Septic shock

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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 2550%.[1]
Contents
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1 Definition 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:

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/mm or elevated > 12000 cells/mm. Heart rate > 90 beats per minute Temperature: Fever > 38.5 C (101.3 F) or hypothermia < 35.0 C (95.0 F)

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.

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

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-. 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.

Volume resuscitation[2] Early antibiotic administration[2] Early goal directed therapy[2]

4. 5.

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]

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 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 38C (100.4F) or less than 36C (96.8F) 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/L or lower than 4000/L, 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: 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) 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 hosts 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 Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators

Cellular mediators Lipopolysaccharide Lipoteichoic acid Peptidoglycan Superantigens Endotoxin Humoral mediators Cytokines TNF-alpha and IL-1

Potent proinflammatory effect

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 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 protein1) 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-1, IL-1, 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 fibrinolysisnamely, 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-PAdependent 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 supplya 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 anoxiathat 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 guts 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 livers 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

 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).

Gram stain of blood showing the 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 A 28-yearold 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 Patients 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 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 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 patients independence, reliance on family support, and need for chronic nursing home or institutionalized care.

Septic Shock Clinical Presentation

Overview Presentation DDx Workup Treatment Medication
Updated: Aug 13, 2012

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 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 patients 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 patients 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/L or a neutrophil band count of greater than 1500/L has about a 50% correlation with bacterial infection. WBC counts of greater than 50,000/L or less than 300/L 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) 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.

Radiography
Chest
Since most patients that present with sepsis have pneumonia, one should obtain a chest radiograph because the clinical examination is unreliable for the detection of pneumonia, especially in elderly patients. Infiltrates are detected with a chest radiograph in about 5% of febrile adults without localizing signs of infection; therefore, chest radiography should be routine in adults who are febrile without localizing symptoms or signs and in patients who are febrile with neutropenia and without pulmonary symptoms.

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

Acute respiratory distress syndrome (ARDS) in a patient who developed septic

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

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

In early ARDS, the chest radiograph results may be normal. The typical findings of noncardiogenic pulmonary edema are bilateral, hazy, symmetric homogenous opacities, which may demonstrate air bronchograms. The margins of pulmonary vessels become indistinct and obscured with disease progression. The usual findings of metastatic pulmonary edema, such as Kerley A or B lines, are not usually observed; a perihilar distribution of opacities is also absent. Furthermore, other findings of cardiogenic pulmonary edema, such as cardiomegaly, vascular redistribution, and pleural effusions, also are not present. With disease progression, the ground glass opacities change into heterogeneous, linear or reticular infiltrates. Days to weeks later, either persistent chronic fibrosis may develop or the chest radiograph appearance becomes more normal. Periodic chest radiographs during the management of ARDS are

particularly important to diagnose barotrauma, adequate positioning of an endotracheal tube and intravascular catheters, and occurrence of nosocomial pneumonia. A scheme to grade the severity of lung injury, the lung injury score, has been proposed. The lung injury score is calculated after evaluating the severity of 4 componentsthe chest roentgenogram score, hypoxemia score, the positive end-expiratory pressure (PEEP) score, and the respiratory system compliance score. A lung injury score of greater than 2.5 is associated with severe lung injury or ARDS.

Abdomen
Acquire supine and upright or lateral decubitus abdominal films because they may be useful when an intra-abdominal source of sepsis is suspected. Abdominal plain films should be obtained if clinical evidence of bowel obstruction or perforation exists.

Extremities
Plain radiographs of the extremities may be helpful when deep soft-tissue infection is suspected. These films can show evidence of soft-tissue gas formation; however, it is important to emphasize that necrotizing fasciitis is a clinical diagnosis (eg, extreme pain, crepitus, bullae, hemorrhage, foulsmelling exudates). If clinical suspicion of necrotizing fasciitis is high, a surgical consultation should be obtained immediately; such a patient should be taken promptly to the operating room (OR) for intervention, often without the need for any imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) can show evidence of subcutaneous and deep tissue inflammation; however, neither modality is sensitive or specific in the setting of necrotizing deep tissue infection, and neither should be relied upon to make this diagnosis. Plain radiographs can also show evidence of osteomyelitis, although MRI is much more sensitive for making this diagnosis.

Ultrasonography
Abdominal ultrasonography is indicated when evidence of acute cholecystitis or ascending cholangitis exists (eg, right upper quadrant abdominal tenderness, fever, vomiting, elevated LFTs, bilirubin, and alkaline phosphatase levels). Surgery or endoscopic retrograde cholangiopancreatography (ERCP) may be urgently necessary in the setting of sepsis with acute cholecystitis or ascending cholangitis.

Computed Tomography
Obesity or the presence of excessive intestinal gas markedly interferes with abdominal imaging by ultrasonography; therefore, CT scanning is preferred. The CT scan is the imaging modality of choice for excluding an intra-abdominal abscess or a retroperitoneal source of infection. An abdominal CT scan should be obtained if the patient has abdominal or flank tenderness in the setting of sepsis. Certain abdominal processes (eg, diverticular abscess, ischemic bowel, appendicitis, perinephric abscess) may require urgent operative intervention. When clinical evidence exists of a deep soft tissue infection, such as crepitus, bullae, hemorrhage, or foul smelling exudate, obtain a plain radiograph. The presence of soft tissue gas often dictates surgical exploration. If evidence of increased intracranial pressure (ICP) (eg, papilledema) or focal mass lesions (focal defects, preceding sinusitis or otitis, recent intracranial surgery) exists, antibiotics should be started and a head CT scan should be obtained. CSF cultures will not be affected by the administration of antibiotics for at least several hours; therefore, proper antibiotic administration should not be delayed by the procedure if there is a high suspicion for meningitis.

If bacterial meningitis is strongly suspected, then a lumbar puncture (LP) should be performed without the delay of obtaining a CT scan. If the opening pressure is elevated, then only as much CSF as is needed for culture should be obtained.

Lumbar Puncture
A lumbar puncture should be performed if clinical evidence or suspicion for meningitis or encephalitis exists. Broad-spectrum antibiotics to cover meningitisshould be administered before starting the procedure. In patients with an acute fulminant presentation, a rapid onset of septic shock, and a severe impairment of mental status, use this procedure to rule out bacterial meningitis.

Other Evaluations
Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are indicated in patients with septic shock. These measures are necessary because these patients often require admission to an intensive care unit (ICU) for invasive monitoring and support. Echocardiography is another modality that may be considered. It has a number of uses in assessing patients with septic shock.[36]

Staging
Two well-defined forms of MODS of sepsis exist. In either, the development of acute lung injury (ALI) or ARDS is of key importance to the natural history, although ARDS is the earliest manifestation in all cases. In the more common form of MODS, the lungs are the predominant, and often the only, organ system affected until very late in the disease. These patients most often present with primary pulmonary disorder (eg, pneumonia, aspiration, lung contusion, near drowning, chronic obstructive pulmonary disease [COPD] exacerbation, hemorrhage, pulmonary embolism). Progression of lung disease occurs to meet the ARDS criteria. Pulmonary dysfunction may be accompanied by encephalopathy or mild coagulopathy and persists for 2-3 weeks. At this time, the patient either begins to recover or progresses to develop fulminant dysfunction in other organ systems. Once another major organ dysfunction occurs, these patients often do not survive. In the second, less common, form of MODS, the presentation is quite different. These patients often have an inciting source of sepsis in organs other than the lung (the common source being intra-abdominal sepsis), extensive blood loss, pancreatitis, and vascular catastrophes. ALI or ARDS develops early, but dysfunction in other organ systems also develops much sooner. The organ systems affected are hepatic, hematologic, cardiovascular, central nervous system (CNS), and renal. Patients remain in a pattern of compensated dysfunction for several weeks and then either recover or deteriorate further and die. Criteria for mild and severe organ dysfunction have been established (see the table below). Table 2. Criteria for Organ Dysfunction (Open Table in a new window)

Organ System Mild Criteria Pulmonary Hypoxia/hypercarbia requiring assisted ventilation for 3-5 d Bilirubin 2-3 mg/dL or other liver

Severe Criteria ARDS requiring PEEP >10 cm H2 O and FiO2 < 0.5 Jaundice with bilirubin 8-

Hepatic

function tests more than twice 10 mg/dL normal, PT elevated to twice normal Renal Oliguria ( < 500 mL/d or increasing Dialysis creatinine) 2-3 mg/dL Stress ulceration with need for transfusion, acalculous cholecystitis DIC Hyperdynamic state not responsive to pressors Coma Combined motor and sensory deficit

Gastrointestinal Intolerance of gastric feeding for more than 5 d Hematologic Cardiovascular CNS aPTT >125% of reference range, platelets < 50-80,000 Decreased ejection fraction with persistent capillary leak Confusion

Peripheral Mild sensory neuropathy nervous system

aPTT = Activated partial thromboplastin time; ARDS = acute respiratory distress syndrome; CNS = central nervous system; DIC = disseminated intravascular coagulation; FiO2 = fraction of inspired oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time.

TREATMENT and MANAGEMENT

Approach Considerations
The treatment of patients with septic shock consists of the following 3 major goals: Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. Identify the source of infection and treat with antimicrobial therapy, surgery, or both. Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiple organ dysfunction syndrome (MODS). The principles in the management of septic shock, based on current literature, include the following components: Early recognition Early and adequate antibiotic therapy Source control Early hemodynamic resuscitation and continued support Corticosteroids (refractory vasopressor-dependent shock)

 Drotrecogin alpha (severely ill if APACHE [Acute Physiology And Chronic Health Evaluation] II score >25) Tight glycemic control Proper ventilator management with low tidal volume in patients with acute respiratory distress syndrome (ARDS) Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes antimicrobial therapy targeting the most likely pathogen, removal or drainage of the infected foci, treatment of complications, and interventions to prevent and treat effects of harmful host responses. Identifying and obtaining source control is an essential component of sepsis management.

General Treatment Guidelines

The major focus of resuscitation from septic shock is supporting cardiac and respiratory functions. The other organ systems also may require attention and support during this critical period. Patients in septic shock generally require intubation and assisted ventilation because respiratory failure either is present at the onset or may develop during the course of the illness. Correction of shock state and abnormal tissue perfusion is the next step in the treatment of patients with septic shock. In 2004, the first set of formal treatment guidelines for septic shock were published.[37] These guidelines were formulated by an international consensus group that was composed of experts from 11 organizations, including the Society of Critical Care Medicine (SCCM), the American College of Chest Physicians (ACCP), the European Society of Intensive Care Medicine (ESICM), and the American College of Emergency Physicians (ACEP). These guidelines, known as the Surviving Sepsis Campaign, were updated in 2008 and reflect the most modern opinion on the treatment of septic shock.[38]

Respiratory support
An initial assessment of airway and breathing is very important in a patient with septic shock. Supplemental oxygen should be administered to all patients with suspected sepsis. Early intubation and mechanical ventilation should be strongly considered for patients with an oxygen requirement, dyspnea or increased respiratory rate, persistent hypotension, or those with evidence of poor peripheral perfusion.

Circulatory support
Patients with suspected septic shock require an initial crystalloid fluid challenge of 20-30 mL/kg (1-2 L) over 30-60 minutes, with additional fluid challenges at rates of up to 1 L over 30 minutes. (A fluid challenge is the rapid administration of volume over a particular period, followed by an assessment of the response.) (See Fluid Resuscitation.) Crystalloid administration is titrated to a central venous pressure (CVP) goal between 8 and 12 mm Hg or signs of volume overload (dyspnea, pulmonary rales, or pulmonary edema on the chest radiograph). Patients with septic shock often require a total 4-6 L or more of crystalloid resuscitation. CVP measurement should not be entirely relied upon, because there is some debate as to how accurately it correlates with intravascular volume status, especially in fluid-resuscitated patients.[39] Urine output (UOP) should also be monitored as a measure of dehydration. UOP lower than 30-50 mL/h should prompt further fluid resuscitation. Some studies have used noninvasive means of estimating CVP for example, ultrasonography to measure inferior vena cava diameter as a surrogate for volume status. Nagdev et al used the difference between inspiratory and expiratory caval diameter (the caval index) to predict CVP and found that a 50% difference predicted a CVP lower than 8 mm Hg with both a sensitivity and a specificity greater than 90%.[40] Given that third-spacing of intravascular fluid is a hallmark of septic shock, it makes sense that administration of colloid might be beneficial. However, colloid resuscitation (with albumin or hetastarch)

has not been shown in meta-analyses to have any benefit over isotonic crystalloid resuscitation (isotonic sodium chloride solution or lactated Ringer solution).[30] The SAFE trial enrolled 7000 intensive care unit (ICU) patients requiring fluid resuscitation, only about 1200 of whom had severe sepsis. Overall, no difference was seen between the 2 treatment groups; however, there was a trend toward improved outcome in patients with severe sepsis who received 4% albumin versus normal saline.[41] These data are inconclusive, especially in regard to the initial resuscitation phase for septic shock in the emergency department (ED); therefore, crystalloid resuscitation is recommended.

Antimicrobial therapy
Recommendations are that antibiotic therapy be administered within the first hour of recognition of septic shock; delays in administration are associated with increased mortality.[38, 6] Selection of antibiotic agents is empirically based on an assessment of the patients underlying host defenses, the potential source of infection, and the most likely responsible organisms. (See Empirical Antimicrobial Therapy.) Antibiotic choice must be broad spectrum, covering gram-positive, gram-negative, and anaerobic bacteria when the source is unknown. In addition, consideration must be given to pathogens with antibiotic resistance, such as methicillinresistant S aureus (MRSA), Pseudomonas species, and gram-negative organisms with extendedspectrum beta-lactamase (ESBL) activity. Patients who are at risk for these types of infection are nursing home residents, residents of chronic care facilities, those with recent hospitalizations, dialysis-dependent patients, or those with chronic medical conditions that require multiple hospitalizations.

Temperature control
Fever generally requires no treatment, except in patients with limited cardiovascular reserve, because of the increased metabolic requirements. Antipyretic drugs and physical cooling methods, such as sponging or cooling blankets, may be used to lower the patients temperature.

Metabolic support
Patients with septic shock develop hyperglycemia and electrolyte abnormalities. Serum glucose should be maintained in the reference range with insulin infusion. (See Tight Glycemic Control.) Hypokalemia, hypomagnesemia, and hypophosphatemia should be measured and corrected if deficient.

Correction of anemia and coagulopathy

Hemoglobin as low as 8 g/dL is well tolerated and does not require transfusion unless the patient has poor cardiac reserve or demonstrates evidence of myocardial ischemia. Thrombocytopenia and coagulopathy are common in patients with sepsis and do not require replacement with platelets or fresh frozen plasma, unless the patient develops active clinical bleeding.

Management of renal dysfunction

UOP and renal function must be monitored closely in all patients with sepsis. Any abnormalities should prompt attention to adequacy of circulating blood volume, cardiac output, and blood pressure; these should be corrected if inadequate.

Nutritional support
Patients with septic shock generally have high protein and energy requirements. Although a brief period (several days) without nutrition is not going to cause deleterious effects, prolonged starvation must be avoided. Early nutritional support is of critical importance in patients with septic shock. The enteral route is preferred, unless the patient has an ileus or other intestinal abnormality. Gastroparesis commonly is observed, which can be treated with motility agents or placement of a small bowel feeding tube.

Diminished bowel sounds should not prevent a trial of enteral nutrition, although motility agents or the use of a small bowel feeding tube may be necessary. The benefits of enteral nutrition are protection of gut mucosa, avoiding translocation of organisms from the gastrointestinal (GI) tract, lowering the complication rate, and lowering cost. Glutamine, an essential amino acid, influences the mucosal integrity of the GI tract. Insufficient levels of glutamine may occur from starvation or lack of enteral feeding, a condition commonly observed with total parenteral nutrition. Glutamine deficiency contributes to mucosal atrophy, predisposing translocation of bacteria or endotoxin from the gut lumen. Enteral nutrition with glutamine-containing formulas can prevent this relapse of systemic inflammatory response syndrome (SIRS) in patients on adequate therapy.

Principles of Early Goal-Directed Therapy

Sepsis treatment has evolved considerably over the past 10 years as it has transitioned from a disease that is a primary concern of critical care physicians in an ICU setting to one that has a major impact in the ED as well. Early recognition and early aggressive therapy for patients with sepsis are the keys to reducing mortality in sepsis. Rivers et al brought this issue to the forefront with a landmark study in 2001, which involved the institution of a treatment protocol for patients with septic shock, termed early goal-directed therapy (EGDT).[42] EGDT emphasizes early recognition of patients with potential sepsis in the ED, early broad-spectrum antibiotics, and a rapid crystalloid fluid challenge, followed by goal-directed therapy for those patients who remain hypotensive or severely ill after this initial therapy. In the study by Rivers et al, patients who did not respond to an initial fluid challenge (20-30 mL/kg bolus) and antibiotics received a central venous catheter in the internal jugular or subclavian vein to measure CVP and an arterial catheter to measure arterial blood pressure directly. EGDT is a 3-step protocol aimed at optimizing tissue perfusion. The first step involves titrating crystalloid fluid administration to CVP by administering 500-mL boluses of fluid until the CVP measures between 8 and 12 mm Hg. CVP is a surrogate for intravascular volume, as excess circulating blood volume is contained within the venous system. Patients with septic shock will frequently require 4-6 L or more of crystalloid to achieve this goal. Clinical signs of volume overload should be monitored as well, including developing periorbital or extremity edema, crackles on pulmonary examination, increasing oxygen requirement, or increased difficulty breathing. In patients who are mechanically ventilated, the target CVP is 12-15 mm Hg due to increased intrathoracic pressure. The second step, if the patient has not improved with fluid alone, is to administer vasopressors to attain a mean arterial pressure (MAP) greater than 65 mm Hg. It is important to administer an adequate crystalloid fluid challenge (at least 2 L normal saline) before administering vasopressors, unless the patient is in extremis and requires immediate vasopressor support. The third step is to evaluate the central venous oxygen saturation (ScvO2), which is measured from the central venous line in the superior vena cava. ScvO2 is the oxygen saturation of blood returning from tissue capillary beds, and it reflects the difference between overall oxygen supply and demand. Like lactate, ScvO2 is an indicator of tissue perfusion. An ScvO2 of less than 70% is considered abnormal and indicative of suboptimal oxygen delivery compared with oxygen demand. Adequate oxygen delivery is first achieved by administering supplemental oxygen by face mask, increasing intravascular circulating volume, and increasing MAPin other words, the first 2 steps of EGDT. Additional means of increasing tissue oxygen delivery include maximizing oxygen delivery to the alveoli (mechanical ventilation with a fraction of inspired oxygen [FiO2] of 1.0), maximizing the hemoglobin concentration (transfuse packed red blood cells [pRBCs] if anemic), and augmenting cardiac output

(dobutamine to increase inotropy once preload has been optimized). The protocol by Rivers et al called for a blood transfusion if the hematocrit was 30%. As a last step in the protocol, dobutamine infusion was started (increasing cardiac output via pure betaagonism) if ScvO2 is less than 70% despite all the above measures being optimized. ScvO2 greater than 70% is therefore the target for EGDT, indicating adequate oxygen delivery. Rivers et al measured ScvO2 via a fiberoptic sensor at the tip of the central venous catheter and a standalone monitor that displayed ScvO2continuously. This concept was based on earlier work targeting treatment goals based on increasing tissue oxygen delivery.[43, 44] An alternative to continuous ScvO2 measurement is to send a venous blood gas from the central venous line for oxygen saturation, measured by a standard blood gas analyzer. Crowe et al implemented a protocol that substituted spot-check ScvO2measurement for continuous measurement and found that compliance with this was less than 30%. Despite low compliance, there was a trend toward decreased mortality in patients with septic shock treated with a protocol that included timely antibiotics, appropriate crystalloid administration, CVP monitoring, and vasopressors titrated to an MAP goal.[45] A recent study suggests that following lactate clearance may be no less effective than monitoring continuous ScvO2 as the third goal in EGDT.[35] However, the advantage of continuous ScvO2 monitoring is that immediate interventions can be made if the ScvO2 drops below 70%. Rivers et al enrolled 263 patients who met criteria for septic shock. These patients were randomized to EGDT or to standard therapy. The latter included placement of a central venous line and an arterial catheter (both of which are relatively invasive measures and probably not standard in most EDs). Despite this, the investigators found an absolute mortality benefit of 16% with EGDT (30% mortality with EGDT vs 46% with standard therapy). When the data were examined closely, it was found that in the EGDT group, patients received, on average, more crystalloid fluid (5.0 L vs 3.5 L), and a much higher percentage of patients received blood transfusion (64% vs 18%). The resulting average ScvO2 measured after therapy was 95% for the EGDT group versus 60% in the standard group. Since the publication of this trial, several studies have shown the value of protocolized care and of socalled sepsis treatment bundles, which include early broad-spectrum antibiotic administration, EGDT focused on achieving ScvO2 above 70%, and rapid lactate clearance. Sepsis bundles also include administration of corticosteroids for refractory shock, tight glycemic control, low tidal volume ventilatory strategies, and administration of recombinant activated protein C (APC) in an ICU setting.

Venous Access
Ensure that all patients in septic shock receive adequate venous access for volume resuscitation. Two large-bore (16-gauge) intravenous (IV) lines should be placed if possible when sepsis is suspected in order to administer aggressive fluid resuscitation and broad-spectrum antibiotics. A central venous catheter should be placed in the internal jugular or subclavian vein in patients with septic shock if hypotension is refractory to a crystalloid fluid bolus of 20-30 mL/kg (1-2 L) over 30-60 minutes or if fluids cannot be infused rapidly enough. A central venous catheter allows administration of medication centrally, and it provides multiple ports for rapid fluid administration, antibiotics, and vasopressors if needed. It also allows the measurement of CVP, a surrogate for volume status, if CVP measurement capability is available.

Urinary Catheterization

An indwelling urinary catheter should be placed in order to follow UOP, which is a marker for adequate renal perfusion and cardiac output. Normal UOP in an adult is greater than 0.5 mL/kg/h or about 30-50 mL/h for most adults.

Cardiac Catheterization
Patients in septic shock require right-heart catheterization with a pulmonary artery (Swan-Ganz) catheter. This catheter provides an accurate assessment of the volume status of a septic patient. The cardiac output measurement can be obtained; furthermore, determination of mixed venous oxygenation is helpful in determining the status of tissue oxygenation. The right-sided cardiac catheterization will detect those patients (25%) with sepsis and hypotension who have underlying congestive heart failure (usually due to myocardial suppressant factor).

Intubation and Mechanical Ventilation

Most patients with sepsis develop respiratory distress as a manifestation of severe sepsis or septic shock. The lung injury is characterized pathologically as diffuse alveolar damage (DAD) and ranges from acute lung injury (ALI) to ARDS. (See Pathophysiology.) These patients need intubation and mechanical ventilation for optimum respiratory support. Intubation should be considered early in the course of sepsis, even in the absence of frank hypoxia or respiratory distress. Delivering oxygen at an FiO2 of 1 directly into the trachea is far superior to delivery via a nonrebreather oxygen mask. Mechanical ventilation, with appropriate sedation and paralysis, also eliminates the work of breathing and decreases the metabolic demands of breathing, which accounts for about 30% of the total metabolic demand at baseline. Alveolar overdistention and repetitive opening and closing of alveoli during mechanical ventilation have been associated with an increased incidence of ARDS. Low tidal volume ventilatory strategies have been used to minimize this type of alveolar injury. The recommended tidal volume is 6 mL/kg with plateau pressures kept below 30 mL H2 O. Positive end-expiratory pressure (PEEP) is required to prevent alveolar collapse at end-expiration.[54]

Goals of Hemodynamic Support

Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation, ultimately causing cellular, and then organ system, dysfunction. Therefore, the goals of hemodynamic therapy are restoration and maintenance of adequate tissue perfusion to prevent multiple organ dysfunction. Careful clinical and invasive monitoring is required for assessment of global and regional perfusion. A MAP lower than 60 mm Hg or a decrease in MAP of 40 mm Hg from baseline defines shock at the bedside. Elevation of the blood lactate level on serial measurements of lactate can indicate inadequate tissue perfusion. Mixed venous oxyhemoglobin saturation serves as an indicator of the balance between oxygen delivery and consumption. A decrease in maximal venous oxygen (MVO2) can be secondary to decreased cardiac output; however, maldistribution of blood flow in patients experiencing septic shock may artificially elevate the MVO2levels. An MVO2 of less than 65% generally indicates decreased tissue perfusion. Regional perfusion in patients with septic shock is evaluated by adequacy of organ function. The evaluation includes evidence of myocardial ischemia, renal dysfunction manifested by decreased urine output or increased creatinine, central nervous system (CNS) dysfunction indicated by a decreased level of consciousness, hepatic injury shown by increased levels of transaminases, splanchnic hypoperfusion manifested by stress ulceration, ileus, or malabsorption.

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

Fluid Resuscitation
Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients with sepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of the patients volume and cardiovascular status. Monitor patients for signs of volume overload, such as dyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chest radiograph. Improvement in the patients mental status, heart rate, MAP, capillary refill, and urine output indicate adequate volume resuscitation. Large volumes of fluid are required as initial therapy in patients with septic shock. Administer fluid therapy with predetermined boluses (500 mL or 10 mL/kg) titrated to the clinical end points of heart rate, UOP, and blood pressure. Continue fluid resuscitation until the clinical end points are reached or the pulmonary capillary wedge pressure exceeds 18 mm Hg. Volume resuscitation can be achieved with either crystalloids or colloid solutions. The crystalloids are 0.9% sodium chloride and lactated Ringer solution; the colloids are albumin, dextrans, and pentastarch. Clinical trials have failed to show either type to be superior as the resuscitation fluid of choice in septic shock. However, 2-4 times more volume of crystalloids than colloids are required, and crystalloids take a longer time to achieve the same end points, whereas the colloid solutions are much more expensive. Data from several studies suggest that formation of pulmonary edema is no different with crystalloids compared to colloids when the filling pressures are maintained at a lower level. However, if the higher filling pressures are required for maintenance of optimal hemodynamics, crystalloids may increase extravascular fluid fluxes because of a decrease in plasma oncotic pressure. In some patients, clinically assessing the response to volume infusion may be difficult. By monitoring the response of the CVP or pulmonary artery occlusion pressure to fluid boluses, the physician can assess such patients. A sustained rise in filling pressure of more than 5 mm Hg after a volume is infused indicates that the compliance of the vascular system is decreasing as further fluid is being infused. Such patients are susceptible to volume overload, and further fluid should be administered with care.

Vasopressor Therapy
If the patient does not respond to several liters of volume infusion with isotonic crystalloid solution (usually 4 L or more) or evidence of volume overload is present, the depressed cardiovascular system can be stimulated by vasopressors, such as dopamine, norepinephrine, epinephrine, phenylephrine, and vasopressin. Vasopressor administration is required for persistent hypotension once adequate intravascular volume expansion has been achieved. Persistent hypotension is typically defined as systolic blood pressure lower than 90 mm Hg or MAP lower than < 65 mm Hg with altered tissue perfusion. The mean blood pressure required for adequate splanchnic and renal perfusion (MAP of 60 or 65 mm Hg) is based on clinical indices of organ function. The goal of vasopressor therapy is to reverse the pathologic vasodilation and altered blood flow distribution that occur as a result of the activation of adenosine triphosphate (ATP)-dependent potassium channels in vascular smooth muscle cells and the synthesis of the vasodilator nitric oxide (NO). In EGDT, vasopressors are recommended once a CVP of 8-12 mm Hg is achieved in the setting of persistent hypotension, and the goal is to titrate the dose to a MAP greater than 65 mm Hg. Vasopressors should be started early, regardless of fluid resuscitation, if frank shock is apparent (systolic blood pressure < 70 mm Hg or signs of profound tissue hypoperfusion).

The recommended first-line agent for septic shock is either norepinephrine or dopamine.[38] Norepinephrine has predominant alpha-receptor agonist effects and results in potent peripheral arterial vasoconstriction without significantly increasing heart rate or cardiac output. The dose range for norepinephrine is 5-20 mcg/min, and it is not based on the weight of the patient. Norepinephrine, in theory, is the ideal vasopressor in the setting of warm shock, where peripheral vasodilation exists in association with normal or increased cardiac output. The typical patient with warm shock has warm extremities but with systemic hypotension and tachycardia, the result of decreased systemic vascular resistance. If dopamine is used, treatment usually begins at a rate of 5-10 g/kg/min IV, and the infusion is adjusted according to the blood pressure and other hemodynamic parameters. Often, patients may require high doses of dopamine (as much as 20 g/kg/min). Presently, norepinephrine is the preferred drug because dopamine is known to cause unfavorable flow distribution. Norepinephrine has been shown to be clinically significantly safer and somewhat more effective in treating septic shock than dopamine.[55] In a systematic review of randomized controlled trials, norepinephrine was significantly superior to dopamine in improving both in-hospital and 28-day mortality in septic shock patients.[78] Second-line vasopressors for patients with persistent hypotension despite maximal doses of norepinephrine or dopamine are epinephrine, phenylephrine, and vasopressin. Epinephrine has been shown to clearly increase MAP in patients unresponsive to other vasopressors, mainly by its potent inotropic effects on the heart. Its adverse effects include tachyarrhythmias, myocardial and splanchnic ischemia, and increased systemic lactate concentrations. Phenylephrine is a pure alpha-receptor agonist, which results in potent vasoconstriction, but this is at the expense of depressed myocardial contractility and heart rate. This agent may be considered first-line in patients with extreme tachycardia; its pure alpha-receptor activity will not result in increased chronotropy.
[56]

Vasopressin has been proposed as a potentially attractive agent in septic shock because it is an endogenous peptide with potent vasoactive effects, and its circulating levels are depressed in septic shock. The characteristics of these agents are described in more detail below.

Norepinephrine
Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. It can increase blood pressure successfully in patients with sepsis who remain hypotensive after fluid resuscitation and dopamine. The dose of norepinephrine may vary from 0.2-1.5 g/kg/min, and large doses as high as 3.3 g/kg/min have been used because of the alpha-receptor down-regulation in sepsis. In patients with sepsis, indices of regional perfusion (eg, urine flow) and lactate concentration have improved following norepinephrine infusion. Two recent trials have shown that a significantly greater proportion of patients treated with norepinephrine were resuscitated successfully, as opposed to the patients treated with dopamine. Therefore, norepinephrine should be used early and should not be withheld as a last resort in patients with severe sepsis who are in shock. The concerns about compromising splanchnic tissue oxygenation have not been proven; the studies have confirmed no deleterious effects on splanchnic oxygen consumption and hepatic glucose production, provided adequate cardiac output is maintained.

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

Dosages range from 2 to 20 g/kg/min. A dosage lower than 5 g/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dosage of 5-10 g/kg/min, beta1-adrenergic effects induce an increase in cardiac contractility and heart rate. At dosages of about 10 g/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and elevation in blood pressure. Dopamine is effective in optimizing MAP in patients with septic shock who remain hypotensive after volume resuscitation. The blood pressure increases primarily as a result of inotropic effect and, thus, will be useful in patients who have concomitant reduced cardiac function. It may be particularly useful in the setting of cold shock, where peripheral vasoconstriction exists (cold extremities) and cardiac output is too low to maintain tissue perfusion. The undesirable effects are tachycardia, increased pulmonary shunting, potential to decrease splanchnic perfusion, and increase in pulmonary arterial wedge pressure. Low-dose (renal-dose) dopamine has been studied; however, several well-designed clinical trials have failed to demonstrate any beneficial effects of such regimens on renal blood flow and function in the setting of circulatory shock of any etiology. Dopamine at a dosage of 2-3 g/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated a beneficial effect of prophylactic or therapeutic low-dose dopamine administration in patients with sepsis who are critically ill. Considering the real side effects of dopamine infusion, the use of renal-dose dopamine should be abandoned.

Epinephrine
Epinephrine can increase MAP by increasing cardiac index and stroke volume, as well as increasing systemic vascular resistance and heart rate. Epinephrine may increase oxygen delivery and oxygen consumption and decreases the splanchnic blood flow. Administration of this agent is associated with an increase in systemic and regional lactate concentrations. The use of epinephrine is recommended only in patients who are unresponsive to traditional agents. The undesirable effects are an increase in lactate concentration, a potential to produce myocardial ischemia, development of arrhythmias, and reduced splanchnic flow.

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

Vasopressin
Vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and excreted by the posterior pituitary. In contrast to endogenous catecholamines (eg, norepinephrine), whose serum levels are universally high in septic shock, vasopressin stores are limited and its levels are low.[57] Furthermore, catecholamine effectiveness on vascular smooth muscle cells is inhibited by the activation of adenosine triphosphate (ATP)-dependent potassium channels and nitric oxide, as mentioned previously. Exogenous administration of vasopressin results in vasoconstriction via activation of V1 receptors on vascular smooth muscle cells that have the effect of inhibiting ATP-dependent potassium channels and, in theory, restoring the effectiveness of catecholamines. Vasopressin is also thought to inhibit NO synthase and therefore counteract the vasodilatory effect of NO. In addition, it increases renal perfusion by causing vasodilation of afferent renal arterioles, in contrast to the renal vasoconstriction caused by catecholamines.

Several small clinic trials have shown that low-dose vasopressin increases MAP and decreases the requirement for catecholamines, such as norepinephrine, while maintaining mesenteric and renal perfusion.[57] However, a large, randomized trial (the VASST trial) failed to show reduced mortality in patients who received vasopressin in addition to norepinephrine as compared with those who received norepinephrine alone, even though vasopressin reduced the requirement for norepinephrine.[58] The major adverse effects attributed to vasopressin (myocardial ischemia, cardiac arrest, mesenteric and digital ischemia) were overall not significantly increased; however, patients with known coronary artery disease or congestive heart failure were excluded from the study. The incidence of digital ischemia was higher with vasopressin use. Also note that the mean time to receiving the drug in this trial was 12 hours; therefore, it does not address the use of vasopressin in early sepsis resuscitation.

Inotropic Therapy and Augmented Oxygen Delivery

Although myocardial performance is altered during sepsis and septic shock, cardiac output generally is maintained in patients with volume-resuscitated sepsis. Data from the 1980s and 1990s suggest a linear relationship between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that the oxygen delivery likely was insufficient to meet the metabolic needs of the patient. However, recent investigators have challenged the concept of pathologic supply dependency, suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation) was not associated with improved patient outcome. Therefore, the role of inotropic therapy is uncertain, unless the patient has inadequate cardiac index, MAP, mixed venous oxygen saturation, and UOP despite adequate volume resuscitation and vasopressor therapy. Patients with severe sepsis or septic shock have hypermetabolism, maldistribution of blood flow, and, possibly, suboptimal oxygen delivery; therefore, attempts at detecting and correcting tissue hypoxia must be made. Lactic acidosis is an indication of either global ischemia (inadequate oxygen delivery) or regional (organ-specific) ischemia. Calculation of pH in the gastric mucosa by gastric tonometry may detect tissue hypoxia in the splanchnic circulation; however, this technique has not been validated extensively and is not available widely. Dobutamine is an inotropic agent that stimulates beta-receptors and results in increased cardiac output. In theory, it can enhance tissue oxygen delivery in patients with septic shock who have received adequate fluid resuscitation and vasopressor support. In EGDT, dobutamine is recommended if there is evidence of tissue hypoperfusion (ScvO2 < 70 mm Hg) after CVP, MAP, and hematocrit goals have been met. In the Rivers et al study, fewer than 15% of patients in the EGDT arm received dobutamine. Although initial aggressive resuscitation to maximize oxygen delivery improves outcome (EGDT), manipulation of oxygen delivery to deliver supraphysiologic oxygen to the tissues with blood transfusion, fluid boluses, or use of inotropes once organ dysfunction has developed has not improved the outcome in patients who are critically ill. Hayes et al reported a higher mortality rate in patients with sepsis who were maintained on high levels of oxygen delivery.[59] In patients with septic shock, the inability to increase oxygen consumption and to decrease lactate levels most likely is a consequence of impaired oxygen extraction or inability to reverse anaerobic metabolism. Boosting oxygen delivery to supranormal levels does not reverse these pathophysiologic mechanisms after the development of organ injury. A trial of increasing oxygen delivery is recommended in patients who have evidence of tissue hypoxia. If augmentation of oxygen delivery is associated with reduction in serum lactate levels and improved target organ perfusion, these interventions may be continued. On the other hand, adequate clinical parameters, such as a MAP, normal cardiac index, and adequate UOP, should be maintained irrespective of the concerns about supply dependence.

Empiric Antimicrobial Therapy

Empirical antimicrobial therapy should be initiated early in patients experiencing septic shock (though it should be noted that they will have little effect on the clinical outcome for at least 24 hours). The following points should always be kept in mind: Early empirical antibiotic coverage is essential; the spectrum will be narrowed when culture results are available. Waiting until cultures are back is an invalid reason to withhold antibiotics. Only 30% of patients with presumed septic shock have positive blood cultures. About 25% of presumed septic shock patients remain culture negative from all sites, but mortality with culture positive counterparts is similar. The selection of appropriate agents is based on the patients underlying host defenses, the potential sources of infection, and the most likely culprit organisms. Antibiotics must be broad-spectrum agents and must cover gram-positive, gram-negative, and anaerobic bacteria because the different classes of these organisms produce an identical clinical picture of distributive shock. If the patient is antibiotic experienced, strongly consider the use of an aminoglycoside rather than a quinolone or cephalosporin for gram-negative coverage. Knowing the antibiotic resistance patterns of both the hospital itself and its referral base (ie, nursing homes) is also important. Administer the antibiotics parenterally, in doses adequate to achieve bactericidal serum levels. Many studies find that the clinical improvement correlates with the achievement of serum bactericidal levels rather than the number of antibiotics administered. When choosing empirical antibiotics, consider the increasing prevalence of methicillin-resistant S aureus (MRSA) and include an agent such as vancomycin or linezolid. This is especially true in patients with a history of IV drug use, those with indwelling vascular catheters or devices, or those with recent hospitalizations or chronic care facility residents. Antianaerobic coverage is indicated in patients with intra-abdominal or perineal infections. Antipseudomonal coverage (ceftazidime, cefepime, ticarcillin, piperacillin, imipenem, meropenem) should be considered in patients who are immunocompromised, especially those with neutropenia or burns. Certain organisms, chiefly Enterobacteriaceae (eg, E coli, K pneumoniae), contain a beta-lactamase enzyme that hydrolyzes the beta-lactam ring of penicillins and cephalosporins and thus inactivates these antibiotics (extended-spectrum beta-lactamase [ESBL]). This phenomenon has become an increasing concern in recent years as its prevalence has increased. Beta-lactam antibiotics that have remained effective against ESBL-producing organisms include cephalomycins (eg, cefotetan) and carbapenems (eg, imipenem, meropenem, ertapenem).[60] In immunocompetent patients, monotherapy with carbapenems (imipenem, meropenem), certain third- or fourth-generation cephalosporins (cefotaxime, cefoperazone, ceftazidime), or extended-spectrum penicillins (ticarcillin, piperacillin), is usually adequate, without the need for a nephrotoxic aminoglycoside. [61] Patients who are immunocompromised typically require dual broad-spectrum antibiotics with overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to others.

Recombinant Human Activated Protein C Therapy

Activated protein C (APC) is an endogenous protein that modulates inflammation and coagulation. Specifically, it inhibits tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6, the mediators thought to play a major role in initiating the inflammatory response seen in sepsis. In addition, it inhibits monocyte and neutrophil adhesion to endothelial cells, and it inhibits thrombin and fibrin production, and thus prevents microvascular thrombi. Sepsis reduces the level of protein C and inhibits conversion of protein C to APC. Administration of recombinant APC inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation. Recombinant human APC (drotrecogin alfa [Xigris]) was originally approved with an

indication to reduce mortality in patients with severe sepsis. The efficacy and safety of drotrecogin alfa has been debated over the past decade. Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011 after analysis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial. Drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study. An early publication by the PROWESS study group demonstrated that the administration of recombinant human APC (drotrecogin alpha, activated) resulted in lower mortality rates in the treatment group than in the placebo group.[62]Notably, this study excluded patients who were expected to die within 28 days (eg, those with end-stage cancer), those with end-stage renal disease or cirrhosis, and those with HIV disease and a CD4 count less than 50. Another study showed the absolute risk of death was reduced by 6.1% in the treatment group (24.7% vs 30.8%). There was a 13% benefit in the sickest patients (817 patients with an APACHE II score >25) and an 18% benefit for the sickest patients with pneumonia (317 patients with APACHE II score >25 and pneumonia).[7] The drawback to APC is an increased incidence of bleeding complications because it inhibits coagulation pathways. Overall bleeding complications were 3.5% in the APC group versus 2% in the placebo group. For this reason, APC is contraindicated in patients with a known hypercoagulable condition, recent major surgery or need for surgery, intracranial surgery or stroke within 3 months, any history of arteriovenous malformation, and cerebral aneurysm or mass. APC is an expensive therapy that is typically instituted once the patient is in the ICU under the care of a critical care physician. Nevertheless, it is good to keep this in mind in the ED and identify patients who may benefit, especially those who are in the most critical condition. Although study data await further confirmation, current recommendations are as follows: Drotrecogin alpha (activated protein C) is the only widely accepted drug specific to the therapy of sepsis. Drotrecogin alpha should be considered for patients with APACHE II scores greater than 25. The main adverse effect of drotrecogin alpha is bleeding. A Cochrane review finally lays to rest the effectiveness of APC in severe sepsis.[63]It harms without any reasonable expectation that it helps the patient with severe sepsis.

Corticosteroid Therapy
Corticosteroid insufficiency has been associated with severe illness.[64] Although theoretical and experimental animal evidence exists for the use of large doses of corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone) in patients with severe sepsis and septic shock, no support exists in the medical literature for the routine use of such doses in these patients. A meta-analysis of prospective, randomized, controlled trials of glucocorticoid use did not report any benefit from corticosteroids and suggested that their use could be harmful.[65] Therefore, high-dose corticosteroids should not be used in patients with severe sepsis or septic shock. However, in a review of 3 meta-analyses, low-dose corticosteroids did not improve survival and were associated with side effects that included superinfections, bleeding, and hyperglycemia.[66] Some trials demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock.[67] Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.

Other studies show that lower-dose steroids may be beneficial for patients with relative adrenal insufficiency. Annane et al studied 299 patients with septic shock, all of whom were intubated, were persistently hypotensive despite crystalloid resuscitation and vasopressor administration, and had evidence of end-organ failure. All patients were randomized to low-dose steroids (hydrocortisone 50 mg q6h and fludrocortisone 50 g daily) versus placebo.[68] Patients were administered a cortisol stimulation test (Cort stim test), which involves measuring cortisol levels before and 30 minutes after administration of cosyntropin (adrenocorticotropic hormone [ACTH]) 0.25 mg IV. A patient whose cortisol level increased by less than 10 g/dL was considered a nonresponder and thus adrenally insufficient. Of the 299 patients with septic shock, 77% were nonresponders. For nonresponders, there was an absolute benefit in mortality of 10% (53% vs 43%) for those who received steroids. Although performing the Cort stim test in the ED may not be practical, given time and resource constraints, it is worth noting that greater than 75% of patients with vasopressor-refractory hypotension were adrenally insufficient. This suggested that the majority of patients with vasopressor-refractory shock would benefit from steroid administration regardless of the results of the Cort stim test. A common choice is hydrocortisone 100 mg IV; a good alternative is dexamethasone 10 mg IV. In 2009, Annane et al published a systematic review of corticosteroid use for severe sepsis and septic shock. Pooled results found that the subgroup of studies using prolonged, low-dose corticosteroid therapy demonstrated a beneficial effect on short-term mortality. No clear benefit was shown with use of highdose corticosteroids for severe sepsis or septic shock.[69] In CORTICUS, the most recent large randomized trial of hydrocortisone versus placebo in patients with septic shock, no difference in mortality rate was noted, even though the patients who received steroids had a more rapid resolution of shock as measured by a shorter duration of vasopressor therapy. [70] However, the incidence of superinfection and recurrent sepsis in those who received steroids was higher. Additionally, the result of the Cort stim test had no bearing on outcome, bringing into question the value of this test in determining who will benefit from steroid treatment. However, the CORTICUS study enrolled all patients with septic shock, regardless of vasopressor response. Therefore, patients in the CORTICUS study had a lower mortality rate than those in the Annane study. The most recent Surviving Sepsis Campaign guidelines from 2008 emphasize that steroids should be administered only in patients with septic shock whose hypotension is poorly responsive to fluid resuscitation and vasopressor therapy.[38] The following key points summarize use of corticosteroids in septic shock: Older, traditional trials of corticosteroids in sepsis were unsuccessful likely because of high doses and poor patient selection. Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependent and possibly relative adrenal insufficiency) have resulted in improved outcome. Corticosteroids should be initiated for patients with vasopressor-dependent septic shock. A Cort stim test may be performed to identify patients with relative adrenal insufficiency, defined recently as failure to increase levels more than 9 g/dL

Tight Glycemic Control

Tight glycemic control has recently become a prominent emphasis in the care of critically ill patients, and recent data has been extrapolated to potentially apply to septic populations. It has been shown to improve mortality both in postoperative surgical patients, including (and particularly) those with sepsis, and in medical ICU patients. A 2001 Belgian study of surgical intensive care unit (SICU) patients that remained in the unit for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucose levels for these patients were maintained from 80-110 mg per dL through the use of intensive insulin therapy. The

benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin. On the basis of the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL, though the logic behind choosing this level is unclear.[37, 71] Van den Berghe documented benefit only once glucose levels were maintained below 110 mg/dl, with increased mortality when blood glucose levels were allowed to reach 130-150 mg/dL.[72] This same group recently finished a large prospective study in medical patients documenting similar benefits in these patients.[73] Tight glycemic control is not without risks. In elderly persons (>75 y) and in those patients with liver failure, excessive hypoglycemic reactions limits its use. Furthermore, to be effective, glycemic control needs to be protocol driven and run by the bedside caregiver, usually the bedside nurse.

Experimental and Other Medical Therapies

Experimental and other medical therapies include nonadrenergic vasopressors and inotropes. The clinical utility of several of these agents remains unproven despite several studies indicating their beneficial effect on hemodynamic instability. Dopexamine has beta 2-adrenergic and dopaminergic effects without any alpha-adrenergic activity and is known to increase splanchnic perfusion. A few small studies have shown that dopexamine increases cardiac index and heart rate and decreases systemic vascular resistance in a dose-dependent manner. The hepatic blood flow and gastric intramucosal pH improve, but results are not reproducible consistently. Dopexamine appears to be promising for patients with sepsis and septic shock, but superiority over the other drugs has not been demonstrated. It continues to be an experimental medication in the United States. Inamrinone (formerly amrinone) and milrinone are inotropic agents with vasodilating properties, and each has a long half-life. The mechanism of action occurs via phosphodiesterase inhibition. These medications are beneficial in cardiac pump failure, but their benefit in patients experiencing septic shock is not well established. Furthermore, these agents have a propensity to worsen hypotension in patients with septic shock. NO is a potent endogenous vasodilator, synthesized from endogenous L-arginine by the enzyme NO synthase. Excessive NO production induces vasodilation and hypotension in patients with sepsis. Inhibitors of NO synthase (N -monomethyl-l-arginine, L-NMMA) in sepsis augment MAP, decreased cardiac output, and increased systemic vascular resistance. Inordinate mortality was the cause of early termination of a randomized trial of NO synthase inhibition with L-NMMA. The clinical benefit of this therapeutic approach in patients with sepsis remains unproven. Despite promising results in animal studies, the use of ibuprofen has not been proven of any benefit in patients with septic shock. The insight that endotoxin, a lipid-polysaccharide compound found in the cell wall of gram-negative bacteria, plays a key role in initiating the humoral cascade observed in septic shock led to the hypothesis that neutralizing the circulating endotoxin with IV administration of an antiendotoxin antibody might be beneficial. Several products have been developed and investigated by carefully conducted human trials. To date, no proven benefit to these agents has been observed. Other methods of extracorporeal elimination of endotoxin, polyclonal antiendotoxin antibodies, or monoclonal antiendotoxin antibodies showed neither improvement in short-term survival nor amelioration of sepsis in humans with septic shock. Trials with some of these compounds are ongoing, and, despite a tendency towards benefit, efficacy data are lacking. Serum levels of TNF and IL-1 are elevated in patients with septic shock. Both produce hemodynamic effects that duplicate those found in sepsis. Many studies indicate that both the mediators play key roles in sepsis and septic shock, and some think that TNF may be the central mediator in sepsis.

Like antiendotoxin antibodies, antibodies to TNF or IL-1 were hypothesized to be useful in patients with septic shock. However, anti-TNF or antiIL-1 antibodies have yet to be shown to improve the outcome in sepsis or septic shock. In 1997, Zeni conducted a meta-analysis and selected 21 trials representing 6429 patients.[74] A small but insignificant beneficial effect was demonstrated. Several other experimental interventions and therapies have undergone clinical trials for sepsis. Although some may have shown benefit, no convincing evidence suggests that these therapies are efficacious. Numerous such interventions or therapies exist, including IV immunoglobulins, interferon gamma, antithrombin III infusion, naloxone, pentoxifylline, growth hormone, granulocyte colony-stimulating factor (G-CSF), and hemofiltration or extracorporeal removal of endotoxins. None has been efficacious in properly designed controlled clinical trials. In a small preliminary study, Cruz et al compared the addition of polymyxin B hemoperfusion to conventional therapy for severe sepsis or septic shock caused by intra-abdominal infection in 64 patients. [75] Polymyxin B is an antibiotic with a high affinity to endotoxin, a principal component of the outer membrane of gram-negative organisms. Thus, polymyxin B can in theory reduce the endotoxin-induced inflammatory response in gram-negative sepsis. In the conventional therapy plus polymyxin B hemoperfusion group, a significant increase in MAP and a significant decrease in vasopressor requirement at 72 hours were observed in comparison with conventional therapy alone. The 28-day mortality rate was 32% in the polymyxin B group and 53% in the conventional therapy group. Polymyxin B hemoperfusion significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality rate in severe sepsis or septic shock when added to conventional therapy.[75] Polymyxin B hemoperfusion is an example of a novel therapy that, like administration of recombinant APC, targets the pathophysiology of septic shock and that may become more widespread in the future.

Surgical Treatment
Patients with infected foci should be taken to surgery after initial resuscitation and administration of antibiotics for definitive surgical treatment. Little is gained by spending hours stabilizing the patient while an infected focus persists. A soft-tissue abscess should be drained promptly in the setting of sepsis because the patients condition will not improve until the inciting bacterial load is removed. A superficial abscess can be drained in the ED; however, any deep abscess or suspected necrotizing fasciitis should be treated in the operating room (OR) for drainage. A thorough search for abscesses should be performed in cases of sepsis of unclear etiology, with particular attention paid to the rectal and perianal area.

Medication Summary
The most important aspect of medical therapy for septic patients includes adequate oxygen delivery, crystalloid fluid administration, and broad-spectrum antibiotics. Although colloid solution is mentioned, mortality benefit of colloid over crystalloid has never been proven. Blood transfusion may also be beneficial for patients with low hemoglobin concentrations. Vasopressors are important for patients who are refractory to adequate fluid resuscitation. Steroid administration should be considered in patients refractory to both fluids and vasopressors, and recombinant human activated protein C (APC) is a therapy that should be considered for the patients in the most critical condition in the intensive care unit (ICU).

Vasopressors
Class Summary
In cardiovascular disorders, vasopressors are used for their alpha1 and beta1 properties. They provide hemodynamic support in acute heart failure and shock.

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

Dosing & Uses

Dosing Forms & Strengths injectable solution

1mg/mL

Acute Hypotension Initial: 8-12 mcg/min IV infusion; titrate to effect

Maintenance: 2-4 mcg/min IV infusion

Cardiac Arrest Initial: 8-12 mcg/min IV infusion; titrate to effect

Maintenance: 2-4 mcg/min IV infusion

Sepsis & Septic Shock 0.01-3 mcg/kg/min IV infusion Beta Blocker Toxicity (Off-label) Should be titrated to age-appropriate blood pressure Calcium Channel Blocker Toxicity (Off-label) Should be titrated to age-appropriate blood pressure Tricyclic Antidepressant Toxicity (Off-label) Should be titrated to age-appropriate blood pressure
Pediatric

Dosing Forms & Strengths injectable solution

1mg/mL

Acute Hypotension Initial: 0.05-0.1 mcg/kg/min IV infusion; titrate to effect Maximum: 1-2 mcg/kg/min Cardiac Arrest Initial: 0.05-0.1 mcg/kg/min IV infusion; titrate to effect Maximum: 1-2 mcg/kg/min Shock 0.05-0.1 mcg/kg/min IV infusion; titrate to effect; not to exceed 2 mcg/kg/min Dopamine (Intropin)
Dopamine stimulates both adrenergic and dopaminergic receptors. Its hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation is produced by higher doses. After initiating therapy, the dose may be increased by 1-4 g/kg/min q10-30min until a satisfactory response is attained. Maintenance doses lower than 20 g/kg/min usually are satisfactory for 50% of the patients treated. Adult AdultPediatric

Dosing Forms & Strengths infusion solution, in D5W

80mg/100mL 160mg/100mL 320mg/100mL injectable solution 40mg/mL 80mg/mL 160mg/mL

Strong Beta-1, Alpha, & Dopaminergic Effects Effects based upon dosing rate
Dopaminergic effects: 0.5-2 mcg/kg/min Beta effects: 2-10 mcg/kg/min Alpha effects: >10 mcg/kg/min

Treatment of Hemodynamic Conditions Hypotension, low cardiac output, poor perfusion of vital organs, used to increase mean arterial pressure in septic shock patients who remain hypotensive after adequate volume expansion
Low dose: 1-5 mcg/kg/min IV may increase urine output and renal blood flow Medium dose: 5-15 mcg/kg/min IV may increase renal blood flow, cardiac output, heart rate, and cardiac contractitlity

High dose: 20-50 mcg/kg/min IV may increase blood pressure and stimulate vasoconstriction Titrate to response Pediatric

Dosing Forms & Strengths infusion solution, in D5W

80mg/100mL 160mg/100mL 320mg/100mL injectable solution 40mg/mL 80mg/mL 160mg/mL

Treatment of Hemodynamic Conditions Hypotension

1-5 mcg/kg/min IV, increase to 5-20 mcg/kg/min, no more than 50 mcg/kg/min IV Titrate to desired response

Dobutamine
Dobutamine is a sympathomimetic amine with stronger beta than alpha effects. It produces systemic vasodilation and increases the inotropic state. Vasopressors augment the coronary and cerebral blood flow during the low-flow state associated with shock. Sympathomimetic amines with both alpha- and betaadrenergic effects are indicated in cardiogenic shock. Dobutamine is used in EGDT if there is evidence that tissue hypoperfusion and myocardial dysfunction is related to sepsis. Dopamine and dobutamine are the drugs of choice to improve cardiac contractility, with dopamine the preferred agent in hypotensive patients. Higher dosages may cause an increase in heart rate, exacerbating myocardial ischemia. AdultPediatricGeriatric

Dosing Forms & Strengths infusion solution in D5W

100mg/100mL 200mg/100mL 400mg/100mL injectable solution 12.5mg/mL

Low Cardiac Output Continuous infusion: 2.5-15 mcg/kg/min IV Initial rate 0.5-1 mcg/kg/min IV, THEN
2-20 mcg/kg/min; no more than 40 mcg/kg/min

Congestive Heart Failure

Continuous infusion: 2.5-15 mcg/kg/min IV Initial rate 0.5-1 mcg/kg/min IV, THEN 2-20 mcg/kg/min; no more than 40 mcg/kg/min

Other Indications & Uses Off-label: Pediatric patients with congenital heart disease undergoing cardiac cath, cardiac stress testing
PediatricGeriatric

Dosing Forms & Strengths infusion solution in D5W

100mg/100mL 200mg/100mL 400mg/100mL injectable solution 12.5mg/mL

Inotropic Support 2-20 mcg/kg/min IV; titrate according to response; no more than 40 mcg/kg/min IV
Geriatric

Low Cardiac Output Continuous infusion: 2.5-15 mcg/kg/min IV Initial rate 0.5-1 mcg/kg/min IV, THEN
2-20 mcg/kg/min; no more than 40 mcg/kg/min

Congestive Heart Failure Continuous infusion: 2.5-15 mcg/kg/min IV Initial rate 0.5-1 mcg/kg/min IV, THEN
2-20 mcg/kg/min; no more than 40 mcg/kg/min

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

Dosing Forms & Strengths autoinjector (EpiPen, Twinject, Adrenaclick, Auvi-Q)

0.15mg 0.3mg injectable solution 0.1mg/mL (1:10,000) 1mg/mL (1:1000)

Cardiac Arrest

0.5-1 mg IV q3-5min PRN High dose: 1-5 mg IVP ETT: 2-2.5 mg q3-5min until IV/IO access established or spontaneous circulation restored Intracardiac: 0.1-1 mg into left ventricular chamber; administration should be restricted only to well-trained personnel May follow initial dose with 1-4 mcg/min IV infusion (1:10,000 solution)

Asthma, Severe/Anaphylaxis 0.2-1 mg SC q5-15min (1:1000 solution), OR

0.1-0.25 mg IM or SC (1:10,000 solution) over 5-10 minutes, OR 0.1 mg IV at rate of 1-4 mcg/min over 5 minutes Autoinjector: 0.3 mg (contents of 1 autoinjector) SC/IM once in anterolateral aspect of the thigh; may repeat dose after 5-15 minutes if symptoms persist

Administration Do not administer autoinjector IV; give only in outer thigh to ensure SC or IM administration
Auvi-Q provides audible and visual cues to assist the user through each step of the injection process Discard remaining volume after dose has been administered Pediatric

Dosing Forms & Strengths autoinjector (EpiPen, Twinject, Adrenaclick, Auvi-Q)

0.15mg 0.3mg injectable solution 0.1mg/mL (1:10,000) 1mg/mL (1:1000)

Asystole/Pulseless Arrest 1st dose (use 1:10,000 solution): 0.01 mg/kg IO/IV Subsequent doses: Repeat above q3-5min
Consider higher dose (1:1000 solution) for special conditions: 0.1-0.2 mg/kg Neonates (<28 days old): 0.01-0.03 mg/kg q3-5min IV/IO/ET IV drip: 0.1-1 mcg/kg/min

Symptomatic Bradycardia 1:10,000 solution: 0.01 mg/kg IO/IV Intratracheal: 0.1 mg/kg (1:1000 solution) Asthma/Anaphylaxis 1:1000 solution: 0.01 mg/kg SC q15min for 3-4 doses or q4hr PRN Autoinjector
Weight <30 kg: 0.15 mg (contents of 1 autoinjector) SC/IM once; may repeat dose

 Weight 30 kg: 0.3 mg (contents of 1 autoinjector) SC/IM once; may repeat dose Nebulization 1:1000 solution diluted in 3 mL 0.9% NaCl <4 years old: 0.5 mg/kg via nebulizer; not to exceed 2.5 mL (2.5 mg)/dose 4 years old: 0.5 mg/kg via nebulizer; not to exceed 5 mL (5 mg)/dose

Administration Do not administer autoinjector IV; give only in outer thigh to ensure SC or IM administration
Auvi-Q provides audible and visual cues to assist the user through each step of the injection process Discard remaining volume after dose has been administered

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

Dosing Forms & Strengths injection solution

20 units/mL

Abdominal Distention 5 U IM initial; repeat q3-4hr PRN (may increase to 10 U) Diabetes Insipidus Titrate dose based on serum Na, serum osmolality, fluid balance and urine output
5-10 U IM/SC or intranasal q6-12hr Continuous IV infusion: initial dose 0.0005 U/kg/hr IV infusion then double dose q30min to reach desired effect; max dose 0.01 U/kg/hr

GI Hemorrhage (Off-label) 0.2-0.4 U/minute IV initially, increase to 0.9 U/min IV if needed, OR

Initial 0.002-0.005 U/kg/min IV then titrate dose as needed to a max of 0.01 U/kg/minute IV, OR 0.1-0.5 U/minute intra-arterial

Vasodilatory Shock (Off-label) 0.02-0.1 U/minute IV infusion Abdominal Roentgenography 10 U IM 2 hr before procedure and then 10 U IM 1/2 hr before film Hepatic Impairment May require lower doses to achieve response

Other Information Cardiac Arrest, V-Fib, Pulseless V-Tach: 40 U IV once Other Indications & Uses Prevent post-op abd distention, cardiac arrest (ACLS)
Off-label: esophageal varices, GI hemorrhage, vasodilatory shock PediatricGeriatric

Dosing Forms & Strengths injection solution

20 units/mL

Abdominal Distention Proportionately reduced adult dose Diabetes Insipidus Titrate dose based on serum Na, serum osmo, fluid balance and urinary output
2.5-10 U IM/SC or intranasal q6-12hr Continuous IV infusion: initial dose 0.0005 U/kg/hr IV infusion then double dose q30min to reach desired effect; max dose 0.01 U/kg/hr

GI Hemorrhage (Off-label) 0.002-0.005 U/kg/min IV initially, increase to 0.01 U/kg/min IV if needed

PediatricGeriatric

Dosing Forms & Strengths injection solution

20 units/mL

Abdominal Distention Proportionately reduced adult dose Diabetes Insipidus Titrate dose based on serum Na, serum osmo, fluid balance and urinary output
2.5-10 U IM/SC or intranasal q6-12hr Continuous IV infusion: initial dose 0.0005 U/kg/hr IV infusion then double dose q30min to reach desired effect; max dose 0.01 U/kg/hr

GI Hemorrhage (Off-label) 0.002-0.005 U/kg/min IV initially, increase to 0.01 U/kg/min IV if needed Phenylephrine
Phenylephrine is a strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles and increased peripheral vascular resistance. It will result in reflex myocardial depression and decreased heart rate; therefore, it must be used with caution. Phenylephrine

is a first-line agent in patients with hypotension and extreme tachycardia. It can be used as an adjunct to norepinephrine or dopamine to augment peripheral AdultPediatric

Dosing Forms & Strengths injectable solution

10mg/mL

Mild to Moderate Hypotension Initial: 2-5 mg IM or SC; not to exceed 5 mg

Maintenance: 1-10 mg

Severe Hypotension/Shock 100-180 mcg increments IV bolus, THEN

40-60 mcg/min continuous IV infusion Pediatric

Dosing Forms & Strengths injectable solution

10mg/mL

Hypotension 5-20 mcg/kg IV bolus q10-15min PRN, OR 0.1-0.5 mcg/kg/min IV continuous infusion

Sepsis
Summary Introduction Risk Factors for Sepsis Recognition of systemic sepsis Investigations Management GBS Colonisation Prolonged Rupture of Membranes Fungal Sepsis Areas of Uncertainty in Clinical Practice

Summary
any baby who is unwell must be considered at risk of sepsis and appropriate antibiotics commenced as soon as possible after taking cultures inability to obtain cultures should not delay administration of antibiotics in babies where antibiotics are commenced until sepsis can be ruled out but who are otherwise well consider care in the postnatal ward provided antibiotics ban be provided there and the baby can be safely observed

Introduction
Neonatal sepsis occurs in 1 to 8 per 1000 live births with the highest incidence occurring among infants of very low birth weight and gestation. It is mandatory to have a high index of suspicion for the possibility of sepsis, as well as a low threshold for commencing antibiotic treatment. While more babies are treated than are infected the consequences of untreated sepsis are devastating. Early onset sepsis (within the first 48 hours of life) often manifests with pneumonia and/or septicaemia equal male and female incidence characterised by high risk of mortality (10 to 30%) predominantly due to organisms acquired from the birth canal occasionally intrapartum haematogenous spread occurs eg Listeria over 80% of cases are due to GBS and gram negative bacteria

Late onset sepsis (after the first 48 hours) due to organisms acquired either around the time of birth or in hospital eg Coagulase Negative Staphylococcus during hospitalisation in the NICU male predominance infants < 1000gms are particularly at risk mortality rate approximately 5% > 70% due to Coagulase Negative Staphylococcus and Staphylococcus aureus, 10 - 15% due to Gram negatives. Candida is an important pathogen, particularly among extremely low birth weight infants gram negatives and GBS predominate among infections acquired outside the NICU setting

Risk Factors for Sepsis

Early onset sepsis prolonged ruptured membranes (> 18 hours) fetal distress maternal pyrexia (> 38 C) or overt infection eg UTI, gastroenteritis/diarrhoeal illness multiple obstetric procedures, including cervical sutures preterm delivery history of GBS infection in previous infant, GBS bacteriuria in this pregnancy

Late onset sepsis prolonged hospitalisation eg preterm infants in a NICU presence of foreign bodies eg intravenous catheters, endotracheal tubes, etc cross infection by staff and parents malformations such as urinary tract anomalies (eg vesico-ureteric reflux) or neural tube defects

Recognition of systemic sepsis

Signs are usually non-specific since other conditions cause similar clinical states (eg cardiac or respiratory failure, metabolic disorders) General features o pallor, lethargy, jaundice o fever, hypothermia, temperature instability (note 1/3 of confirmed sepsis cases are normothermic) o poor handling o hypoglycaemia/hyperglycaemia o blood gas derangements (including acidosis and lactate accumulation) Respiratory o increased respiratory rate o apnoea o grunting o cyanosis Cardiovascular System o tachycardia o bradycardic episodes o poor perfusion o hypotension Cutaneous o petechiae o bruising o bleeding from puncture sites GIT o o poor feeding vomiting

o o o o CNS o o o

abdominal distension feed intolerance bilious aspirates/vomits loose stools

lethargy irritability seizures

Any baby who is unwell must be considered at risk of sepsis and appropriate antibiotics commenced as soon as possible after taking cultures. Inability to obtain cultures should not delay administration of antibiotics.

Investigations
General investigations include parameters important in assessment of general well being of the infant eg blood gases, true blood glucose Infection related tests Non-specific markers eg C-reactive protein (CRP), Full Blood Examination CRP rises approximately 12 hours after onset of sepsis and returns to normal within 2 to 7 days of successful treatment. If the CRP remains elevated or rises after initial improvement, care must be taken to look for possible collections, including endocarditis (particularly if 'long-lines' have been used) or fungal infection. CRP is raised in 85 % of episodes of confirmed sepsis with a specificity of 90%. It can, therefore, be normal in cases of true sepsis and should be used in conjunction with clinical signs and culture results. FBE -The Polymorphonucleocyte (PMN) count can be normal in 1/3 of cases of confirmed sepsis, but can also be elevated in the absence of infection. Neutropenia in the face of confirmed sepsis can indicate that the baby is extremely unwell. A raised immature to total white cell ratio (I:T ratio > 0.3) is about 85 % sensitive and specific - particularly for early onset sepsis. Tests to identify the infective organism

Early onset sepsis Blood culture (mandatory) Lumbar puncture (LP) should be performed where the 'index of suspicion' of meningitis is high ie abnormal conscious state or seizures. LP may need to be delayed until after the infant's condition has stabilised sufficiently to tolerate the procedure and abnormalities of coagulation status have been controlled. If the initial blood culture is positive. LP must be performed to exclude meningitis since the presence of meningitis alters the length of antibiotic treatment as well as prognosis. there is little to be gained from performing urine aspiration for culture, as haematogenous spread is the mechanism behind positive urine cultures in the first few days of life

Late onset sepsis

Blood cultures (mandatory) SPA specimen of urine should be obtained, as a primary UTI is not uncommon as a cause of sepsis after 5 days of age The role of LP in late onset sepsis is controversial and depends on the clinical setting

Non-NICU infants suspected of being septic - LP should be performed to exclude CNS infection. If there is a high clinical index of CNS infection, appropriate treatment should be instituted early even if the LP is delayed until the baby is stable enough to tolerate the procedure. Infants in NICU - The role of LP is limited since the commonest organism causing sepsis is the Coagulase Negative Staph (CONS). CONS rarely cause CNS infection unless a Ventriculoperitoneal shunt is present. LP when CONS is isolated from blood culture is reserved for infants who are not following the expected clinical course despite appropriate antibiotics. LP is performed when the infant's condition is suggestive of meningitis or blood culture identifies an organism other than CONS. . ETT cultures and skin swabs are of limited value for babies in NICU situations. Their value is as a guide to the profile and sensitivity of organisms in the nursery, particularly Staphylococcus aureus.

Management
Place of Care The septic baby should be managed in the Special Care Nursery where they can be observed closely.

However in some cases where antibiotics are commenced whilst sepsis is being ruled out (eg brief unexplained respiratory distress or the GBS positive mother with inadequate intrapartum antibiotic prophylaxis) the baby is clinically well and the septic markers are benign. In these cases it may be appropriate for the baby to be managed in the postnatal ward so as to keep mother and baby together. In such cases it may be possible for the IV cannula to be flushed and the IV antibiotics given in the postnatal ward. However the following caveats must apply Nursing staff caring for the baby must be competent to do so (ie as part of their employment be rostered from time to time in the Special Care Nursery) The baby is medically cleared by the Paediatrician to be managed in the postnatal ward on a case by case basis The baby remains under the care of the Paediatrician(s) The baby has regular observations of temperature, pulse rate and respiratory rate with IV cannula flushes. Any abnormalities of these parameters must result in readmission to the Special Care Nursery

Where Hospital in the Home (HITH) facilities exist consideration may be given to completing the final dose(s) of antibiotics at home. General Measures In the septic baby in addition to the administration of antibiotics, great attention to supportive care is needed. Antibiotics should be considered as only part of the management of a septic neonate.

General o thermal care o incubator nursing o phototherapy if warranted o monitoring of oxygen saturation, heart rate and blood pressure Respiratory - support for apnoea, hypoxia, hypercapnoea, and respiratory distress Cardiovascular o plasma volume expanders (normal saline - 10 to 20 mls/kg initially) o inotropic support is often needed (see management of shock) Correction of fluid, electrolyte, glucose and haematological derangements (including blood, platelets and clotting factors) the unstable infant usually needs enteral feedings withheld.

Antibiotic choice Given the usual causative organisms the following regimes are recommended initially. Antibiotic choice can then be rationalised on the basis of culture results and clinical course. Early onset sepsis Benzylpenicillin - 60mg/kg IV 12 hrly 120mg/kg/dose 12 hrly if meningitis suspected Gentamicin - 5 mg/kg IV 36 hrly if >=1200g, 48hrly if <1200g.

Note: both can be given IM if IV access is not possible If history or clinical appearance suggests the possibility of Listeria, amoxycillin 50mg/kg IV 12hourly can be used instead of benzylpenicillin (although data indicating that this is superior is lacking). For treatment of meningitis (until sensitivities are known) Cefotaxime - 50mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 8 hourly after that time Amoxycillin - 50mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 8 hourly after that time

Late onset sepsis Flucloxacillin and gentamicin are the usual first choice antibiotics except when suspected septic shock due to Gram negative organism use Vancomycin, Gentamicin +/- Vancomycin meningitis use Amoxicillin and Cefotaxime necrotizing enterocolitis use Amoxicillin, Gentamicin, Metronidazole

Vancomycin 15 mg/kg 18 hrly for term babies. Gentamicin 5 mg/kg 36hrly for term babies <= 7days, 24hrly if > 7days. Flucloxacillin 25mg/kg/dose 12 hourly for preterm babies or term babies in the first week of life, 6-8 hourly after that time. Doses of antibiotics need to be adjusted for age of the baby and on the basis of levels in the case of gentamicin and vancomycin.

An aminoglycoside other than gentamicin may be used in some hospitals at times depending on the profile of prevalent organisms. When to stop Antibiotics Duration of antibiotic treatment depends upon the clinical condition of the infant and the organism identified on culture. where the likelihood of infection is low, with a baby in good condition and infective indices negative, antibiotics can be ceased if cultures are negative after 48 hours sepsis strongly suspected, despite negative blood culture at 48 hours. It is advisable to repeat blood culture and continue antibiotics for at least 5 days providing infective indices have normalised. Another approach is to continue antibiotics for 48 hours after indices have normalised proven gram negative bacteraemia, with clear CSF, treat for 10 days, antibiotics can be rationalised in the face of culture and sensitivities proven GBS bacteraemia, with clear CSF, 10 days treatment should be sufficient meningitis, treat for 14 days for GBS and 21 days for gram negative organisms. In some centres, 48-hourly LPs are performed in cases of gram negative meningitis, with treatment continuing for 14 days after the first negative culture - in practice this usually equates with a 21 day treatment course UTI - treat with IV antibiotics for at least 5 days, a total of 10 days treatment is needed. The infant can be managed with appropriate oral antibiotics for the latter half of the treatment course if clinical condition is satisfactory. Ongoing prophylactic antibiotics will be needed until renal investigations (ultrasound and/or MCU) are completed

Special Circumstances
The GBS colonised mother At delivery approximately 15% of women are colonised with GBS. Up to 70% of infants born to colonised women are themselves colonised. Infection occurs in 1% of colonised infants. 75% of early onset GBS disease in neonates occurs in term babies. The incidence of GBS disease varies, with the rate being 3 per 1000 live births in the USA, compared to 0.3 per 1000 in Australia and the UK. The risk is 3 times higher in the Aboriginal community. Screening for GBS remains the subject of heated debate, but it is known that intrapartum administration of antibiotics (penicillin or amoxycillin) reduces neonatal colonisation by 90%, and early onset GBS disease by 90%.

The CDC in the USA recommends that all women be screened with anorectal and vaginal swabs at 35 -37 weeks' gestation. Intrapartum antibiotics are given according to the following strategies if screening is performed administer to o GBS colonised women o Non-colonised women with risk factors present if screening is not performed administer to women with risk factors o Preterm onset of labour (<37weeks) o ROM for >18 hours o Maternal fever (>38C) o Previous baby with invasive GBS disease o GBS bacteriuria this pregnancy

Use of the CDC guidelines is estimated to result in around 27% of women receiving antibiotics, with an associated reduction in early onset GBS disease of around 85%. The disadvantages of such an approach are the risk of maternal complications (anaphylaxis), and the cost (GBS rates of >0.5 per 1000 live births are needed to justify such an approach on a cost-effectiveness basis). Intrapartum chemoprophylaxis consists of penicillin 1.2gms IV statim, then 0.6gms 4hrly (erythromycin can be used in cases of penicillin allergy). Should the infant be delivered before prophylaxis has been administered to the mother, or within 4 hours of the initial dose, the infant should be observed closely in hospital for 48 hours. Some workers recommend giving a single intramuscular injection of 100mg penicillin, IM, to such an infant while others recommend taking an FBE and blood culture prior to observation. Occasional treatment failure has been associated with the single IM dose regime. If the infant is initially (or becomes) symptomatic, or if significant prematurity (<35 weeks gestation) is present, the infant should undergo a septic evaluation and treatment with intravenous antibiotics despite maternal intrapartum prophylaxis. Prolonged Rupture of Membranes (PROM) The majority of women will come into labour within 24 hours of rupture of the membranes; however, this may be delayed in up to 4% of cases. PROM for greater than 18 hours may lead to increased risk of infection in mother and baby - particularly if the mother is GBS positive or undergoes repeated vaginal examinations. In practice, the risk is greatest for preterm infants, but 75% of early onset GBS sepsis occurs in term babies. Since there is a lack of evidence from trials available there is debate as to the role of prophylactic antibiotics in PROM. Obstetric staff will need to consider signs of possible maternal sepsis, as well as risk factors such as GBS colonisation in deciding to administer antenatal antibiotics. Babies born with a background of PROM need to be viewed as potentially at risk of sepsis. Preterm infants, particularly those <35 weeks, are usually screened for sepsis and treated with IV antibiotics until infection in the baby has been excluded. Term infants if there are no risk factors, apart from the PROM, the infant is usually observed closely and treated only if symptoms develop if there is a risk factor present in addition to PROM, such as GBS positive mother, maternal intrapartum fever or suspected chorioamnionitis that infant should be treated as potentially septic, even if completely asymptomatic

any symptomatic baby needs septic evaluation performed and treatment for infection regardless of the presence or absence of risk factors

Fungal sepsis Generally seen in VLBW infants in NICU. Risk factors include multiple courses of IV antibiotics, presence of central lines and extensive areas of skin breakdown. Consideration of fungal sepsis is particularly necessary when such infants deteriorate whilst receiving antibiotics. Empirical treatment with Amphotericin until cultures are reported as clear for fungal organisms is appropriate. SPA of urine must be performed prior to starting Amphotericin as bag specimens will often be contaminated with Candida colonising the skin. If fungal sepsis is confirmed, then the addition of a further antifungal (e.g. fluconazole mg/kg stat, then 2mg/kg 48hrly) may be useful. Duration of treatment depends upon the site of infection but generally ranges from 3 to 6 weeks. Ultrasound of the kidneys and formal fundoscopy should be performed.

Areas of Uncertainty in Clinical Practice

The role of antigen tests for GBS is controversial

Urine specimens for GBS antigen can be positive when babies are colonised, even when a SPA specimen is taken. If a bag specimen is used, then contamination with skin GBS colonisation will result in a positive test. Antigen tests are more sensitive and specific for CSF specimens, but cannot be relied upon to exclude infection. Antigen testing results need to be viewed from the point of view of adding supplementary evidence of possible infection, but cannot be relied upon to prove or disprove GBS infection, and are thus of limited value. Similar limitations exist in testing for other bacterial antigens. Antifungal prophylaxis

A recent Cochrane review failed to demonstrate a reduction in fungal colonisation among patients receiving prophylactic oral nystatin compared to placebo. All patients in these trials were immunocompromised but beyond the neonatal period. A RCT of intravenous fluconazole compared to placebo during the first 6 weeks of life in 100 infants of less than 1000gm birthweight showed a reduction in fungal colonization and invasive fungal infection. Treatment with Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF has been shown to increase PMN counts in VLBW babies, but the effect on sepsis reduction or mortality from sepsis has not been demonstrated. Intravenous immunoglobulin (IVIG)

Studies involving IVIG show a possible improvement in mortality in babies given IVIG as part of the treatment of sepsis. However, larger trials are needed to examine the role of IVIG in neonates with sepsis. Other ancillary treatments that have been used include exchange transfusion and neutrophil transfusions, but insufficient data is available to recommend their use.

Nursing Care Plan | NCP Septic Shock

Septic shock is a clinical syndrome associated with severe systemic infection. It is a sepsisinduced shock with hypotension despite adequate fluid replacement. Patients have perfusion abnormalities, including lactic acidosis, oliguria (urine output 400 mL/day), or an acute alteration in mental status. Often septic shock is characterized by decreased organ perfusion, hypotension, and organ dysfunction. Septic shock is the major cause of death in intensive care units; the mortality rate is as high as 50% to 80% depending on the patient population. The incidence has increased during the last 50 years in North America probably owing to an increased number of patients who are immunocompormised, the increased use of invasive devices, and a longer life span for the elderly. It occurs in 2 cases per each 100 hospital discharges, and approximately 70% of the patients who develop septic shock need intensive care. Septic shock is part of the continuum associated with the systemic inflammatory response syndrome (SIRS), defined by two or more changes in the following four factors: body temperature, heart rate, respiratory function, and peripheral leukocyte count. Sepsis, on the other hand, is defined as systemic host response to infection with SIRS plus a documented infection, and severe sepsis is defined as sepsis with hypotension, despite fluid resuscitation, and evidence of inadequate tissue perfusion. The syndrome usually begins with the development of a local infectious process. Bacteria from the local infection enter the systemic circulation and release toxins into the bloodstream. Gram-negative bacteria release endotoxins from their cell membrane as they lyse and die, whereas gram-positive bacteria release exotoxins throughout their life span. These toxins trigger the release of cytokines (proteins released by cells to signal other cells) such as tumor necrosis factor and the interleukins (ILs). They also activate phagocytic cells such as the macrophages. The complex chemical reactions lead to multiple system effects. As the syndrome progresses, blood flow becomes more sluggish, tissues become hypoxic, and acidosis develops. Ultimately, major organ systems (such as the lungs, kidneys, liver, and blood coagulation) fail, which leads to multiple organ dysfunction syndrome. Although any microorganism may cause septic shock, it is most often associated with gramnegative bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas, and Serratia. Gram-positive bacteria such as Staphylococcus aureus can also cause septic shock and, in past years, have led to outbreaks of toxic shock syndrome. A fungal infection causes septic shock in less than 3% of the cases. Lower respiratory infections cause 25% of the cases of septic shock, urinary tract

infections cause 25%, and soft tissue infections cause 15% of the cases. Common factors or conditions that are associated with septic shock include diabetes mellitus, malnutrition, alcohol abuse, cirrhosis, respiratory infections, hemorrhage, cancer, and surgery. People with traumatic injuries with either peritoneal contamination, burns, prolonged intravenous (IV) cannulation, abscesses, or multiple blood transfusions are at particular risk as well. Nursing care plan assessment and physical examination Patients appear critically ill and may have already been intubated and on mechanical ventilation for adult respiratory distress syndrome (ARDS). Because of the severity of the patients condition, you may not be able to interview him or her for a complete history. You may obtain a great deal of information from the family and from other healthcare providers when the patient is transferred to your care. Because patients with septic shock are among the most critical of all patients treated in a hospital, they are admitted to a critical care unit for management. Patients often have a history of either an infection or a critical event, such as a traumatic injury, perforated bowel, or acute hemorrhage. Some patients may also have a long-standing IV catheter or a Foley catheter. Determine the cause for the patients admission to the hospital and any history of a chronic disease such as cancer, diabetes mellitus, or pneumonia. Note any brief periods of decreased tissue perfusion such as hemorrhage, severe hypotension, or cardiac arrest that may demand emergency management before the development of septic shock. Take a thorough medication history, with particular attention to recent antibiotic administration or total parenteral nutrition. Ask if the patient has been exposed to any treatmentsuch as organ transplantation, radiation therapy, or chemotherapy that would lead to immunosuppression. Three stages have been identified, but all patients do not progress with the same pattern of symptoms. In early septic shock (early hyperdynamic, compensated stage), some patients are tachycardic, with warm and flushed extremities and a normal blood pressure. As shock progresses, the diastolic blood pressure drops, the pulse pressure widens, and the peripheral pulses are bounding. The patients temperature may be within normal limits, elevated, or below normal, and the patient may be confused or agitated. Often, the patient has a rapid respiratory rate, and peripheral edema may develop. In the second stage (late hyperdynamic, uncompensated stage), widespread organ dysfunction begins to occur. Blood pressure falls, and the patient becomes hypotensive. Increased peripheral edema becomes apparent. Respirations become more rapid and labored; you can hear

rales when you auscultate the lungs; and the patients sputum may become copious, pink, and frothy. In late septic shock, the blood pressure falls below 90 mm Hg for adults, the patients extremities become cold, and signs of multiple organ failure (decreased urinary output, abdominal distension, absence of bowel sounds, bleeding from invasive lines, petechiae, cardiac dysrhythmias, hypoxemia, and hypercapnia) develop. As the syndrome progresses, patients may develop symptoms that change their behavior and appearance and situations that increase their anxiety and that of their family members. Ultimately, the family may be faced with the death of a loved one. Continuously assess the coping mechanisms and anxiety levels in both patients and families. Nursing care plan primary nursing diagnosis: Infection related to exposure to bacteria from trauma, invasive instrumentation, or contamination. Nursing care plan intervention and treatment plan The primary goals of treatment in septic shock are to maintain oxygen delivery to the tissues and to restore the vascular volume, blood pressure, and cardiac output. IV fluids are administered to increase the volume within the vascular bed; crystalloids (normal saline solution or lactated Ringers injection) are usually the fluids of choice. Vasopressors, such as dopamine or norepinephrine (Levophed), may also be required to maintain an adequate blood pressure. The patient is also placed on broad-spectrum IV antibiotics. If the patients hemoglobin and hematocrit are insufficient to manage oxygen delivery, the patient may need blood transfusions. A pulmonary artery catheter is inserted to monitor fluid, circulatory, and gas exchange status. An aggressive search for the source of sepsis is an essential part of the treatment. Any indwelling catheters, whether they are urinary, intravascular, intracerebral, or intra-arterial, are discontinued if possible or moved to another location. A surgical consultation may be performed to search for undrained abscesses or to dbride wounds. If complications such as ARDS develop, more aggressive treatment is instituted. Intubation, mechanical ventilation, and oxygenation are required for severe respiratory distress or failure. Patients often need ventilator adjuncts, such as positive end-expiratory pressure, pressure-control ventilation, or inverse inspiration-to-expiration ratio ventilation. Total parenteral feeding or enteral feedings may be instituted for patients who are unable to consume adequate calories. Monitor the success of nutritional therapy with daily weights. During supportive care, the entire healthcare team needs to

monitor the patients condition carefully with serial cardiopulmonary assessments, including vital signs, physical assessment, and continuous hemodynamic monitoring. Patients should be attached to a pulse oximeter for continuous assessment of the arterial oxygen saturation. The patients level of consciousness is important. In children, monitor the childs activity level and the response to parents or significant others. Priorities of nursing care for the patient with septic shock include maintaining airway, breathing, and circulation; preventing the spread of infection; increasing the patients comfort; preventing injury; and supporting the patient and family. Monitor the patient continuously for airway compromise and prepare for intubation when necessary. Maintain strict aseptic technique when you manipulate invasive lines and tubes. Use universal precautions at all times. Unless the patient is endotracheally intubated, place patients with a decreased level of consciousness in a side-lying position, and turn them every 2 hours to protect them from aspiration. To increase the intubated patients comfort, provide oral care at least every 2 hours. Maintain skin integrity by placing the patient on an every-2-hour turning schedule. Post the schedule at the head of the bed to increase the visibility of the routine. Implement active and passive range of motion as appropriate to the patients condition. Provide the family with information about diagnosis, prognosis, and treatment. Expect the patient and family to have high levels of anxiety and fear, given the grave nature of septic shock. Support effective coping strategies, and provide adequate time for the expression of feelings. Nursing care plan discharge and home health care guidelines Instruct patients who have been identified as high risk to call the healthcare provider at the first signs of infection. Teach high-risk individuals to avoid exposure to communicable diseases and to use good hand-washing technique. Reinforce the need for immunizations against infectious diseases such as influenza. Encourage patients to consume a healthy diet, get adequate rest, and limit their alcohol intake. Instruct patients and families about the purpose, dosage, route, desired effects, and side effects of all medications. Explain that it is particularly important that the patient take the entire antibiotic prescription until it is finished.

Septic shock
24 January, 2006
VOL: 102, ISSUE: 04, PAGE NO: 25

WHAT IS IT?
WHAT IS IT? - Septic shock is the result of an overwhelming infection in the blood. It usually follows severe injury or is experienced by immunocompromised patients. - Endotoxins or exotoxins are released from bacteria in the blood causing vasodilation, which results in a dramatic fall in blood pressure. Vital organs such as the brain, heart, kidneys and liver may cease functioning. CAUSES - Septic shock is most prevalent in older people and the very young. - It can be caused by any bacterium but the most common are Gram negative enteric bacilli, such as Escherichia coli, pseudomonas and Gram positive staphylococcal infections. - Fungi and in rare instances viruses can cause septic shock. - All these organisms release toxins that can cause direct damage to tissue and result in reduced organ function. The effect is mainly on the walls of the smaller blood vessels, causing interstitial fluid leak, increased vascular permeability and vasodilation. - Any inflammatory response may contribute to the overall shock. - The eventual result of septic shock is reduced circulation, lowered blood pressure and high cardiac output. - Those with underlying illnesses, for example diabetes, haematologic cancers and diseases of the genitourinary system, are at increased risk of septic shock. - Other risk factors include recent infection, long-term courses of antibiotics, recent surgery and severe burns. - Bacterial toxins can also result in disseminated intravascular coagulation, which is potentially fatal if it is not treated immediately. SYMPTOMS Symptoms include: - Extremes of temperature; - Shortness of breath; - Lightheadedness; - Palpitations; - Lowered temperature in the extremities;

- Agitation; - Lethargy; - Confusion; - Increased heart rate; - Reduced blood pressure, especially when standing; - Reduced urine output. DIAGNOSIS There are various diagnostic tests for septic shock, including: - Blood cultures - can identify infection; - Blood gases - can identify low oxygen concentration and acidosis; - Chest X-rays - can identify pneumonia or pulmonary oedema; - Blood tests - can identify poor organ function or failure. TREATMENT Septic shock is a medical emergency and must be treated immediately. Treatment includes: - Antibiotics to address underlying infection; - Intravenous fluids to restore blood volume; - Oxygen therapy to relieve respiratory distress; - Medication to treat hypotension; - Haemodynamic monitoring; - Medication to counter inflammatory response, limiting the damage to vital organs.