1. Septic Shock http://emedicine.medscape.com/article/168402-overview
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 stream
which causes sign of illness.” The definition did not change much over the years, because the terms sepsis and
septicemia referred to several ill-defined clinical conditions present in a patient with bacteremia. In practice, the terms
often were used interchangeably; however, fewer than half the patients with signs and symptoms of sepsis have
positive 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 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 body site, 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 associated clinical evidence indicates inadequate perfusion of major organ
systems, with progressive failure of organ system functions.
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 from a mild degree
of 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, and
vasopressor 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 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:
Hypovolemic shock
Obstructive shock
Distributive shock
Cardiogenic shock
These classes of shock should be considered and systemically differentiated before establishing a definitive
diagnosis 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 clammy
extremities, hypotension, dry skin and mucus membranes, and poor turgor.
Obstructive shock results from impedance of circulation by an intrinsic or extrinsic obstruction. Pulmonary embolism
and pericardial tamponade both result in obstructive shock.
Distributive shock is caused by such conditions as direct arteriovenous shunting and is characterized by decreased
resistance or increased venous capacity from the vasomotor dysfunction. These patients have high cardiac output,
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hypotension, large pulse pressure, a low diastolic pressure, and warm extremities with a good capillary refill. These
findings 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 maintain
adequate cardiac output. These patients demonstrate clinical signs of low cardiac output, while evidence exists of
adequate intravascular volume. The patients have cool clammy extremities, poor capillary refill, tachycardia, narrow
pulse 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 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 a commonly understood definition. 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.[1, 2]
Systemic inflammatory response syndrome (SIRS) is a term that was developed in an attempt to describe the clinical
manifestations that result from the systemic response to infection. Criteria for SIRS are considered to be met if at
least 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 than
32 mm Hg
White 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 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 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, 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, the use of
sepsis-specific biomarkers has not yet translated to establishing a clinical diagnosis of sepsis in the emergency
department (ED).
With sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion is typically included:
Alteration in mental state
Hypoxemia (arterial oxygen tension [PaO2] < 72 mm Hg at fraction of inspired oxygen [FiO2] 0.21; overt
pulmonary disease not the direct cause of hypoxemia)
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Elevated plasma lactate level
Oliguria (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, 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 greater than 4 mg/dL)
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 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 commonly 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, 7]
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.
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 300
Bilateral opacities on chest radiograph compatible with pulmonary edema
Pulmonary artery occlusion pressure less than 18 mm Hg or no clinical evidence of left atrial hypertension if
PaO2 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 Sepsis
Bacterial Sepsis
Toxic Shock Syndrome
Pediatric Toxic Shock Syndrome
Pathophysiology
The pathophysiology of septic shock is not precisely understood, but it involves a complex interaction between the
pathogen and the host’s immune system. The normal physiologic response to localized infection includes the
activation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, the release of
inflammatory 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 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 (see the table below).
Table 1. Mediators of Sepsis (Open Table in a new window)
Type Mediator Activity
Cellular Lipopolysaccharide Activation of macrophages, neutrophils, platelets, and endothelium releases
mediators Lipoteichoic acid various cytokines and other mediators
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Peptidoglycan
Superantigens
Endotoxin
Humoral Cytokines Potent proinflammatory effect
mediators TNF-alpha and IL-1β
Neutrophil chemotactic factor
IL-8
Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibits
IL-6 cytokine production, induces immunosuppression
IL-10 Activation and degranulation of neutrophils
Cytotoxic, augments vascular permeability, contributes to shock
MIF
Involved in hemodynamic alterations of septic shock
G-CSF
Promote neutrophil and macrophage, platelet activation and chemotaxis,
Complement other proinflammatory effects
Nitric oxide
Lipid mediators
Enhance vascular permeability and contributes to lung injury
Phospholipase A2
Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration
and adhesion, and play a role in pathogenesis of sepsis
PAF
Eicosanoids
Arachidonic acid
metabolites
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, 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. 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 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.
The chemokines (monocyte chemoattractant protein–1) orchestrate the migration of leukocytes during endotoxemia
and sepsis. The other cytokines that have a supposed role in sepsis are IL-10, interferon gamma, IL-12, macrophage
migration 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 just
mentioned, which play a pivotal role in initiating sepsis and shock. Various bacterial cell wall components are known to
release the cytokines, including lipopolysaccharide (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 the
gram-negative bacteria is the lipid A moiety of lipopolysaccharide. The gram-positive bacteria cell wall leads to
cytokine induction via lipoteichoic acid.
Additionally, gram-positive bacteria may secrete the 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.
A dual role exists for neutrophils; they are necessary for defense against microorganisms but also may become toxic
inflammatory 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 vascular
endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and
accelerating 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 factor
XII to the subendothelial surface. This activates factor XII, and then 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.
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Inflammatory cytokines, such as IL-1α, IL-1β, and TNF-alpha, 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 complex and the presence of D-dimer in plasma,
indicating activation of the clotting system and fibrinolysis.[14, 15] 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).
The levels of protein C and endogenous activated protein C (APC) are also decreased in sepsis. Endogenous APC is
an important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin, via thrombomodulin, activates protein
C, which then functions as an antithrombotic in the microvasculature. Endogenous APC also enhances fibrinolysis by
neutralizing PAI-1 and by 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.[16]
Circulatory abnormalities
As noted (see Background), septic shock falls under the category of distributive shock, which is characterized by
pathologic vasodilation and shunting of blood from vital organ to nonvital tissues such as skin, skeletal muscle, and
adipose. 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 tissue 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.[17] 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 result in dependency of blood pressure on cardiac output, causing
vasodilation to result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic
shock, the rise in cardiac output often is 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 (the hyperdynamic phase
of sepsis and shock).
Even though cardiac output is elevated, the performance of the heart, reflected by stroke work as calculated from
stroke volume and blood pressure, usually is depressed. Factors responsible for myocardial depression of sepsis are
myocardial 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 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 the
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 capacity
to 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 to
regional 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 activity
of central mechanisms (eg, the autonomic nervous system). The regional regulation and the release of vasodilating
substances (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 to
edema 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 is
relatively 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 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. However, this concept is
controversial, 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 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 multiple organ dysfunction syndrome. 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 because of the following proposed
mechanisms:
Hypoxic hypoxia - The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of
tissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities
contribute to the septic microcirculatory defect in sepsis. Reactive oxygen species, lytic enzymes, vasoactive
substances (eg, NO), and endothelial growth factors lead to microcirculatory injury, which is compounded by the
inability 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 to
use oxygen even when it is present.
Apoptosis (programmed cell death) - This is the principal mechanism by which dysfunctional cells normally are
eliminated. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but
other tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement of
apoptosis plays a critical role in tissue injury in patients with sepsis.
Immunosuppression - The interaction between proinflammatory and anti-inflammatory mediators may lead to an
imbalance 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 partial
thromboplastin 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. Vasoactive
mediators cause vasodilatation and increase the microvascular permeability at the site of infection. NO plays a central
role in the vasodilatation of septic shock. Impaired secretion of vasopressin also may occur, which may permit the
persistence of vasodilatation.
Changes in both systolic and diastolic ventricular performance occur in patients with sepsis. Through the use of the
Frank-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 not
receive appropriate oxygen delivery.
The microcirculation is the key target organ for injury in patients with sepsis syndrome. 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 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 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, compared with
patients 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 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. As many as 40% of patients with severe sepsis
develop ALI.
ALI 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 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, which
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 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, a progressive respiratory failure and pulmonary
fibrosis develop.
The central pathologic finding in ARDS is severe injury to the alveolocapillary unit. Following initial extravasation of
intravascular fluid, inflammation and fibrosis of pulmonary parenchyma develops into a morphologic picture, termed
diffuse alveolar damage (DAD). The clinical and pathological evolution can be categorized into the following 3
overlapping phases (Katzenstein, 1986): (1) the exudative phase of edema and hemorrhage, (2) the proliferative
phase 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 other
histological 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.
Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, is
pathologically 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, is
pathologically 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 as
the 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, which
convert the exudate to cellular granulation tissue, occurs; excessive collagen deposition, transforming into fibrous
tissue, occurs.
This photomicrograph shows a delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II
pneumocytes 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 stain
showing 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. The
collagenous fibrosis completely remodels the lung, the air spaces are irregularly enlarged, and alveolar duct fibrosis is
apparent. 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 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. The
optimal 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. This
may 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 contribute
to both the initiation and progression of sepsis. The reticuloendothelial system of the liver 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.
Renal dysfunction
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
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Central nervous system (CNS) involvement in sepsis produces encephalopathy and peripheral neuropathy. The
pathogenesis is poorly defined.
Etiology
Most patients who develop sepsis and septic shock have underlying circumstances that interfere with the 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.
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 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, with the exception of patients who are
immunocompromised with neutropenia, where an obvious source often is not found. Multiple sites of infection may
occur in 6-15% of patients.
Causative microorganisms
Before the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causing
sepsis. More recently, gram-negative bacteria have become the key pathogens causing severe sepsis and septic
shock.
Anaerobic pathogens are becoming less important as a cause of sepsis. In one institution, the incidence of anaerobic
bacteremia declined by 45% over a 15-year period. Fungal infections are the cause of sepsis in 0.8-10.2% of patients
with 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 abdominal
and 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 common
pathogens:
Streptococcus pneumoniae
Klebsiella pneumoniae
Staphylococcus aureus
Escherichia coli
Legionella species
Haemophilus species
Anaerobes
Gram-negative bacteria
Fungi
Urinary tract infections are the cause of septic shock in 25% of patients, and the following are the common pathogens:
E coli
Proteus species
Klebsiella species
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Pseudomonas species
Enterobacter species
Serratia species
Soft tissue infections are the cause of septic shock in 15% of patients, and the following are the common pathogens:
S aureus
Staphylococcus epidermidis
Streptococci
Clostridia
Gram-negative bacteria
Anaerobes
GI tract infections are the cause of septic shock in 15% all patients, and the following are the common pathogens:
E coli
Streptococcus faecalis
Bacteroides fragilis
Acinetobacter species
Pseudomonas species
Enterobacter species
Salmonella species
Infections of the male and female reproductive systems are the cause of septic shock in 10% of patients, and the
following are the common pathogens:
Neisseria gonorrhoeae
Gram-negative bacteria
Streptococci
Anaerobes
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 most
common 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, solid
malignancy, hematologic malignancy)
Immunosuppression (eg, neutropenia, immunosuppressive therapy, corticosteroid therapy, IV drug abuse [see
the image below], complement deficiencies, asplenia)
Major surgery, trauma, burns
Invasive procedures (eg, catheters, intravascular devices, prosthetic devices, hemodialysis and peritoneal
dialysis catheters, endotracheal tubes)
Previous antibiotic treatment
Prolonged hospitalization
Other 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 to
bilateral 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 septic
shock 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 per
1000 admissions in 1970 to 8.7 per 1000 in 1987. Between 1980 and 1992, the incidence of nosocomial blood
stream infection in 1 institution increased from 6.7 cases per 1000 discharges to 18.4 per 1000. The increase in the
number of patients who are immunocompromised and an increasing use of invasive diagnostic and therapeutic
devices 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 large
sample from the major centers reported the incidence of severe sepsis as 3 cases per 1000 population and 2.26
cases per 100 hospital discharges. Out of these cases, 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.
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 Discharge
Survey 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 of
disease, increased performance of invasive procedures and organ transplantation, increased use of
immunosuppressive agents and chemotherapy, increased use of indwelling lines and devices, and increase in chronic
diseases 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 the
definition 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 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 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 studies
report a higher incidence: 12.6 cases per 100,000 population per year for ARDS and 18.9 cases per 100,000
population per year for acute lung injury. The mortality rate from ARDS has been documented at approximately 50% in
most studies.
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International statistics
A Dutch surveillance study examined the incidence, causes, and outcome of sepsis in patients admitted to a university
hospital. 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] At
present, most sepsis episodes are observed in patients older than 60 years. Advanced age is a risk factor for
acquiring 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 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.
Sex distribution for septic shock
Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock are consistently greater
in men. The percentage of male patients varies from 52% to 66%.However, it is not clear whether this difference can
be 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 the
white 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, which
might explain the higher rates of infection. However, development of acute organ dysfunction was independent of
comorbidities. 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 some
studies, 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 a
reduction in hospital mortality rates from 28% to 18% for septicemia over the years; however, more overall deaths
occurred 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 on
the degree of illness. The following clinical characteristics are related to the severity of sepsis:
An abnormal host response to infection
Site and type of infection
Timing and type of antimicrobial therapy
Offending organism
Development of shock
Any underlying disease
Patient’s long-term health condition
Location 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 meeting
SIRS 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 prognostic
factors are advanced age, infection with a resistant organism, impaired host immune status, poor prior functional
status, and continued need for vasopressors past 24 hours. Development of sequential organ failure, despite
adequate 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 is
enlarged 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 of
severe sepsis, and 77% of all deaths occurred within the first 14 days. The risk factors for early mortality in this study
were higher severity of illness score, the presence of 2 or more acute organ failures at the time of sepsis, shock, and
a low blood pH (< 7.3).
Studies have shown that appropriate antibiotic administration (ie, antibiotics that are effective against the organism that
is ultimately identified) has a significant influence on mortality. For this reason, initiating broad-spectrum coverage until
the 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 greatest
adverse 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, ranging
from 18-25%. Sepsis and multiorgan failure are the most common cause of death in ARDS patients. Approximately
16% of patients with ARDS died from irreversible respiratory failure. Most patients who showed improvement achieved
maximal 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 on
its 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 intubation
and thus were a sicker subset. There have been no studies to date that have prospectively evaluated the effect of
single-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 well
characterized. New evidence shows that septic shock in elderly persons leads to significant long-term cognitive and
functional disability compared with those hospitalized with nonsepsis conditions. Septic shock is often a major sentinel
event 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 Health
Center, as well as Shock, Sepsis (Blood Infection), and Cardiopulmonary Resuscitation (CPR).
Contributor Information and Disclosures
Author
Michael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine, Bioengineering, Cardiovascular
Disease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of
Pittsburgh 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 of
Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic
Society, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, and
Society of Critical Care Medicine
Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards
Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting fee
Consulting
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, 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 of Sciences, and Society for Academic
Emergency Medicine
Disclosure: Nothing to disclose.
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, School of Medicine, University of
Texas 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 Emergency
Physicians, and Association of Military Surgeons of the US
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.
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
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16. Septic Shock http://emedicine.medscape.com/article/168402-overview
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.
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 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.
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
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17. Septic Shock http://emedicine.medscape.com/article/168402-overview
Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness Medical
Society
Disclosure: Nothing to disclose.
Specialty Editor Board
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.
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
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.
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.
Chief Editor
Michael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine, Bioengineering, Cardiovascular
Disease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of
Pittsburgh 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 of
Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic
Society, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, and
Society of Critical Care Medicine
Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards
Lifesciences Honoraria Consulting; Applied Physiology, Ltd Honoraria Consulting; Cheetah Medical Consulting fee
Consulting
Acknowledgments
The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors R Phillip
Dellinger, MD, Ismail Cinel, MD, PhD,Steven Manders, MD, Clara-Dina Cokonis, MD, and Dane Salandy, MD†,to the
development and writing of the source articles.
References
1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of
innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of
Chest Physicians/Society of Critical Care Medicine. Chest. Jun 1992;101(6):1644-55. [Medline].
2. [Best Evidence] American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in
sepsis. Crit Care Med. Jun 1992;20(6):864-74. [Medline].
3. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS
17 of 21 9/3/2011 9:12 AM

18. Septic Shock http://emedicine.medscape.com/article/168402-overview
International Sepsis Definitions Conference. Crit Care Med. Apr 2003;31(4):1250-6. [Medline].
4. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic
shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis.
JAMA. Sep 27 1995;274(12):968-74. [Medline].
5. Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, et al. Epidemiology of sepsis
syndrome in 8 academic medical centers. JAMA. Jul 16 1997;278(3):234-40. [Medline].
6. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation
of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med.
Jun 2006;34(6):1589-96. [Medline].
7. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety
of recombinant human activated protein C for severe sepsis. N Engl J Med. Mar 8 2001;344(10):699-709.
[Medline].
8. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus
Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J
Respir Crit Care Med. Mar 1994;149(3 Pt 1):818-24. [Medline].
9. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. Jan 21 1999;340(3):207-14.
[Medline].
10. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. Jan 9
2003;348(2):138-50. [Medline].
11. Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S, et al. Severe sepsis and septic
shock: review of the literature and emergency department management guidelines. Ann Emerg Med. Jul
2006;48(1):28-54. [Medline].
12. Lorente JA, Landín L, De Pablo R, Renes E, Rodríguez-Díaz R, Liste D. Effects of blood transfusion on
oxygen transport variables in severe sepsis. Crit Care Med. Sep 1993;21(9):1312-8. [Medline].
13. Schuetz P, Jones AE, Aird WC, Shapiro NI. Endothelial cell activation in emergency department patients with
sepsis-related and non-sepsis-related hypotension. Shock. Aug 2011;36(2):104-8. [Medline]. [Full Text].
14. Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation
in sepsis. JAMA. Aug 25 1993;270(8):975-9. [Medline].
15. Mammen EF. Antithrombin III and sepsis. Intensive Care Med. Jul 1998;24(7):649-50. [Medline].
16. Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit
Care. 2005;9 Suppl 4:S20-6. [Medline].
17. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. Aug 23 2001;345(8):588-95.
[Medline].
18. Cetinbas F, Yelken B, Gulbas Z. Role of glutamine administration on cellular immunity after total parenteral
nutrition enriched with glutamine in patients with systemic inflammatory response syndrome. J Crit Care. Dec
2010;25(4):661.e1-6. [Medline].
19. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis
in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. Jul
2001;29(7):1303-10. [Medline].
20. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979
through 2000. N Engl J Med. Apr 17 2003;348(16):1546-54. [Medline].
21. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency
departments. Crit Care Med. Aug 2007;35(8):1928-36. [Medline].
22. Baughman RP, Gunther KL, Rashkin MC, Keeton DA, Pattishall EN. Changes in the inflammatory response of
the lung during acute respiratory distress syndrome: prognostic indicators. Am J Respir Crit Care Med. Jul
1996;154(1):76-81. [Medline].
18 of 21 9/3/2011 9:12 AM

19. Septic Shock http://emedicine.medscape.com/article/168402-overview
23. Kieft H, Hoepelman AI, Zhou W, Rozenberg-Arska M, Struyvenberg A, Verhoef J. The sepsis syndrome in a
Dutch university hospital. Clinical observations. Arch Intern Med. Oct 11 1993;153(19):2241-7.
24. Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor D. The association of sepsis syndrome and
organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med.
Nov 2006;48(5):583-90, 590.e1. [Medline].
25. Mayr FB, Yende S, Linde-Zwirble WT, Peck-Palmer OM, Barnato AE, Weissfeld LA, et al. Infection Rate and
Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis. JAMA. Jun
2010;303(24):2495-2503.
26. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic
inflammatory response syndrome (SIRS). A prospective study. JAMA. Jan 11 1995;273(2):117-23. [Medline].
27. Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med. 2000;26
Suppl 1:S64-74. [Medline].
28. Jung B, Nougaret S, Chanques G, et al. The Absence of Adrenal Gland Enlargement during Septic Shock
Predicts Mortality: A Computed Tomography Study of 239 Patients. Anesthesiology. Aug
2011;115(2):334-343. [Medline].
29. Janda S, Young A, Fitzgerald JM, Etminan M, Swiston J. The effect of statins on mortality from severe
infections and sepsis: a systematic review and meta-analysis. J Crit Care. Dec 2010;25(4):656.e7-22.
[Medline].
30. Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: an evidence-based review. Crit
Care Med. Nov 2004;32(11 Suppl):S451-4. [Medline].
31. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among
survivors of severe sepsis. JAMA. Oct 27 2010;304(16):1787-94. [Medline].
32. Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and
raised lactate concentrations in septic shock: a prospective study. Lancet. Mar 5-11 2005;365(9462):871-5.
[Medline].
33. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, et al. Serum lactate as a predictor of
mortality in emergency department patients with infection. Ann Emerg Med. May 2005;45(5):524-8. [Medline].
34. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, et al. Early lactate clearance is
associated with improved outcome in severe sepsis and septic shock. Crit Care Med. Aug
2004;32(8):1637-42. [Medline].
35. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous
oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. Feb 24
2010;303(8):739-46. [Medline]. [Full Text].
36. Griffee MJ, Merkel MJ, Wei KS. The role of echocardiography in hemodynamic assessment of septic shock.
Crit Care Clin. Apr 2010;26(2):365-82, table of contents. [Medline].
37. Dellinger RP, Carlet JM, Masur H. Surviving Sepsis Campaign guidelines for management of severe sepsis
and septic shock. Crit Care Med. Mar 2004;32(3):858-73. [Medline].
38. [Guideline] Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis
Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med.
Jan 2008;36(1):296-327. [Medline].
39. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic
review of the literature and the tale of seven mares. Chest. Jul 2008;134(1):172-8. [Medline].
40. Nagdev AD, Merchant RC, Tirado-Gonzalez A, Sisson CA, Murphy MC. Emergency department bedside
ultrasonographic measurement of the caval index for noninvasive determination of low central venous
pressure. Ann Emerg Med. Mar 2010;55(3):290-5. [Medline].
41. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid
resuscitation in the intensive care unit. N Engl J Med. May 27 2004;350(22):2247-56. [Medline].
19 of 21 9/3/2011 9:12 AM

20. Septic Shock http://emedicine.medscape.com/article/168402-overview
42. Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic
shock. N Engl J Med. Nov 8 2001;345(19):1368-77. [Medline].
43. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, et al. A trial of goal-oriented hemodynamic
therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. Oct 19 1995;333(16):1025-32.
[Medline].
44. Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure,
heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med. Mar
1996;14(2):218-25. [Medline].
45. Crowe CA, Mistry CD, Rzechula K, Kulstad CE. Evaluation of a modified early goal-directed therapy protocol.
Am J Emerg Med. Jul 2010;28(6):689-93. [Medline].
46. Kortgen A, Niederprüm P, Bauer M. Implementation of an evidence-based "standard operating procedure"
and outcome in septic shock. Crit Care Med. Apr 2006;34(4):943-9. [Medline].
47. Shapiro NI, Howell MD, Talmor D, Lahey D, Ngo L, Buras J, et al. Implementation and outcomes of the
Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med. Apr 2006;34(4):1025-32. [Medline].
48. Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, et al. Implementation of a bundle of quality
indicators for the early management of severe sepsis and septic shock is associated with decreased
mortality. Crit Care Med. Apr 2007;35(4):1105-12. [Medline].
49. Micek ST, Roubinian N, Heuring T, Bode M, Williams J, Harrison C, et al. Before-after study of a standardized
hospital order set for the management of septic shock. Crit Care Med. Nov 2006;34(11):2707-13. [Medline].
50. Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, et al. Translating research to clinical
practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the
emergency department. Chest. Feb 2006;129(2):225-32. [Medline].
51. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an
emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock.
Chest. Aug 2007;132(2):425-32. [Medline]. [Full Text].
52. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, et al. Improvement in
process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. May 21
2008;299(19):2294-303. [Medline].
53. [Guideline] Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, et al. The Surviving
Sepsis Campaign: results of an international guideline-based performance improvement program targeting
severe sepsis. Crit Care Med. Feb 2010;38(2):367-74. [Medline].
54. Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory
distress syndrome: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S548-53. [Medline].
55. Vasu TS, Cavallazzi R, Hirani A, et al. Norephinephrine or Dopamine for Septic Shock: A Systematic Review
of Randomized Clinical Trials. J Intensive Care Med. Mar 24 2011;[Medline].
56. Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an
evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S455-65. [Medline].
57. Russell JA. Vasopressin in septic shock. Crit Care Med. Sep 2007;35(9 Suppl):S609-15. [Medline].
58. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus
norepinephrine infusion in patients with septic shock. N Engl J Med. Feb 28 2008;358(9):877-87. [Medline].
59. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill
patients. N Engl J Med. Jun 16 1994;330(24):1717-22. [Medline].
60. Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging
public-health concern. Lancet Infect Dis. Mar 2008;8(3):159-66. [Medline].
61. Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and
septic shock: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S495-512. [Medline].
20 of 21 9/3/2011 9:12 AM

21. Septic Shock http://emedicine.medscape.com/article/168402-overview
62. McCoy C, Matthews SJ. Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe
sepsis. Clin Ther. Feb 2003;25(2):396-421. [Medline].
63. Marti-Carvajal AJ, Sola I, Lathyris D, Cardona AF. Human recombinant activated protein C for severe sepsis.
Cochrane Database Syst Rev. Apr 13 2011;4:CD004388. [Medline].
64. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. Feb 20
2003;348(8):727-34. [Medline].
65. Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, et al. Corticosteroid treatment for sepsis: a
critical appraisal and meta-analysis of the literature. Crit Care Med. Aug 1995;23(8):1430-9. [Medline].
66. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to
resolve clinical trial controversies. Intensive Care Med. Mar 2011;37(3):420-9. [Medline].
67. Briegel J, Forst H, Haller M. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a
prospective, randomized, double-blind, single-center study. Crit Care Med. Apr 1999;27(4):723-32.
[Medline].
68. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, et al. Effect of treatment with low
doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. Aug 21
2002;288(7):862-71. [Medline].
69. [Best Evidence] Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, et al.
Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. Jun
10 2009;301(22):2362-75. [Medline].
70. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients
with septic shock. N Engl J Med. Jan 10 2008;358(2):111-24. [Medline].
71. Dellinger RP, Carlet JM, Masur H. Surviving Sepsis Campaign guidelines for management of severe sepsis
and septic shock. Intensive Care Med. Apr 2004;30(4):536-55.
72. Van den Berghe G, Wouters PJ, Bouillon R. Outcome benefit of intensive insulin therapy in the critically ill:
Insulin dose versus glycemic control. Crit Care Med. Feb 2003;31(2):359-66. [Medline].
73. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med.
Feb 2 2006;354(5):449-61.
74. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a
reassessment. Crit Care Med. Jul 1997;25(7):1095-100. [Medline].
75. Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B
hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. Jun 17
2009;301(23):2445-52. [Medline].
76. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving
acute respiratory distress syndrome: a randomized controlled trial. JAMA. Jul 8 1998;280(2):159-65.
[Medline].
77. Nathens AB, Rotstein OD. Selective decontamination of the digestive tract in acute severe pancreatitis--an
indication whose time has come. Clin Infect Dis. Oct 1997;25(4):817-8. [Medline].
21 of 21 9/3/2011 9:12 AM