eMedicine Specialties > Emergency Medicine > Infectious Diseases

Shock, Septic

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

Updated: Aug 12, 2009

Introduction

Background

The basis of sepsis is the presence of infection and a subsequent systemic inflammatory response to that infection that results in physiologic alterations that occur at the capillary endothelial level. Systemic inflammatory response syndrome (SIRS) is a term that was developed in an attempt to describe the clinical manifestations that result from this inflammatory cascade, or systemic response to infection. Meeting SIRS criteria is considered having at least 2 of the following 4 clinical parameters abnormal: (1) body temperature, (2) heart rate, (3) respiratory rate, and (4) peripheral leukocyte count.

Sepsis syndromes are clinically defined on a spectrum of increasing disease severity as sepsis, severe sepsis, and septic shock. Sepsis is the presence of SIRS in the setting of infection. Severe sepsis is infection with evidence of end-organ dysfunction as a result of hypoperfusion. Septic shock is severe sepsis with persistent hypotension despite fluid resuscitation and resulting tissue hypoperfusion.

Bacteremia is defined as the presence of viable bacteria within the liquid component of blood. Bacteremia may be primary (without an identifiable focus of infection) or, more often, secondary (with an intravascular or extravascular focus of infection). While 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.^2,3,4,5

Pathophysiology

The physiologic response to 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 and increased endothelial permeability, and activation of coagulation pathways. Sepsis is characterized by a similar response to infection, although on a systemic level, resulting in diffuse endothelial dysfunction. In the case of bacterial infection, the inciting event is the interaction with the host immune cells of endotoxins contained within the bacterial cell wall of gram-negative organisms. In gram-positive organisms, this interaction occurs with either cell wall components or exotoxins released by the organism.

As a result of these interactions, cellular activation occurs with the release of cytokine and noncytokine mediators, the most notorious of which are tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6). These factors are implicated in the diffuse activation of a systemic inflammatory response. As a result, mediators with vasodilatory and endotoxic properties are released systemically, including prostaglandins, thromboxane A2, and nitric oxide. This results in vasodilation and endothelial damage, which leads to hypoperfusion and capillary leak. In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.^6,7

The following systems and mediators are stimulated in septic shock:

• Arachidonic acid metabolites (eg, leukotrienes, prostaglandins, thromboxanes)
• The complement system
• IL-1 and IL-6
• TNF-alpha
• The coagulation cascade
• The fibrinolytic system
• Catecholamines
• Glucocorticoids
• Prekallikrein
• Bradykinin
• Histamines
• Beta-endorphins
• Enkephalins
• Adrenocorticoid hormone
• Circulating myocardial depressant factor(s)

The complex interplay of inflammatory cells and mediators leads to dysfunction of capillary endothelium that results in vasodilation and capillary leak. This further initiates a cascade of endothelial injury, global tissue hypoxia, microthrombus formation, abnormal oxygen utilization due to mitochondrial dysfunction, all which lead to organ dysfunction and eventual failure. The insidious nature of sepsis is that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal.⁸

Frequency

United States

The National Center for Health Statistics published a large retrospective analysis using the National Hospital Discharge Survey of 500 nonfederal US hospitals with 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 has increased 3-fold, between 1979 and 2000, from 83 cases to 240 cases per year per 100,000 population. The reasons for this 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, which holds true today.⁹

Angus et al published linked data from several sources related to hospital discharge from all hospitals from 7 large states. 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.¹⁰ A more recent large survey of emergency department visits showed that severe sepsis accounts for more than 500,000 ED visits annually (0.7% of total visits), the majority of patients presented to EDs without an academic affiliation, and that mean ED length of stay is approximately 5 hours.¹¹

Mortality/Morbidity

The mortality rate of severe sepsis and septic shock is frequently quoted as anywhere from 20-50%. Given that there is a spectrum of disease from sepsis to severe sepsis to septic shock, mortality varies depending on the degree of illness. Factors that are consistently associated with increased mortality in sepsis include advanced age, comorbid conditions, and clinical evidence of organ dysfunction.^10,12 Simply meeting SIRS criteria without evidence of organ dysfunction has not been shown to predict increased mortality, although increasing number of SIRS criteria met has been associated with higher mortality.¹³

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%.¹⁰

The morbidity of sepsis is significant given that tissue hypoperfusion leads to organ dysfunction and failure. Acute respiratory distress syndrome (ARDS) is a significant sequela of severe sepsis and one that results in mortality rates that approach 50%. It also leads to prolonged intensive care unit (ICU) length of stay and increased incidence of ventilator-associated pneumonia. Other significant complications of septic shock include myocardial dysfunction, acute renal failure and chronic dysfunction, disseminated intravascular coagulation (DIC), and liver failure. Prolonged tissue hypoperfusion can lead to long-term neurologic and cognitive sequelae as well.⁷

Race

One large epidemiologic study showed that the risk of septicemia in the nonwhite population is almost twice that of the white population, with the highest risk to black men. Potential reasons for this include issues relating to access to health care and increased prevalence of underlying medical conditions.⁹

Sex

Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock is consistently greater in men. 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.^9,10

Age

A strong correlation exists between advanced age and the incidence and mortality of septic shock, with a sharp increase in the number of cases in patients older than 50 years.^10,12

Clinical

History

Symptoms of sepsis usually are 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.

The following localizing symptoms are some of the most useful clues to the etiology sepsis:

• 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 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 - Focal pain or tenderness, focal erythema, edema, fluctuance

Physical

The hallmark 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 maldistribution of perfusing blood, capillary endothelial leak, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for the clinician is recognize that this process is underway when it may not be clearly manifest in the vital signs or clinical examination.

The American College of Chest Physicians/Society of Critical Care Medicine in 1992 defined the systemic inflammatory response syndrome (SIRS) as a group of vital signs and a laboratory value that if abnormal may indicate that sepsis physiology is occurring at the microvascular and cellular level.¹ Meeting SIRS criteria is defined by the having at least 2 of the following 4 abnormalities:

• Temperature higher than 38°C or lower than 36°C
• Heart rate greater than 90 beats per minute
• Respiratory rate greater than 20 breaths per minute
• WBC count higher than 12,000/mm³ or lower than 4,000/mm³ or with more than 10% immature forms (bands)

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. One large observational study demonstrated that, in the setting of suspected infection, just meeting SIRS criteria without evidence of organ dysfunction did not predict increased mortality, which emphasizes the importance of identifying organ dysfunction over the presence of SIRS criteria.¹² However, there is evidence that suggests that meeting increasing number of SIRS criteria is associated with increased mortality.

Fever is a common feature of sepsis. 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, note that simply mounting a fever is an insensitive indicator of sepsis. In fact, hypothermia is more predictive of illness severity.

Tachycardia is a common feature of sepsis and indicative of a systemic response to a stressor. Tachycardia is the physiologic mechanism of increasing cardiac output and increasing oxygen delivery to tissues. It is an indicator of hypovolemia and the need for intravascular fluid repletion. It may also result from fever itself. Narrow pulse pressure and tachycardia are also considered the earliest signs of shock.

Increased respiratory rate is also a common and often unappreciated 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. Of note, tachypnea is the most predictive of the SIRS criteria of adverse outcome. This is likely because tachypnea is also an indicator of pulmonary organ dysfunction, and a feature commonly associated with pneumonia and ARDS, all of which are associated with increased mortality in sepsis.

Altered mental status is a common feature of sepsis syndromes. 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 cause.

The physical examination should first involve assessment of the patient's general condition, including an assessment of airway, breathing, and circulation (ABCs) and mental status. Attention should be paid to skin color and temperature. Pallor, grayish, or mottled skin are signs of poor tissue perfusion seen in septic shock. Skin is often warm in early septic shock as peripheral dilation and increased cardiac output occur (warm shock). As septic shock progresses, depletion of intravascular volume and decreased cardiac output lead to cool, clammy extremities and delayed capillary refill. Petechiae or purpura can be associated with disseminated intravascular coagulation (DIC) and are an ominous sign.

It is important in septic shock to perform a thorough physical examination in order to elucidate 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 findings suggest a focal (usually bacterial) infection:

• CNS infection - Profound depression in mental status, meningismus
• Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal exudate, stridor, cervical lymphadenopathy
• Chest and pulmonary infections - Localized rales or evidence of consolidation
• Cardiac infections - Any new murmur, especially in patients with a history of intravenous drug use
• Abdominal and gastrointestinal infections - Focal tenderness, guarding or rebound, rectal tenderness or swelling
• Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, cervical motion pain, adnexal tenderness or masses, cervical discharge
• Bone and soft-tissue infections - Focal skin erythema and associated pain or tenderness, fluctuance, pain with joint range of motion, joint effusions and associated warmth/erythema
• Skin infections - Petechiae, purpura, erythema, fluctuance

Causes

Sepsis is a disease seen most frequently in elderly persons and in those with comorbid conditions that predispose to infection, such as diabetes or any immunocompromising disease. The latter are at especially high risk, including those with cancer on chemotherapeutic agents, those with end-stage renal or liver disease, those with advanced HIV, or those on steroids for any other immunocompromising agent for chronic conditions. Patients with indwelling catheters or devices are also at high risk.

Differential Diagnoses

Workup

Laboratory Studies

Laboratory studies for suspected cases of sepsis and/or septic shock may include the following:

• CBC with differential
• The WBC count and the white cell 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 greater than 15,000/mm³ or a neutrophil band count greater than 1500/mm³ has about a 50% correlation with bacterial infection.
• The WBC count is also a component of the SIRS criteria, with WBC >12 or WBC <4 or bands >10% being positive.
• Hemoglobin concentration dictates oxygen-carrying capacity in blood, which is crucial in sepsis to maintain adequate tissue perfusion. The goal is to maintain hematocrit greater than 30% and hemoglobin greater than 10 g/dL.
• Platelets are an acute-phase reactant and are typically elevated in the setting of inflammation. However, platelet counts may decrease in the setting of DIC.
• Comprehensive chemistry panel
• Sodium and chloride levels are abnormal in severe dehydration.
• Decreased bicarbonate can point to acute acidosis.
• Increased blood urea nitrogen and creatinine levels can point to severe dehydration or renal failure.
• Glucose control is important in the management of sepsis, with hyperglycemia associated with higher mortality.
• Liver function tests (LFTs) and bilirubin, alkaline phosphatase, and lipase levels are important in evaluating for multiorgan failure or a potential source of sepsis (eg, biliary disease, pancreatitis, hepatitis).
• Serum lactate is a marker 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. Lactate levels greater than 2.5 mmol/L are associated with an increase in mortality.Levels greater 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%.¹⁴ It has been hypothesized that lactate clearance can be a helpful measure of tissue reperfusion and an indication of adequate therapy.
• Coagulation studies (PT/aPTT)
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are elevated in DIC.
• Fibrinogen levels are decreased and fibrin split products are increased in the setting of DIC.
• Blood cultures
• Blood cultures should be obtained in patients who have suspected sepsis in order to isolate a specific organism to tailor antibiotic therapy. Note, however, that blood cultures are positive in fewer than 50% of cases of sepsis.
• A set of cultures from an indwelling intravenous catheter is especially important, as these catheters are a frequent source of bacteremia.
• Urinalysis and urine culture
• Urinary tract infection is a common source of sepsis, especially in elderly patients. Febrile adults without localizing symptoms or signs have a rate of occult urinary tract infection of 10-15%.
• Again, obtaining a culture is important in order to isolate a specified organism and to tailor antibiotic therapy.
• Gram stain and culture, when applicable
• Sputum specimen should be obtained if pneumonia is suspected.
• Any abscess should be drained promptly, and purulent material sent to the microbiology laboratory for analysis.
• CSF specimen should be obtained if meningitis is suspected.

Imaging Studies

Imaging should be performed as deemed appropriate to search for a source of infection.

• Chest radiography
  • Infiltrates are detected with a chest radiograph in about 5% of febrile adults without localizing signs of infection; therefore, a chest radiography should be routine in the workup of fever with an unclear etiology.
  • Chest radiography is useful in detecting radiographic evidence of acute respiratory distress syndrome (ARDS), which carries a high mortality rate. Evidence of ARDS on a chest radiograph should prompt early intubation and mechanical ventilation, even if the patient has not yet shown signs of overt respiratory distress.
• Abdominal plain films should be obtained if clinical evidence of bowel obstruction or perforation exists.
• 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 ERCP may be urgently necessary in the setting of sepsis with acute cholecystitis or ascending cholangitis.
• Abdominal CT scan should be obtained if the patient has abdominal or flank tenderness in the setting of sepsis. Certain abdominal processes may require urgent operative intervention (eg, diverticular abscess, ischemic bowel, appendicitis, perinephric abscess).
• 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, necrotizing fasciitis is a clinical diagnosis (eg, extreme pain, crepitus, bullae, hemorrhage, foul-smelling exudates). If clinical suspicion of necrotizing fasciitis is high, a surgical consultation should be obtained immediately as such a patient should be taken promptly to the operating room for intervention—often without the need for any imaging. CT or 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 should not be relied upon to make the diagnosis.
  • Plain radiographs can also show evidence of osteomyelitis, although MRI is much more sensitive for making this diagnosis.

Procedures

• Orotracheal intubation and mechanical ventilation
  • Intubation should be considered early in the course of sepsis in order to optimize ventilation and oxygenation, even in the absence of frank hypoxia or respiratory distress.
  • Delivering oxygen at an FiO₂ of 1 directly to 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.
• Intravenous access
  • Two large-bore (16-gauge) intravenous lines should be placed if possible when sepsis is suspected in order to administer aggressive fluid resuscitation and broad-spectrum antibiotics.
  • A central venous (CV) 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 CV catheter allows for administration of medication centrally, and it provides multiple ports for rapid fluid administration, antibiotics, and vasopressors if needed. It also allows for the measurement of central venous pressure (CVP), a surrogate for volume status, if CVP measurement capability is available.
• Urinary catheter (Foley catheter)
  • A urinary catheter should be placed in order to follow urinary output, a rough indicator of intravascular fluid status and tissue perfusion pressure.
  • Normal urinary output in an adult is about 0.5 mL/kg/h or about 30-50 mL/h for most adults.
• Cutaneous or soft-tissue abscess drainage
  • A soft-tissue abscess should be drained promptly in the setting of sepsis because the patient's 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 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.
• A lumbar puncture should be performed if clinical evidence or suspicion for meningitis or encephalitis exists.
  • Broad-spectrum antibiotics to cover meningitis should be administered before starting the procedure.
  • If evidence of increased intracranial pressure (papilledema) or focal mass lesions (focal defects, preceding sinusitis or otitis) 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 of meningitis.

Treatment

Prehospital Care

The initial treatment of sepsis and septic shock involves the administration of supplemental oxygen and volume infusion with isotonic crystalloids. Prehospital personnel should initiate these therapies.

Emergency Department Care

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 emergency department as well. Early recognition and early aggressive therapy for patients with sepsis have a significant impact on mortality.

Rivers et al brought this issue to the forefront with a landmark study in 2001, where they instituted a treatment protocol for patients with septic shock, termed Early Goal Directed Therapy (EGDT).¹⁵ 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, the patients who did not respond to an initial fluid challenge (20-30 mL/kg bolus) and antibiotics received a CV catheter in the internal jugular or subclavian vein to measure central venous pressure (CVP) and an arterial catheter to directly measure arterial blood pressure.

EGDT is basically 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 goal 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 first 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 CV 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. Similar to lactate, ScvO₂ is an indicator of adequate tissue oxygenation. An SvO₂ 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 mean arterial pressure, or namely the first two steps of EGDT.
  • Additional means of increasing tissue oxygen delivery are to maximize oxygen delivery to the alveoli (mechanical ventilation with FiO₂ 1.0), maximize the hemoglobin concentration (transfuse pRBCs if anemic), and augment cardiac output (dobutamine to increase inotropy once preload has been optimized). The protocol by Rivers et al called for a blood transfusion for hematocrit <30%.
  • As a last step in the protocol, dobutamine infusion was started (increasing cardiac output) if ScvO₂ <70% despite all the above measures being optimized.
• ScvO₂ >70 mm Hg is therefore the target goal of EGDT, indicating adequate oxygen delivery. Rivers et al measured ScvO₂ by means of a fiberoptic sensor at the tip of the CV catheter and a stand-alone monitor that displayed ScvO₂ continuously. This concept was based on earlier work that targeted treatment goals that were based on increasing tissue oxygen delivery.^16,17 An alternative to continuous ScvO₂ measurement is to send a venous blood gas from the CV line for oxygen saturation, measured by a standard blood gas analyzer.

Rivers et al enrolled 263 patients who met criteria for septic shock:

• Suspected infection
• 2 of the 4 SIRS criteria
• Persistent systolic blood pressure <90 mm Hg after initial fluid bolus or lactate concentration >4 mmol/L

These patients were randomized to EGDT versus "standard" therapy, the latter which included placement of a CV line and arterial catheter (both relatively invasive measures and probably not standard in most EDs). Despite this, they found an absolute mortality benefit of 16% with EGDT (30% mortality with EGDT vs 46% mortality with standard therapy).

When the data were examined closely, it was found that patients in the EGDT group 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 SvO₂ measured after therapy was 95% for the EGDT group versus 60% in the standard group.

Since the publication of the Rivers et al trial, data from several centers have shown the value of protocolized care and what are referred to as sepsis treatment bundles, which include early broad-spectrum antibiotic administration, EGDT focused on achieving ScvO2 >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 in an ICU setting.^18,19,20,21

General considerations in the treatment of septic shock and components of sepsis treatment bundles

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.

Patients with suspected septic shock require an initial crystalloid fluid challenge of 20-30 mL/kg (1-2 L) over a period of 30-60 minutes with additional fluid challenges at rates of up to 1 L over 30 minutes. Crystalloid administration is titrated to a CVP goal between 8 and 12 mm Hg or signs of volume overload (dyspnea, pulmonary rales, or pulmonary edema on the chest radiograph). A fluid challenge refers to the rapid administration of volume over a particular time period followed by an assessment of the response. Patients with septic shock often require a total 4-6 L or more of crystalloid resuscitation.¹⁸

Colloid resuscitation (with albumin or hetastarch) has not previously been shown in meta-analyses to have any benefit over isotonic crystalloid resuscitation (isotonic sodium chloride solution or lactated Ringer solution).²² The SAFE trial enrolled 7000 ICU patients requiring fluid resuscitation, only about 1200 of whom had severe sepsis. Overall, there was no difference between the two treatment groups; however, there was a trend toward improved outcome in patients with severe sepsis who received 4% albumin versus normal saline.²³ These data are inconclusive, especially regarding the initial resuscitation phase for septic shock in the ED, and crystalloid resuscitation is recommended.

It is recommended that antibiotic therapy be administered within the first hour of recognition of septic shock, and delays in antibiotic administration have been associated with increased mortality.^18,4 Selection of particular antibiotic agents is empirically based on an assessment of the patient's underlying host defenses, the potential source of infection, and the most likely responsible organisms. Antibiotic choice must be broad spectrum, covering gram-positive, gram-negative, and anaerobic bacteria when the source is unknown.

• When choosing empiric antibiotics, consider the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and include an agent such as vancomycin or linezolid. This is especially true in patients with a history of intravenous drug use, those with indwelling vascular catheters or devices, or those with recent hospitalizations or chronic care facility residents. Antipseudomonal coverage (ceftazidime, cefepime, ticarcillin, piperacillin, imipenem, meropenem) should be considered in patients who are immunocompromised, especially those with neutropenia or burns.
• There is evidence that in immunocompetent patients that monotherapy with an agent such as a carbapenem (imipenem, meropenem), certain third- or fourth-generation cephalosporins (cefotaxime, cefoperazone, ceftazidime), or extended-spectrum penicillins (ticarcillin, piperacillin), is adequate, without having to add a nephrotoxic aminoglycoside.²⁴

Vasopressors administration is required for persistent hypotension once adequate intravascular volume expansion has been achieved. Persistent hypotension is typically defined as systolic blood pressure (SPB) <90 mm Hg or mean arterial pressure (MAP) <65 mm Hg with altered tissue perfusion. The goal of vasopressor therapy is to reverse pathologic vasodilation and altered blood flow distribution that occurs as a result of the inflammatory response to infection. 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 (SBP <70 mm Hg and signs of tissue hypoperfusion).

• The recommended first-line agent for septic shock is either norepinephrine or dopamine.¹⁸ Norepinephrine has predominant alpha-receptor agonist effects and results in potent peripheral arterial vasoconstriction without significantly increasing heart rate or cardiac output. Norepinephrine, in theory, is the ideal vasopressors in the setting of warm shock, where peripheral vasodilation exists in the setting of normal or increased cardiac output. The typical patient with warm shock has warm extremities but with systemic hypotension and tachycardia. The dose range for norepinephrine is 5-20 mcg/min, and it is not based on the weight of the patient.
• Dopamine has a much greater effect on beta-receptors, thus increasing mean arterial pressure primarily through increasing myocardial contractility, stroke volume, and heart rate. However, at higher doses, it has more alpha-receptor effects and increases peripheral vasoconstriction. Dopamine may be more useful in the setting of cold shock, where peripheral vasoconstriction exists (cold extremities) and cardiac output is too low to maintain tissue perfusion. Doses range from 2-20 mcg/kg/min.
• 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 mean arterial pressure 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 in patients with extreme tachycardia.²⁵
• 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.
  • Several small clinic trials have shown that low-dose vasopressin increases mean arterial pressure and decreases the requirement for catecholamines, such as norepinephrine, while maintaining mesenteric and renal perfusion.²⁶
  • However, a large, randomized trial failed to show a mortality difference in patients who received vasopressin in addition to norepinephrine compared with those who received norepinephrine alone, despite the fact that it reduced the requirement for norepinephrine. 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 the use of vasopressin.²⁷

Dobutamine is an inotropic agent that stimulates beta-receptors and results in increased cardiac output. 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.

Administration of steroids (eg, methylprednisolone, hydrocortisone, dexamethasone) has theoretical benefits in the setting of severe sepsis by inhibiting the massive inflammatory cascade that is unleashed. Cortisol is a naturally occurring stress hormone that promotes vascular tone and endothelial integrity, and it is thought to potentiate the effect of vasopressors. Corticosteroid insufficiency has been associated with severe illness.²⁸ High-dose steroid administration with methylprednisolone at 30 mg/kg for in septic shock that was investigated in the 1980s was shown to increase mortality.²⁹

• More recent data show that lower-dose steroids can be beneficial for patients with relative adrenal insufficiency. Annane et al studied 299 patients with septic shock, all who were intubated, persistently hypotensive despite crystalloid resuscitation and vasopressor administration, and had evidence of end-organ failure. Patients were administered a cortisol stimulation test (Cort stim test), which involves measuring cortisol levels before and 30 minutes after administration of cosyntropin (ACTH) 0.25 mg IV. An increase in cortisol level less than 10 mcg/dL was considered "nonresponder," and thus adrenally insufficient. Of the 299 patients with septic shock, 77% were nonresponders. All patients were randomized to low-dose steroids (hydrocortisone 50 mg q6h and fludrocortisone 50 mcg daily) versus placebo. For nonresponders, there was an absolute benefit in mortality of 10% (53% vs 43% mortality rate) for those who received steroids.³⁰
• Although performing the Cort stim test in the ED may not be practical due to 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.
• CORTICUS is the most recent large trial that randomized 499 patients with septic shock to receive either hydrocortisone or placebo.³¹ Even though the patients who received steroids had a more rapid resolution of shock measured by a shorter duration of vasopressor therapy, no difference in mortality rate was noted. 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 emphasize that steroids should be administered only in patients with septic shock whose hypotension is poorly responsive to fluid resuscitation and vasopressor therapy.¹⁸
• Annane et al conducted 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 high-dose corticosteroids for severe sepsis or septic shock.³²

Activated protein C (APC) is an endogenous protein that modulates inflammation and coagulation. Specifically, it inhibits TNF-alpha, 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. APC levels have been shown to be low in sepsis.

• The PROWESS study enrolled 1,690 patients with sepsis and organ dysfunction who were randomized to recombinant human APC (drotrecogin alpha) or placebo. Of note, this study excluded patients who were expected to die within 28 days (eg, end-stage cancer), those with end-stage renal disease or cirrhosis, and those with HIV and a CD4 count less than 50. There was an absolute benefit of 6% in mortality at 28 days with the administration of APC (25% mortality rate vs 31% in the placebo group). They reported 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).⁵
• The drawback to APC is an increased incidence of bleeding complications because it inhibits coagulation. Overall bleeding complications were 3.5% in the APC group versus 2% in the placebo group (p=0.06). 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 (AVM), 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.

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 the conventional therapy plus polymyxin B hemoperfusion group, a significant increase in mean arterial pressure (MAP) and significant decrease for vasopressor requirement at 72 hours were observed compared 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.³³

Consultations

• Patients with sepsis who respond to initial ED treatment (eg, oxygen administration, intravenous fluids, antibiotics) and who are hemodynamically stable can be admitted to a general hospital unit, optimally to one with close nursing observation and monitoring. Such patients do not require invasive hemodynamic monitoring and do not usually require admission to an ICU. Consultation with a family practitioner, general internist, pediatrician, or surgeon who can admit the patient is appropriate.
• Patients who do not respond to initial ED treatment or those who are in septic shock require admission to an ICU for continuous monitoring and intensive therapy. Consultation with a critical care physician or internist with appropriate expertise is advised.
• Obtain surgical consultation if an infectious source amenable to surgery is suspected. Certain conditions will not respond to standard treatment for septic shock until the source of infection is surgically removed. Examples include cholecystitis, ischemic bowel, diverticular abscess, perinephric abscess, infected ureteral stone, deep cutaneous or perirectal abscess, and necrotizing fasciitis.

Medication

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 is also important 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 APC is a therapy that should be considered for the patients in the most critical condition in the ICU.

Isotonic crystalloid

These agents are standard intravenous fluids used for volume resuscitation, referred to as crystalloids. These fluids expand intravascular volume and also diffuse through capillary endothelium into interstitial tissue spaces. Typically, about 30% of administered isotonic fluid stays intravascular; therefore, large quantities may be required to maintain adequate circulating volume. It is important to watch for signs of over-resuscitation, which include respiratory difficulty, low oxygen saturation, crackles on lung examination, or peripheral or periorbital edema.

Normal saline (NS), lactated Ringers (LR)

Both fluids are essentially isotonic and have equivalent volume-restorative properties. While some differences between metabolic changes are seen with administration of large quantities of either fluid, for practical purposes and in most situations, differences are clinically irrelevant. Importantly, hemodynamic effect, morbidity, and mortality are not demonstrably different in resuscitation with isotonic sodium chloride solution or lactated Ringer solution.

Dosing

Adult

1-2 L IV initially, followed by reassessment of hemodynamic response; titrate further 500-mL boluses q15min to urine output >0.5 mL/kg/h (30-50 mL/h in most adults) or CVP >8-12 mm Hg

Pediatric

20 mL/kg IV initially, administered rapidly, usually over 20-30 min; amounts approaching 40-60 mL/kg IV may be required during the first few hours of resuscitation

Interactions

None reported

Contraindications

Pulmonary edema (added fluid promotes more edema and may lead to ARDS); in the case of pulmonary edema or ARDS, the patient should be intubated and fluid administration titrated to CVP

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Major complication is interstitial edema; edema of extremities is an unsightly but insignificant complication; brain or lung edema potentially is fatal; during resuscitation of septic shock, close monitoring of cardiovascular and pulmonary function is required; fluids should be stopped when desired hemodynamic response is seen or pulmonary edema develops

Colloids

Colloid solutions provide an oncotically active substance that expands plasma volume to a greater degree than do isotonic crystalloids and reduce the incidence of pulmonary and cerebral edema. About 50% of the administered colloid stays in the intravascular space. Despite the theoretical benefit of a colloid solution, no clear evidence has shown a benefit of a colloid solution over standard crystalloid resuscitation in the initial treatment of septic shock.

Albumin (Albuminar)

For certain types of shock or impending shock; useful for plasma volume expansion and maintenance of cardiac output; a solution of isotonic sodium chloride solution and 5% albumin is available for volume resuscitation.

Dosing

Adult

250-500 mL IV over 20-30 min, with reassessment of hemodynamic response

Pediatric

4-5 mL/kg IV over 30 min, with reassessment of hemodynamic response

Interactions

None reported

Contraindications

Documented hypersensitivity; pulmonary edema; protein load of 5% albumin

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

While use is theoretically attractive, no proven benefit compared with isotonic crystalloids exists

Antibiotics

Empiric antibiotics that cover the infecting organism, started early, have been shown to reduce mortality in septic shock. To provide the necessary coverage, broad-spectrum and/or multiple antibiotics are started. Monodrug therapy is possible in immunocompetent adults with an antipseudomonal penicillin, carbapenem, or third-generation cephalosporin (eg, cefotaxime, cefuroxime). However, multi-drug empiric coverage is often used. Vancomycin should be considered in skin infections and when MRSA is a concern. It is also advisable to add clindamycin for soft-tissue infections, which has excellent group A streptococci and anaerobic coverage.

Typical coverage for a pulmonary source is a fluoroquinolone and a third-generation cephalosporin. Coverage for suspected abdominal source should include gram-positive, gram-negative, and anaerobic organisms, such as ampicillin or vancomycin, third-generation cephalosporin or aminoglycoside or fluoroquinolone, and clindamycin or metronidazole. Antibiotics in septic shock should be administered IV.

Ticarcillin and clavulanate (Timentin)

Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positive organisms (variable against Staphylococcus epidermidis and no coverage against MRSA), most gram-negative organisms, and most anaerobes. Excellent coverage for abdominal and urinary sources.

Dosing

Adult

3.1 g IV q4-6h

Pediatric

75 mg/kg IV q6h

Interactions

Tetracyclines may decrease effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in the same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels

Contraindications

Documented hypersensitivity; severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Obtain CBC before initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT levels during therapy; exercise caution with hepatic insufficiencies; perform urinalysis, determine BUN and creatinine levels during therapy, and adjust dose if values become elevated; monitor blood levels to prevent possible neurotoxic reactions

Piperacillin and tazobactam (Zosyn)

Inhibits biosynthesis of cell wall mucopeptide; effective during the stage of active multiplication; antipseudomonal activity.

Dosing

Adult

3.375 g IV q6h

Pediatric

75 mg/kg IV q6h

Interactions

Tetracyclines may decrease effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels

Contraindications

Documented hypersensitivity; severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Obtain CBC before initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT levels during therapy; exercise caution with hepatic insufficiencies; perform urinalysis, determine BUN and creatinine levels during therapy, and adjust dose if values become elevated; monitor blood levels to prevent possible neurotoxic reactions

Ceftriaxone (Rocephin)

Used because of an increasing prevalence of penicillinase-producing microorganisms. Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested. Excellent gram-negative activity and used for suspected abdominal or urinary source. Adjunct to fluoroquinolone or macrolide for pulmonary infection. Excellent CNS penetration for suspected meningitis. Does not have antipseudomonal activity.

Dosing

Adult

1 g IV q6-12h

Pediatric

50 mg/kg IV q12h

Interactions

Probenecid may decrease ceftriaxone clearance, causing an increase in ceftriaxone levels; ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity when used concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in renal impairment; caution in breastfeeding women and in patients with penicillin allergy

Cefotaxime (Claforan)

Third-generation cephalosporin with enhanced gram-negative coverage (especially Escherichia coli, Proteus species, and Klebsiella species; has variable activity against Pseudomonas species. Similar coverage to that of ceftriaxone.

Dosing

Adult

1-2 g IV q4h

Pediatric

50 mg/kg IV q8h

Interactions

Probenecid may decrease cefotaxime clearance, causing an increase in cefotaxime levels; furosemide and aminoglycosides may increase nephrotoxicity when used concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe renal impairment; associated with severe colitis

Cefepime (Maxipime)

Fourth-generation cephalosporin. Gram-negative coverage comparable to ceftazidime but has better gram-positive coverage (comparable to ceftriaxone). Poor capacity to cross blood-brain barrier precludes use for treatment of meningitis.

Dosing

Adult

1-2 g IV q12h; pseudomonal infections require higher doses

Pediatric

50 mg/kg IV q8h; not to exceed 2 g

Interactions

Probenecid may increase effects of cefepime; aminoglycosides increase the nephrotoxic potential of cefepime

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dosage adjustments required in patients with renal insufficiency. High doses may cause CNS toxicity; prolonged use of cefepime may predispose patients to superinfection

Ciprofloxacin (Cipro)

Fluoroquinolone with variable activity against streptococci, activity against MSSA and S epidermidis, activity against most gram-negative organisms, and no activity against anaerobes; trovafloxacin (Trovan) overcomes many of these limitations and may be an alternative, although use should be restricted to patients with serious infections.

Dosing

Adult

400 mg IV q12h

Pediatric

10-15 mg/kg IV q12h

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Levofloxacin (Levaquin)

Fluoroquinolone with excellent gram-positive and gram-negative coverage. Excellent agent for pneumonia. Excellent abdominal coverage as well. High urine concentration and therefore reduce dosing in urinary tract infection.

Dosing

Adult

750 mg IV q24h for pneumonia
500 mg IV q24h for abdominal source
250 mg IV q24h for urinary source

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; caution when taking warfarin concurrently; may result in elevated prothrombin time/INR

Clindamycin (Cleocin)

Previously used primarily for its activity against anaerobes; has some activity against streptococci and MSSA. Now found to have good coverage for community-acquired MRSA. Advised in suspected necrotizing fasciitis given its effectiveness against group A streptococci (GAS), and it has been shown to decrease exotoxin release in toxic shock syndrome.

Dosing

Adult

600-900 mg IV q8h

Pediatric

5-10 mg/kg IV q8h

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Metronidazole (Flagyl)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa; usually used with other antimicrobial agents except when used for Clostridium difficile enterocolitis in which monotherapy is appropriate.

Dosing

Adult

Loading dose: Infuse 15 mg/kg IV over 1 h (1 g per 70 kg)
Maintenance dose: Infuse 7.5 mg/kg IV over 1 h q6-8h (500 mg per 70 kg) beginning 6 h after loading dose; not to exceed 4 g in 24 h

Pediatric

Administer as in adults

Interactions

May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity of metronidazole; disulfiramlike reaction may occur with orally ingested ethanol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Vancomycin (Vancocin)

Gram-positive coverage and good hospital-acquired MRSA coverage. Now used more frequently because of high incidence of MRSA. Should be given to all septic patients with indwelling catheters or devices. Advisable for skin and soft-tissue infections.

Dosing

Adult

1 g or 15 mg/kg IV q12h

Pediatric

30-40 mg/kg/d IV divided q12h

Interactions

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal failure, neutropenia; red man syndrome is caused by too rapid IV infusion (dose given over a few min) but rarely happens when dose given IV over 2 h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Imipenem and cilastatin (Primaxin)

Carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes; used for treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of their potential for toxicity. Has been used as single-drug therapy for sepsis.

Dosing

Adult

500 mg IV q6h

Pediatric

10-15 mg/kg IV q6h

Interactions

Coadministration with cyclosporine may increase CNS adverse effects of both; coadministration with ganciclovir may result in generalized seizures

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in renal insufficiency; avoid in children <12 y

Meropenem (Merrem)

Carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem. Has been used as single-drug therapy for sepsis.

Dosing

Adult

1 g IV q8h

Pediatric

40 mg/kg IV q8h

Interactions

Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Pseudomembranous colitis and thrombocytopenia may occur and may require immediate discontinuation

Vasopressors

Vasopressors should be used in patients with persistent hypotension (SBP <90 mm Hg or MAP <65 mm Hg with evidence of hypoperfusion) despite adequate fluid resuscitation and left ventricular filling pressure. Vasopressors may need to be started earlier in patients with extreme hypotension. Vasopressors act to increase mean arterial pressure through increased vasoconstriction (primarily alpha1-receptor agonism) and enhanced cardiac output (primarily beta1-receptor agonism). Vasopressin is the only exception to this, acting on separate vascular endothelial receptors to cause vasoconstriction.

Norepinephrine (Levophed)

Stimulation of alpha-receptors resulting in potent vasoconstriction. Also has some beta-receptor effect as well, resulting in minimal inotropy with increased cardiac output, minimal effects on heart rate. Considered first-line agent in septic shock refractory to fluid resuscitation.

Dosing

Adult

2-20 mcg/min IV infusion

Pediatric

0.1-2 mcg/kg/min IV

Interactions

Effects increase when administered concurrently with tricyclic antidepressants, MAO inhibitors, antihistamines, guanethidine, methyldopa, and ergot alkaloids; atropine may block reflex tachycardia caused by norepinephrine and enhances pressor response

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before giving norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease

Dopamine (Intropin)

Naturally occurring endogenous catecholamine that stimulates beta1- and alpha1-adrenergic and dopaminergic receptors in a dose-dependent fashion; stimulates release of norepinephrine.
In low doses (2-5 mcg/kg/min), acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilatation in these beds. In midrange doses (5-15 mcg/kg/min), acts on beta-adrenergic receptors to increase heart rate and contractility. In high doses (15-20 mcg/kg/min), acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise MAP.
Can be used as first-agent vasopressor in septic shock. Increases mean arterial pressure mostly through its beta-receptor effects and subsequent increase in stroke volume. It can also significantly increase heart rate as compared with norepinephrine.

Dosing

Adult

1-20 mcg/kg/min IV

Pediatric

Administer as in adults

Interactions

MAO inhibitors may prolong effects of dopamine; beta-adrenergic blockers may antagonize peripheral vasoconstriction caused by high doses of dopamine; butyrophenones (eg, haloperidol) and phenothiazines can suppress dopaminergic renal and mesenteric vasodilation induced with low-dose dopamine infusion; concurrent administration of diuretic agents with low-dose dopamine may produce additive effects on urine flow; hypotension and bradycardia may occur with phenytoin; dopamine may decrease effects of phenytoin

Contraindications

Documented hypersensitivity; pheochromocytoma or ventricular fibrillation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Correct hypovolemia with crystalloid or whole blood if possible before dopamine administration; monitoring central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia; patients who have received MAO inhibitors within 2 or 3 wk prior to administration of dopamine, should receive initial doses no greater than 1/10 initial dose; ventricular arrhythmias and hypertension may occur when administering dopamine to patients receiving cyclopropane or halogenated hydrocarbon anesthetics

Epinephrine (Adrenalin, Bronitin, EpiPen)

Used for hypotension refractory to dopamine or norepinephrine. Alpha-agonist effects include increased peripheral vascular resistance. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects. Both potent vasoconstrictor and inotropic agent. Results in increased MAP in the setting of maximal doses of norepinephrine or dopamine in cases of refractory septic shock. Also consider steroid administration in these patients.

Dosing

Adult

1 mcg/min IV titrated according to hemodynamic response; typical dosage range is 1-10 mcg/min

Pediatric

0.1-1 mcg/kg/min IV titrated according to hemodynamic response

Interactions

Increases toxicity of beta- and alpha-blocking agents and that of halogenated inhalational anesthetics

Contraindications

Documented hypersensitivity; cardiac arrhythmias, angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; during labor (may delay second stage of labor)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias

Phenylephrine (Neo-Synephrine)

Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles and increased peripheral vascular resistance. Will result in reflex myocardial depression and decreased heart rate; therefore, it must be used with caution. Can be used as adjunct to norepinephrine or dopamine to augment peripheral vasoconstriction.

Dosing

Adult

IV infusion: 0.1-0.5 mcg/kg/min

Pediatric

Administer as in adults

Interactions

Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects of phenylephrine, and pressor response may be increased 2- to 3-fold
Guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension

Contraindications

Documented hypersensitivity; severe hypertension or ventricular tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients, hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, use is not a substitute for replacement of blood, fluids and electrolytes, and plasma (promptly restore with loss); dilute IV and administer via large vein; extravasation precautions required

Vasopressin (Pitressin)

Endogenous hormone peptide, antidiuretic hormone (ADH), that, at physiologic concentrations, increases water resorption at the distal renal tubular epithelium. Also promotes smooth muscle contraction in vascular beds in renal, splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Vasopressin levels are low in septic shock. In low infusion doses, exogenous vasopressin provides potent vasoconstriction at the expense of reflex myocardial depression, similar to phenylephrine.

Dosing

Adult

0.01-0.1 U/min IV titrated according to response

Pediatric

Not established

Interactions

Lithium, epinephrine, demeclocycline, heparin, and alcohol may decrease effects; chlorpropamide, urea, fludrocortisone, and carbamazepine may potentiate effects

Contraindications

Documented hypersensitivity; coronary artery disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia

Corticosteroid

These agents may maintain vascular tone in states of shock.

Hydrocortisone (Cortef, Hydrocort, Hydrocortone, HydroTex, Solu-Cortef)

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

Dosing

Adult

100 mg IV q8h for 24-48 h; once patient is stable, initiate PO hydrocortisone (50 mg q8h for another 48 h; may taper dose to 30-50 mg/d in divided doses)

Pediatric

<12 years: 1-2 mg/kg IV bolus, followed by 25-150 mg/d divided q6-8h
>12 years: 1-2 mg/kg IV bolus, followed by 150-250 mg/d divided q6-8h

Interactions

CYP450 2D6 and 3A3/4 substrate; corticosteroid clearance may increase with phenytoin, barbiturates, or rifampin treatment or decrease with estrogens; cholestyramine may decrease AUC; corticosteroids may increase digitalis toxicity secondary to hypokalemia; coadministration with potassium-depleting agents (eg, diuretics) may increase risk of hypokalemia; corticosteroids may decrease growth-promoting effect of GH; decreases effects of salicylates and vaccines used for immunization; monitor for hypokalemia with coadministration of diuretics or amphotericin B; antagonizes effects of anticholinergics; may increase anticoagulant effects of warfarin; decreases hypoglycemic effects of sulfonylureas and insulin; increases toxicity of cyclosporine

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Human Activated Protein C, Recombinant

These agents may improve mortality.

Drotrecogin alfa (Xigris)

Activated protein C (APC) is an endogenous protein that has natural anticoagulant and anti-inflammatory effects. Its levels are low in septic shock, which is hypothesized to exacerbate the proinflammatory response and microthrombus formation in end-organ vascular beds that leads to organ dysfunction. Exogenous administration of APC has been shown to improve the mortality in a very ill subset of patients with septic shock. Having an anticoagulant effect, use of APC increases the risk for serious bleeding.

Dosing

Adult

24 mcg/kg/h IV continuous infusion for 96 h; ideally, initiate within 48 h of sepsis onset

Pediatric

Not established

Interactions

None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors); heparin and warfarin are thought to decrease efficacy of APC

Contraindications

Documented hypersensitivity; severe head trauma, intracranial surgery, or stroke within 3 mo; history of intracerebral vascular malformation, aneurysm, or mass lesion; major surgery within past 12 h or planned surgery; chronic renal failure; thrombocytopenia <30 G/L; esophageal varices, cirrhosis, or congenital bleeding diathesis; any other condition that would place patient at high risk for serious bleeding

Precautions

Pregnancy

Precautions

Bleeding is most common serious adverse effect; caution with conditions that increase risk of bleeding including INR >3, concurrent therapeutic heparin (>15 U/kg/h), within 6 wk of GI bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors administration, within 3 mo of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs

Follow-up

Further Inpatient Care

• Patients with sepsis, severe sepsis, and septic shock require admission to the hospital.
• If patients with suspected sepsis respond to early goal-directed therapy (EGDT) in the ED and show no evidence of end-organ hypoperfusion, then they can be admitted to a regular hospital bed for further treatment and close observation.
• Patients with refractory septic shock with organ dysfunction require admission to an ICU for continued goal-directed therapy.

Transfer

• Patients with severe sepsis and septic shock require admission to an ICU for careful monitoring and goal-directed therapy. If an appropriate ICU bed or physician is not available, the patient should be transferred with advanced life support monitoring to another hospital with the available resources.

Deterrence/Prevention

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

Complications

• Acute respiratory distress syndrome (ARDS) is a major complication of sepsis and septic shock. The incidence of ARDS in septic shock is anywhere from 20-40%, occurring more frequently when a pulmonary source of infection exists. ARDS is characterized by widespread inflammatory changes in the lungs the lead to aggressive fibrosis. The pathophysiology of ARDS is related in part to the general endothelial dysfunction that is seen in septic shock. It is characterized by a break down of the endothelial barrier, an influx of inflammatory cells and mediators, and interstitial and alveolar exudates. This leads to subsequent fibrinosis and scarring.
• Alveolar overdistention and repetitive opening and closing of alveoli during mechanical ventilation has 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 while maintaining plateau pressures <30 mL H₂ O. PEEP is required to prevent alveolar collapse at end-expiration.³⁴
• Other complications of septic shock include renal dysfunction, disseminated intravascular coagulation (DIC), mesenteric ischemia, myocardial ischemia and dysfunction, and other complications related to prolonged hypotension and organ dysfunction.

Prognosis

• The mortality rate of sepsis varies widely based on factors such as severity of illness upon hospital presentation, patient’s age and comorbid conditions, nature of infection, and infecting organism. The mortality rate for severe sepsis is quoted as anywhere between 30% and 50%.
  • 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.
  • End-organ failure is a major contributor to mortality in sepsis and septic shock. The complications with the greatest adverse effect on survival are ARDS, DIC, and acute renal failure.

Patient Education

• For excellent patient education resources, visit eMedicine's Shock Center and Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Shock and Sepsis (Blood Infection).

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize early sepsis in the ED and administer broad-spectrum antibiotics concurrent with a rapid fluid challenge
• Failure to intubate and mechanically ventilate a patient with septic shock and ARDS before the patient develops frank respiratory failure
• Failure to recognize evidence of tissue hypoperfusion and organ dysfunction in patients with severe sepsis but who are not yet hypotensive
• Failure to consult a surgeon for potential intra-abdominal infection or soft tissue abscess or fasciitis requiring intervention in the operating room

Special Concerns

• 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.
• This article does not cover sepsis of the neonate or infant. Although many of the concepts of EGDT apply to children as well, special consideration must be given to neonates, infants, and small children regarding fluid resuscitation, appropriate antibiotic coverage, intravenous access, and vasopressor therapy. See Sepsis and Neonatal Sepsis.
• Controversy exists over the use of etomidate as an induction agent for patients with sepsis with debate centered around its association with adrenal insufficiency. At the time of this writing, there is not sufficient evidence to support avoiding the use of etomidate as an induction agent in the setting of sepsis. The interested reader is referred to this summary in Journal Watch, Emergency Medicine as accessed November 13, 2008.

References

1. ACCP. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. Jun 1992;20(6):864-74. [Medline].

2. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA. Sep 27 1995;274(12):968-74. [Medline].

3. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. Jul 16 1997;278(3):234-40. [Medline].

4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. Jun 2006;34(6):1589-96. [Medline].

5. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. Mar 8 2001;344(10):699-709. [Medline].

6. Nguyen HB, Rivers EP, Abrahamian FM, et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. Jul 2006;48(1):28-54. [Medline].

7. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. Jan 21 1999;340(3):207-14. [Medline].

8. Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit Care. 2005;9 Suppl 4:S20-6. [Medline].

9. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. Apr 17 2003;348(16):1546-54. [Medline].

10. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. Jul 2001;29(7):1303-10. [Medline].

11. Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe sepsis in United States emergency departments. Crit Care Med. Aug 2007;35(8):1928-36. [Medline].

12. Shapiro N, Howell MD, Bates DW, et al. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med. Nov 2006;48(5):583-90, 590.e1. [Medline].

13. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. Jan 11 1995;273(2):117-23. [Medline].

14. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med. May 2005;45(5):524-8. [Medline].

15. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. Nov 8 2001;345(19):1368-77. [Medline].

16. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med. Oct 19 1995;333(16):1025-32. [Medline].

17. Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med. Mar 1996;14(2):218-25. [Medline].

18. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. Jan 2008;36(1):296-327. [Medline].

19. Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based "standard operating procedure" and outcome in septic shock. Crit Care Med. Apr 2006;34(4):943-9. [Medline].

20. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med. Apr 2006;34(4):1025-32. [Medline].

21. Nguyen HB, Corbett SW, Steele R, et al. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. Apr 2007;35(4):1105-12. [Medline].

22. Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S451-4. [Medline].

23. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. May 27 2004;350(22):2247-56. [Medline].

24. Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S495-512. [Medline].

25. Beale RJ, Hollenberg SM, Vincent JL, et al. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S455-65. [Medline].

26. Russell JA. Vasopressin in septic shock. Crit Care Med. Sep 2007;35(9 Suppl):S609-15. [Medline].

27. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. Feb 28 2008;358(9):877-87. [Medline].

28. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. Feb 20 2003;348(8):727-34. [Medline].

29. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. Aug 1995;23(8):1430-9. [Medline].

30. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. Aug 21 2002;288(7):862-71. [Medline].

31. [Best Evidence] Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. Jan 10 2008;358(2):111-24. [Medline].

32. [Best Evidence] Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. Jun 10 2009;301(22):2362-75. [Medline].

33. [Best Evidence] Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. Jun 17 2009;301(23):2445-52. [Medline].

34. Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review. Crit Care Med. Nov 2004;32(11 Suppl):S548-53. [Medline].

Keywords

septic shock, sepsis syndromes, bacteremia, sepsis, sepsis treatment, sepsis symptoms, systemic inflammatory response syndrome, SIRS, sepsis with hypotension, septic infection, gram-negative bacteremia, Staphylococcus aureus bacteremia, adult respiratory distress syndrome, ARDS, liver failure, acute renal failure, ARF, disseminated intravascular coagulation, DIC, sepsis syndrome, hypovolemic shock, cardiogenic shock, distributive shock, obstructive shock

Contributor Information and Disclosures

Author

Michael R Filbin, MD, Clinical Instructor, Department of Emergency Medicine, Massachusetts General Hospital
Michael R Filbin, MD is a member of the following medical societies: American College of Emergency Physicians, Massachusetts Medical Society, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Daniel J Dire, MD, FACEP, FAAP, FAAEM, Clinical Associate Professor, Department of Emergency Medicine, University of Texas-Houston
Daniel J Dire, MD, FACEP, FAAP, FAAEM is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American Academy of Pediatrics, American College of Emergency Physicians, and Association of Military Surgeons of the US
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Eric L Weiss, MD, DTM&H, Director of Stanford Travel Medicine, Medical Director of Stanford Lifeflight, Assistant Professor, Departments of Emergency Medicine and Infectious Diseases, Stanford University School of Medicine
Eric L Weiss, MD, DTM&H is a member of the following medical societies: American College of Emergency Physicians, American College of Occupational and Environmental Medicine, American Medical Association, American Society of Tropical Medicine and Hygiene, Physicians for Social Responsibility, Southeastern Surgical Congress, Southern Association for Oncology, Southern Clinical Neurological Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, J Stephan Stapczynski, MD, to the development and writing of this article.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous editor, Charles V Pollack, Jr, MD, to the development and writing of this article.

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