Septic Shock

Septic shock
From Wikipedia, the free encyclopedia

Septic shock

Classification and external resources

ICD-10

A41.9

ICD-9

785.52

DiseasesDB

11960

MedlinePlus

000668

MeSH

D012772

Septic shock is a medical condition as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site.[1] It can causemultiple organ dysfunction syndrome (formerly known as multiple organ failure) and death.[1] Its most common victims are children, immunocompromisedindividuals, and the elderly, as their immune systems cannot deal with the infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25–50%.[1]
Contents
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1 Definition

o     

1.1 Types

2 Causes 3 Pathophysiology 4 Treatment 5 Epidemiology 6 References

[edit]Definition

In humans, septic shock has a specific definition requiring several conditions to be met for diagnosis:

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First, SIRS (systemic inflammatory response syndrome) must be diagnosed by finding at least any two of the following: Tachypnea (high respiratory rate) > 20 breaths per minute, or on blood gas, a PCO2 less than 32 mmHg signifying hyperventilation. White blood cell count either significantly low, < 4000 cells/mm³ or elevated > 12000 cells/mm³. Heart rate > 90 beats per minute Temperature: Fever > 38.5 °C (101.3 °F) or hypothermia < 35.0 °C (95.0 °F)

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Second, there must be sepsis and not an alternative form cause of SIRS. Sepsis requires evidence of infection, which may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection.

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Third, signs of end-organ dysfunction are required such as renal failure, liver dysfunction, changes in mental status, or elevated serum lactate.

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Finally, septic shock is diagnosed if there is refractory hypotension (low blood pressure that does not respond to treatment). This signifies that intravenous fluid administration alone is insufficient to maintain a patient's blood pressure from becoming hypotensive.

[edit]Types
A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in ischemia and organ dysfunction. Cytokines released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure causing tissue hypoxia. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.

[edit]Causes
When bacteria or viruses are present in the bloodstream, the condition is known as bacteremia or viremia. Sepsis is a constellation of symptoms secondary to infection that manifest as disruptions in heart rate, respiratory rate, temperature and WBC. If sepsis worsens to the point of end-organ dysfunction (renal failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criteria have been met for septic shock. The precipitating infections which may lead to septic shock if severe enough

include appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancre atitis, and necrotizing fasciitis.

[edit]Pathophysiology
Most cases of septic shock (approximately 70%) are caused by endotoxin-producing Gramnegative bacilli[citation needed]. Endotoxins are bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core common to all Gram-negative bacteria, and a complex polysaccharide coat (including O antigen) unique for each species. Analogous molecules in the walls of Gram-positive bacteria and fungi can also elicit septic shock. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4), resulting in profound activation of mononuclear cells and production of potent effector cytokines such as IL-1 and TNF-α. These cytokines act on endothelial cells and have a variety of effects including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes. At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated intravascular coagulation (DIC). The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.

[edit]Treatment
Treatment primarily consists of the following. 1. 2. 3. 4. 5. Volume resuscitation[2] Early antibiotic administration[2] Early goal directed therapy[2] Rapid source identification and control. Support of major organ dysfunction.

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock.[3] Both however are still listed as first line in guidelines.[3] Antimediator agents may be of some limited use in severe clinical situations however are controversial:[4]

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Low dose steroids (hydrocortisone) for 5 – 7 days led to improved outcomes.[5][6] Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use. [7] Other reviews however comment that it may be effective in those with very severe disease.[4] The first and only activated protein C drug, drotrecogin alfa (Xigris), was voluntarily withdrawn in October of 2011 after it failed to show a benefit in patients with septic shock, including the more severe disease subgroups.

[edit]Epidemiology
Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 50 percent even in industrialized countries.[8] According to the US CDC, septic shock is the 13th leading cause of death in the United States, and the #1 cause of deaths in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increase in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are nosocomial infections. The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to Gram staining gram-negative bacilli that produce endotoxins; however, with the emergence of MRSA and the increased use of arterial and venous catheters, Gram-positive cocci are implicated approximately as commonly asbacilli. In rough order of increasing severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death. 35% of septic shock cases derive from urinary tract infections, 15% from the respiratory tract, 15% from skin catheters (such as IVs); over 30% of all cases are idiopathic in origin. The mortality rate from sepsis is approximately 40% in adults, and 25% in children, and is significantly greater when left untreated for more than 7 days.[9]

Septic shock
Septic shock is a serious condition that occurs when an overwhelming infection leads to life-threatening low blood pressure. See also:     Causes Septic shock occurs most often in the very old and the very young. It also occurs in people who have other illnesses. Any type of bacteria can cause septic shock. Fungi and (rarely) viruses may also cause the condition. Toxins released by the bacteria or fungi may cause tissue damage, and may lead to low blood pressure and poor organ function. Some researchers think that blood clots in small arteries cause the lack of blood flow and poor organ function. The body also produces a strong inflammatory response to the toxins. This inflammation may contribute to organ damage. Risk factors for septic shock include:           Diabetes Diseases of the genitourinary system, biliary system, or intestinal system Diseases that weaken the immune system such as AIDS Indwelling catheters (those that remain in place for extended periods, especially intravenous lines and urinary catheters and plastic and metal stents used for drainage) Leukemia Long-term use of antibiotics Lymphoma Recent infection Recent surgery or medical procedure Recent use of steroid medications Acute respiratory distress syndrome Disseminated intravascular coagulation Meningococcemia Waterhouse-Friderichsen syndrome

Symptoms Septic shock can affect any part of the body, including the heart, brain, kidneys, liver, and intestines. Symptoms may include:     Cool, pale extremities High or very low temperature, chills Lightheadedness Low blood pressure, especially when standing

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Low or absent urine output Palpitations Rapid heart rate Restlessness, agitation, lethargy, or confusion Shortness of breath Skin rash or discoloration

Exams and Tests Blood tests may be done to check for infection, low blood oxygen level, disturbances in the body's acidbase balance, or poor organ function or organ failure. A chest x-ray may show pneumonia or fluid in the lungs (pulmonary edema). A urine sample may show infection. Additional studies, such as blood cultures, may not become positive for several days after the blood has been taken, or for several days after the shock has developed. Treatment Septic shock is a medical emergency. Patients are usually admitted to the intensive care unit of the hospital. Treatment may include:      Breathing machine (mechanical ventilation) Drugs to treat low blood pressure, infection, or blood clotting Fluids given directly into a vein (intravenously) Oxygen Surgery

There are new drugs that act against the extreme inflammatory response seen in septic shock. These may help limit organ damage. Hemodynamic monitoring -- the evaluation of the pressures in the heart and lungs -- may be required. This can only be done with special equipment and intensive care nursing. Outlook (Prognosis) Septic shock has a high death rate. The death rate depends on the patient's age and overall health, the cause of the infection, how many organs have failed, and how quickly and aggressively medical therapy is started. Possible Complications Respiratory failure, cardiac failure, or any other organ failure can occur. Gangrene may occur, possibly leading to amputation. When to Contact a Medical Professional

Go directly to an emergency department if you develop symptoms of septic shock. Prevention Prompt treatment of bacterial infections is helpful. However, many cases of septic shock cannot be prevented. Alternative Names Bacteremic shock; Endotoxic shock; Septicemic shock; Warm shock

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, 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 (PaCO 2) 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 the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

In 2001, as a follow-up to the original ACCP/SCCM conference, an International Sepsis Definitions Conference was convened, with representation not only from the ACCP and the SCCM but also from the European Society of Intensive Care Medicine (ESICM), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). The following definitions of sepsis syndromes were published 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:

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Alteration in mental state Hypoxemia (arterial oxygen tension [PaO2] < 72 mm Hg at fraction of inspired oxygen [FiO 2] 0.21; overt pulmonary disease not the direct cause of hypoxemia)  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 PaO 2/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 Cellular mediators Mediator Lipopolysaccharide Lipoteichoic acid Peptidoglycan Superantigens Endotoxin Humoral mediators Cytokines TNF-alpha and IL-1β Neutrophil chemotactic factor IL-8 Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibits cytokine production, induces immunosuppression IL-6 Activation and degranulation of neutrophils IL-10 Cytotoxic, augments vascular permeability, contributes to shock Potent proinflammatory effect Activity Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators

MIF

Involved in hemodynamic alterations of septic shock

G-CSF

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

Complement Nitric oxide Lipid mediators

Enhance vascular permeability and contributes to lung injury

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

Phospholipase A2

PAF

Eicosanoids

Arachidonic acid

metabolites Adhesion molecules

Selectins

Leukocyte integrins

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. 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 (PAI1) 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. 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

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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.

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.

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). The 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

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

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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 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, andNeisseria meningitidis is the most common cause of such infections (see the image below).

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Gram stain of blood showing the presence of Neisseria meningitidis.

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

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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

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Other factors, such as childbirth, abortion, and malnutrition

A 28-year-old woman who was a previous intravenous drug user (human immunodeficiency virus [HIV] status: negative) 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.

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 14.320%. 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 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 cm 3, 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 longterm 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.

Septic Shock Clinical Presentation
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Updated: Aug 13, 2012

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History
Physical Examination Complications Show All Multimedia Library Tables References

History
Sepsis or septic shock is systemic inflammatory response syndrome (SIRS) secondary to a documented infection (see Background). Detrimental host responses to infection occupy a continuum that ranges from sepsis to severe sepsis to septic shock and multiple organ dysfunction syndrome (MODS). The specific clinical features depend on where the patient falls on that continuum. Symptoms of sepsis are often nonspecific and include fever, chills, rigors, fatigue, malaise, nausea, vomiting, difficulty breathing, anxiety, or confusion. These symptoms are not pathognomonic for sepsis syndromes and may be present in a wide variety of other conditions. Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis, especially in elderly individuals. Fever is a common symptom of sepsis. The hypothalamus resets so that heat production and heat loss are balanced in favor of a higher temperature. Fever may be absent in elderly or immunosuppressed patients. An inquiry should be made about fever onset (abrupt or gradual), duration, and maximal temperature. These features have been associated with increased infectious burden and severity of illness. However, simply mounting a fever is an insensitive indicator of sepsis; in fact, hypothermia is more predictive of illness severity and death. Chills are a secondary symptom associated with fever, which is a consequence of increased muscular activity that produces heat and raises the body temperature. Sweating occurs when the hypothalamus returns to its normal set point and senses the higher body temperature, stimulating perspiration to evaporate excess body heat. Alteration in mental function often occurs. Mild disorientation or confusion is especially common in elderly individuals. Apprehension, anxiety, agitation, and, eventually, coma are manifestations of severe sepsis. The exact cause of metabolic encephalopathy is not known; alteration in amino acid metabolism may play a role. Hyperventilation with respiratory alkalosis is a common feature of patients with sepsis secondary to stimulation of the medullary respiratory center by endotoxins and other inflammatory mediators. The localizing symptoms referable to organ systems may provide useful clues to the etiology of sepsis and are as follows:   Head and neck infections - Severe headache, neck stiffness, altered mental status, earache, sore throat, sinus pain or tenderness, cervical or submandibular lymphadenopathy Chest and pulmonary infections - Cough (especially if productive), pleuritic chest pain, dyspnea

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Abdominal and gastrointestinal (GI) infections - Abdominal pain, nausea, vomiting, diarrhea Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethral discharge, dysuria, frequency, urgency Bone and soft tissue infections - Localized limb pain or tenderness, focal erythema, edema, and swollen joint

Physical Examination
The hallmarks of severe sepsis and septic shock are changes that occur at the microvascular and cellular level with diffuse activation of inflammatory and coagulation cascades, vasodilation and vascular maldistribution, capillary endothelial leak, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for the clinician is to recognize that this process is under way when it may not be clearly manifested in the vital signs or clinical examination. The physical examination should first involve assessment of the patient’s general condition, including an assessment of airway, breathing, and circulation (ABCs) and mental status. An acutely ill, flushed, and toxic appearance is observed universally in patients with serious infections. Examine vital signs, and observe for signs of hypoperfusion. Carefully examine the patient for evidence of localized infection. Ensure that the patient’s body temperature is measured accurately and that rectal temperatures are obtained. Oral and tympanic temperatures are not always reliable. Fever may be absent, but patients generally have tachypnea and tachycardia. Attention should be paid to skin color and temperature. Pallor, grayish, or mottled skin are signs of poor tissue perfusion seen in septic shock. In the early stages of sepsis, cardiac output is well maintained or even increased. The vasodilation may result in warm skin, warm extremities, and normal capillary refill (warm shock). As sepsis progresses, stroke volume and cardiac output fall. The patients begin to manifest the following signs of poor perfusion: cool skin, cool extremities, and delayed capillary refill (cold shock). Petechiae or purpura (see the image below) can be associated with disseminated intravascular coagulation (DIC) and are an ominous sign.

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

Tachycardia is a common feature of sepsis and indicative of a systemic response to stress. Tachycardia is the physiologic mechanism of increasing cardiac output and thus increasing oxygen delivery to tissues. It indicates hypovolemia and the need for intravascular fluid repletion; however, tachycardia often persists in sepsis despite adequate fluid repletion. Tachycardia may also be a result of fever itself. Narrow pulse pressure and tachycardia are considered the earliest signs of shock. Increased respiratory rate is a common and often underappreciated feature of sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed as a cause. As tissue hypoperfusion ensues, the respiratory rate also increases in order to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious.

Notably, tachypnea is the most predictive of the SIRS criteria for adverse outcome. This is likely because tachypnea is also an indicator of pulmonary organ dysfunction and a feature commonly associated with pneumonia and acute respiratory distress syndrome (ARDS), both of which are associated with increased mortality in sepsis. Altered mental status is another common feature. It is considered a sign of organ dysfunction and is associated with increased mortality. Mild disorientation or confusion is especially common in elderly individuals. Other manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtundation or comatose states. The cause of these mental status abnormalities is not entirely understood, but, in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a causative factor. In septic shock, it is important to identify any potential source of infection. This is particularly important in cases where a site of infection can be removed or drained, as in certain intra-abdominal infections, soft tissue abscesses and fasciitis, or perirectal abscesses. The following physical signs help to localize the source of an infection:         Central nervous system (CNS) infection - Profound depression in mental status, signs of meningismus (neck stiffness) Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal erythema and exudates, inspiratory stridor, cervical lymphadenopathy Chest and pulmonary infections - Dullness on percussion, bronchial breath sounds, localized rales, any evidence of consolidation Cardiac infections - Any new murmur, especially in patients with a history of intravenous (IV) drug use Abdominal and GI infections - Abdominal distention, localized tenderness, guarding or rebound tenderness, rectal tenderness or swelling Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, pain on cervical motion, adnexal tenderness or masses, cervical discharge Bone and soft tissue infections - Focal erythema, edema, tenderness, crepitus in necrotizing infections, fluctuance, pain with joint range of motion, joint effusions and associated warmth/erythema Skin infections - Petechiae, purpura, erythema, ulceration, bullous formation, fluctuance

Complications
Acute respiratory distress syndrome
Acute lung injury (ALI) leading to ARDS is a major complication of severe sepsis and septic shock. The incidence of ARDS is approximately 18% in patients with septic shock, and mortality rates approach 50%. ARDS also leads to prolonged intensive care unit (ICU) stays and an increased incidence of ventilatorassociated pneumonia. ALI and ARDS secondary to severe sepsis demonstrate the manifestations of underlying sepsis and the associated multiple organ dysfunction. Pulmonary manifestations include acute respiratory distress and acute respiratory failure resulting from severe hypoxemia caused by intrapulmonary shunting. Fever and leukocytosis may be present secondary to the lung inflammation. The severity of ARDS may vary from mild lung injury to severe respiratory failure. The onset of ARDS usually is within 12-48 hours of the inciting event. The patients demonstrate severe dyspnea at rest, tachypnea, and hypoxemia; anxiety and agitation also are present.

Other complications
Acute renal failure (ARF) occurs in 40-50% of patients with septic shock. ARF complicates therapy and worsens the overall outcome. Disseminated intravascular coagulation (DIC) occurs in 40% of patients with septic shock.

Other complications of septic shock include chronic renal dysfunction, mesenteric ischemia, myocardial ischemia and dysfunction, liver failure, and other complications related to prolonged hypotension and organ dysfunction. Prolonged tissue hypoperfusion can lead to long-term neurologic and cognitive sequelae as well.[9]

Approach Considerations
Several imaging modalities are used to detect a clinically suspected focal infection, the presence of a clinically occult focal infection, and a complication of sepsis and septic shock.

Complete Blood Count With Differential
The white blood cell (WBC) count and the WBC differential can be somewhat helpful in predicting bacterial infection, albeit an elevated WBC count is not specific to infection. In the setting of fever without localizing signs of infection, a WBC count of greater than 15,000/µL or a neutrophil band count of greater than 1500/µL has about a 50% correlation with bacterial infection. WBC counts of greater than 50,000/µL or less than 300/µL are associated with significantly decreased rates of survival. Hemoglobin concentration dictates oxygen-carrying capacity in blood, which is crucial in shock to maintain adequate tissue perfusion. The goal is to maintain a hematocrit of greater than 30% and a hemoglobin concentration higher than 10 g/dL. Platelets, an acute-phase reactant, usually increase at the onset of any serious stress and are typically elevated in the setting of inflammation. However, the platelet count will fall with persistent sepsis, and disseminated intravascular coagulation (DIC) may develop.

Blood Chemistry
At regular intervals, obtain metabolic assessment with serum electrolytes, including magnesium, calcium, phosphate, and glucose. Sodium and chloride levels are abnormal in severe dehydration. Decreased bicarbonate can point to acute acidosis. Glucose control is important in the management of sepsis, with hyperglycemia associated with higher mortality. Serum lactate is perhaps the best serum marker for tissue perfusion given that it is elevated in conditions of anaerobic metabolism, which occurs when tissue oxygen demand exceeds supply. This can result from decreased arterial oxygen content (hypoxemia), decreased perfusion pressure (hypotension), maldistribution of flow, and decreased diffusion of oxygen across capillary membranes to target tissues, and decreased oxygen utilization on a cellular level. There is also evidence that lactate can be elevated in sepsis in the absence of tissue hypoxia, as a consequence of mitochondrial dysfunction and downregulation of pyruvate dehydrogenase, which is the first step in oxidative phosphorylation.[32] Lactate levels higher than 2.5 mmol/L are associated with an increase in mortality. The higher the serum lactate, the worse the degree of shock and the higher the mortality rate. levels higher than 4 mmol/L in patients with suspected infection have been shown to increase mortality odds 5-fold and are associated with a mortality rate approaching 30%.[33] It has been hypothesized that lactate clearance is a measure of tissue reperfusion and an indication of adequate therapy.[34, 35] Assess renal and hepatic function with the following:      Serum creatinine Blood urea nitrogen (BUN) Bilirubin Alkaline phosphatase Alanine aminotransferase (ALT)

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

Coagulation Studies
Assess the coagulation status with the prothrombin time (PT) and the activated partial thromboplastin time (aPTT). Patients with clinical evidence of a coagulopathy require additional tests to detect the presence of DIC. The PT and the aPTT are elevated in DIC. Fibrinogen levels are decreased and fibrin split products increased in the setting of DIC.

Blood Culture
Blood cultures should be obtained in patients who have suspected sepsis in order to isolate a specific organism and tailor antibiotic therapy. Note, however, that blood cultures are positive in fewer than 50% of cases of sepsis. The blood culture is the primary means for the diagnosis for intravascular infections (eg, endocarditis) and infections of indwelling intravascular devices. The individuals at high risk for endocarditis are intravenous (IV) drug abusers and patients with prosthetic heart valves. The patients at risk for bacteremia include adults who are febrile with an elevated WBC count or neutrophil band count, elderly patients who are febrile, and patients who are febrile with neutropenia. These populations have a 20-30% incidence of bacteremia. The incidence of bacteremia increases to at least 50% in patients with sepsis and evidence of end-organ dysfunction.

Urinalysis and Urine Culture
Perform a urinalysis and urine culture for every patient who is septic. Urinary tract infection (UTI) is a common source for sepsis, especially in elderly individuals. Adults who are febrile without localizing symptoms or signs have a 10-15% incidence of occult urinary tract infection. Again, obtaining a culture is important in order to isolate a specified organism and to tailor antibiotic therapy.

Gram Stain and Culture of Secretions and Tissue
Obtain secretions or tissue for Gram stain and culture from the sites of potential infection. The Gram stain is the only immediately available test that can document the presence of bacterial infection and guide the choice of initial antibiotic therapy. If pneumonia is suspected, a sputum specimen should be obtained. Any abscess should be drained promptly, and purulent material sent to the microbiology laboratory for analysis. If meningitis is suspected, a cerebrospinal fluid (CSF) specimen should be obtained.