infection in the development of severe forms of sepsis.

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

Sex distribution for septic shock

Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock are consistently greaterin men. The percentage of male patients varies from 52% to 66%.However, it is not clear whether this difference canbe attributed to an underlying higher prevalence of comorbid conditions, a higher incidence of lung infection in men, or

whether women are inherently protected against the inflammatory injury that occurs in severe sepsis.[20, 19]

Incidence of septic shock by race

One large epidemiologic study showed that the risk of septicemia in the nonwhite population is almost twice that in thewhite population, with the highest risk accruing to black men. Potential reasons for this include issues relating to

decreased access to health care and increased prevalence of underlying medical conditions.[20]

A more recent 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.[25]

In this study, black patients with septic shock had a higher incidence of underlying diabetes and renal disease, whichmight explain the higher rates of infection. However, development of acute organ dysfunction was independent ofcomorbidities. Furthermore, the incidence of septic shock and severe invasive infection was higher in the young,healthy black population, which suggests a possible genetic predisposition to developing septic shock.

Prognosis

The mortality rate of severe sepsis and septic shock is frequently quoted as anywhere from 20% to 50%. In somestudies, the mortality rate specifically caused by the septic episode itself is specified and is 14.3-20%.

In recent years, mortality rates seem to have decreased. The National Center for Health Statistics study showed areduction in hospital mortality rates from 28% to 18% for septicemia over the years; however, more overall deathsoccurred due to the increased incidence of sepsis. The study by Angus et al, which likely more accurately reflects the

incidence of severe sepsis and septic shock, reported a mortality rate of about 30%.[19]

Given that there is a spectrum of disease from sepsis to severe sepsis to septic shock, mortality varies depending onthe degree of illness. The following clinical characteristics are related to the severity of sepsis:

An abnormal host response to infectionSite and type of infectionTiming and type of antimicrobial therapyOffending organismDevelopment of shockAny underlying diseasePatient’s long-term health conditionLocation of the patient at the time of septic shock

Factors consistently associated with increased mortality in sepsis include advanced age, comorbid conditions, and


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clinical evidence of organ dysfunction.[19, 24] One study found that in the setting of suspected infection, just meetingSIRS criteria without evidence of organ dysfunction did not predict increased mortality; this emphasizes the

importance of identifying organ dysfunction over the presence of SIRS criteria.[24] However, there is evidence to

suggest that meeting increasing numbers of SIRS criteria is associated with increased mortality.[26]

In patients with septic shock, several clinical trials have documented a mortality rate of 40-75%. The poor prognosticfactors are advanced age, infection with a resistant organism, impaired host immune status, poor prior functionalstatus, and continued need for vasopressors past 24 hours. Development of sequential organ failure, despiteadequate supportive measures and antimicrobial therapy, is a harbinger of poor outcome. The mortality rates were 7%

with SIRS, 16% with sepsis, 20% with severe sepsis, and 46% with septic shock.[27]

A link between impaired adrenal function and higher septic shock mortality has been suggested. The adrenal gland isenlarged in patients with septic shock compared with controls. A study by Jung et al found that an absence of this

enlargement, indicated by total adrenal volume of less than10 cm3, was associated with increased 28-day mortality in

patients with septic shock.[28]

In 1995, a multicenter prospective study published by Brun-Buisson (1995) reported a mortality rate of 56% during

ICU stays and 59% during hospital stays.[4] Twenty-seven percent of all deaths occurred within 2 days of the onset ofsevere sepsis, and 77% of all deaths occurred within the first 14 days. The risk factors for early mortality in this studywere higher severity of illness score, the presence of 2 or more acute organ failures at the time of sepsis, shock, anda low blood pH (< 7.3).

Studies have shown that appropriate antibiotic administration (ie, antibiotics that are effective against the organism thatis ultimately identified) has a significant influence on mortality. For this reason, initiating broad-spectrum coverage untilthe specific organism is cultured and antibiotic sensitivities are determined is important.

The long-term use of statins appears to have a significant protective effect on sepsis, bacteremia, and pneumonia.[29]

End-organ failure is a major contributor to mortality in sepsis and septic shock. The complications with the greatestadverse effect on survival are ARDS, DIC, and ARF. (See Clinical Presentation.)

The frequency of ARDS in sepsis has been reported from 18-38%, the highest with gram-negative sepsis, rangingfrom 18-25%. Sepsis and multiorgan failure are the most common cause of death in ARDS patients. Approximately16% of patients with ARDS died from irreversible respiratory failure. Most patients who showed improvement achievedmaximal recovery by 6 months, with the lung function improving to 80-90% of predicted values.

Controversy exists over the use of etomidate as an induction agent for patients with sepsis, with debate centered onits association with adrenal insufficiency. Sprung et al, in the CORTICUS study, reported that patients who received

etomidate had a significantly higher mortality rate than those who did not receive etomidate.[30]

However, the authors did not address the fact that those patients receiving etomidate required orotracheal intubationand thus were a sicker subset. There have been no studies to date that have prospectively evaluated the effect ofsingle-dose etomidate on the mortality of septic shock.

Although sepsis mortality is known to be high, its effect on the quality of life of survivors was previously not wellcharacterized. New evidence shows that septic shock in elderly persons leads to significant long-term cognitive andfunctional disability compared with those hospitalized with nonsepsis conditions. Septic shock is often a major sentinelevent that has lasting effects on the patient’s independence, reliance on family support, and need for chronic nursing

home or institutionalized care.[31]

Patient Education

For patient education information, see the Shock Center, Blood and Lymphatic System Center, and Public HealthCenter, as well as Shock, Sepsis (Blood Infection), and Cardiopulmonary Resuscitation (CPR).

Contributor Information and DisclosuresAuthorMichael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine, Bioengineering, CardiovascularDisease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University ofPittsburgh School of Medicine, University of Pittsburgh Medical Center


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Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies: American College ofChest Physicians, American College of Critical Care Medicine, American Heart Association, American ThoracicSociety, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, andSociety of Critical Care Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; EdwardsLifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting feeConsulting

Coauthor(s)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, ProgramDirector, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve UniversitySchool of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, AmericanAcademy of Emergency Medicine, American College of Chest Physicians, American College of EmergencyPhysicians, American College of Physicians, American Heart Association, American Thoracic Society, ArkansasMedical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for AcademicEmergency Medicine


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

Daniel J Dire, MD 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 EmergencyPhysicians, and Association of Military Surgeons of the US


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


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 MicrographicSurgery and Cutaneous Oncology


Theodore J Gaeta, DO, MPH, FACEP Clinical Associate Professor, Department of Emergency Medicine, WeillCornell Medical College; Vice Chairman and Program Director of Emergency Medicine Residency Program,Department of Emergency Medicine, New York Methodist Hospital; Academic Chair, Adjunct Professor, Departmentof 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 ClinicalEducation, American College of Emergency Physicians, Clerkship Directors in Emergency Medicine, Council ofEmergency Medicine Residency Directors, New York Academy of Medicine, and Society for Academic EmergencyMedicine


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


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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 forDermatologic Surgery


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

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


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


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 Medicineand 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


Vicken Y Totten, MD, MS, FACEP, FAAFP Assistant Professor, Case Western Reserve University School ofMedicine; 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 ofEmergency Physicians and Society for Academic Emergency Medicine


Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University HealthSciences 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


Eric L Weiss, MD, DTM&H Medical Director, Office of Service Continuity and Disaster Planning, FellowshipDirector, Stanford University Medical Center Disaster Medicine Fellowship, Chairman, SUMC and LPCHBioterrorism 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 EmergencyPhysicians, American College of Occupational and Environmental Medicine, American Medical Association,American Society of Tropical Medicine and Hygiene, Physicians for Social Responsibility, Southeastern Surgical


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Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness MedicalSociety


Specialty Editor BoardCory 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 ofCritical Care Medicine


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

Disclosure: Medscape Salary Employment

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 andInfectious Diseases Society of America


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


Chief EditorMichael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine, Bioengineering, CardiovascularDisease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University ofPittsburgh School of Medicine, University of Pittsburgh Medical Center

Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies: American College ofChest Physicians, American College of Critical Care Medicine, American Heart Association, American ThoracicSociety, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, andSociety of Critical Care Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; EdwardsLifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting feeConsulting

AcknowledgmentsThe authors and editors of eMedicine gratefully acknowledge the contributions of previous authors R PhillipDellinger, MD, Ismail Cinel, MD, PhD,Steven Manders, MD, Clara-Dina Cokonis, MD, and Dane Salandy, MD†,to thedevelopment and writing of the source articles.

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