Shock, Septic



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

Nothing to disclose.

Specialty Editor(s)

Daniel J Dire, MD, FACEP, FAAP, FAAEM, Clinical Professor, Department of Emergency Medicine, University of Texas-Houston; Clinical Professor, Department of Pediatrics, University of Texas Health Sciences Center, San Antonio, Texas

Talecris Biotherapeutics Honoraria Speaking and teaching

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

Nothing to disclose.

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

eMedicine Salary Employment

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

Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital

WebMD Salary Employment


Sepsis is a common, deadly, and often underappreciated disease process in emergency departments. The basis of sepsis is the presence of infection associated with a systemic inflammatory response that results in physiologic alterations that occur 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.

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. Meeting SIRS criteria is considered as having at least 2 of the following 4 clinical parameters abnormal:

The presence of SIRS criteria is of course not specific to sepsis, but, in the presence of infection, an increasing number of SIRS criteria 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 endothelial dysfunction of sepsis; however, the use of sepsis-specific biomarkers has not yet translated to establishing a clinical diagnosis of sepsis in emergency departments.

Clinicians often use the terms sepsis, severe sepsis, and septic shock without a commonly understood definition. In 2001, an International Sepsis Definitions Conference was convened and 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.[1]Sepsis is the presence of infection in association with meeting SIRS criteria. The clinical significance of meeting SIRS criteria in the absence of organ dysfunction or shock is still unclear. Severe sepsis is defined as evidence of end-organ dysfunction such as altered mental status, episode of hypotension, elevated creatinine, or evidence of disseminated intravascular coagulopathy. Septic shock is defined as persistent hypotension despite adequate fluid resuscitation or tissue hypoperfusion manifested by a lactate greater than 4 mg/dL.

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]


The pathophysiology of septic shock is not precisely understood, but it involves a complex interaction between the pathogen and the host's immune system. The normal physiologic response to localized infection includes the activation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, the release of inflammatory mediators, local vasodilation, increased endothelial permeability, and activation of coagulation pathways. These mechanisms are in play during septic shock but on a systemic scale, leading to diffuse endothelial disruption, vascular permeability, vasodilation, and thrombosis of end-organ capillaries.

The cascade of inflammation and thrombosis can be triggered by endotoxins contained within the cell wall of gram-negative bacteria or exotoxin released by gram-positive bacteria. 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.

As a result of these interactions, immune cellular activation occurs with the release of cytokine and noncytokine mediators. The most common inflammatory mediators associated with sepsis are tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6), all implicated in the diffuse activation of a systemic inflammatory response. Mediators with vasodilatory and endotoxic properties are also 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, 8] The following systems and mediators are activated in septic shock:

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 mechanisms implicated in this pathologic vasodilation are multifactorial, but primary factors are thought to be (1) activation of ATP-sensitive potassium channels in vascular smooth muscle cells and (2) activation of nitric oxide synthase. K-ATP channels are directly activated by lactic acidosis. Nitric oxide (NO) also activates potassium channels. Potassium efflux from cells results in hyperpolarization, inhibition of calcium influx, and vascular smooth muscle relaxation.[9] The resulting vasodilation can be refractory to endogenous vasoactive hormones such as norepinephrine and epinephrine that are released during shock.

Endothelial dysfunction and vascular maldistribution of distributive shock results 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. Furthermore, activation of the coagulation cascade and fibrin deposition cause microthombi to form in end-organ capillaries. These factors lead to organ dysfunction and eventual failure. The insidious nature of sepsis is such that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal.[10]



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.[11]

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.[12] 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.[13]


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.[12, 14] 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.[15]

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%.[12]

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%. ARDS 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.[6]


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.[11]

A more recent large epidemiologic study ties the increased incidence of septic shock in the black population to increased infection rates requiring hospitalization and increased development of organ dysfunction.[16] 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.


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.[11, 12]


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.[12, 14]


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.

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


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 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 underway when it may not be clearly manifested 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.[17] Meeting SIRS criteria is defined by the having at least 2 of the following 4 abnormalities:

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.[14] However, there is evidence that suggests that meeting increasing numbers 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 and death.

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. 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, both 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.

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:


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 particularly 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.

Laboratory Studies

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

Imaging Studies

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


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 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).[22] 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 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 a 3-step protocol aimed at optimizing tissue perfusion.

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 were based on increasing tissue oxygen delivery.[23, 24] 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.

Crowe et al implemented a protocol that substituted "spot-check" ScvO2 measurement 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 a MAP goal.[25] A recent study suggests that following lactate clearance may be equally as effective compared with monitoring continuous ScvO 2 as the third goal in EGDT.[21] However, the advantage of continuous ScvO 2 monitoring is that immediate interventions can be made if the ScvO 2 drops below 70%.

Rivers et al enrolled 263 patients who met criteria for septic shock: suspected infection, 2 of the 4 SIRS criteria, and 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 ScvO2 measured after therapy was 95% for the EGDT group versus 60% in the standard group.

Since the publication of the Rivers et al trial, a number of studies 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.[26, 27, 28, 29, 30, 31, 32, 33]

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

In 2004, the first set of formal treatment guidelines for septic shock were published that describe the many aspects of sepsis care.[34] These guidelines were formulated by an international consensus group that was composed of experts from 11 organizations, including the Society of Critical Care Medicine, American College of Chest Physicians, European Society of Intensive Care Medicine, and American College of Emergency Physicians. These guidelines are known as the Surviving Sepsis Campaign. These guidelines were updated in 2008 and reflect the most modern opinion on the treatment of septic shock.[35]

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. CVP measurement should not be entirely relied upon as there is some debate as to its accurate correlation with intravascular volume status, especially in the fluid-resuscitated patient.[36]

It is also important to monitor urine output (UOP) as a measure of dehydration. UOP less than 30-50 mL/h should prompt further fluid resuscitation. There have also been studies using noninvasive means of estimating CVP, for example, using ultrasound to measure inferior vena cava diameter as a surrogate for volume status. Nagdev et al used the difference between caval diameter between inspiration and expiration, or the caval index, to predict CVP. They found that a difference of 50% predicted CVP < 8 with a sensitivity and specificity both greater than 90%.[37]

Considering 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).[38] The SAFE trial enrolled 7000 ICU patients requiring fluid resuscitation, only about 1200 of whom had severe sepsis. Overall, no difference was seen 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.[39] These data are inconclusive, especially in regard to the initial resuscitation phase for septic shock in the ED; therefore, crystalloid resuscitation is recommended.

Recommendations are 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.[35, 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.

In addition, consideration must be given to pathogens with antibiotic resistance, such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas species, and gram-negative organisms with extended-spectrum 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.

Vasopressor 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 activation of 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 (SBP < 70 mm Hg or signs of profound tissue hypoperfusion).

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.

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.[45] High-dose steroid administration with methylprednisolone at 30 mg/kg for septic shock that was investigated in the 1980s was shown to increase mortality.[46]

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.

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.[50] 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 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.[50] This is an example of a novel therapy that targets the pathophysiology of septic shock, similar to APC, and which may become more widespread in the future.


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

Class Summary

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. Isotonic crystalloid resuscitation provides a medium to transport oxygen-carrying hemoglobin molecules to vital organs. Typically, about 30% of administered isotonic fluid stays in the intravascular space; therefore, large quantities may be required to maintain adequate circulating volume. Adequate intravascular volume also recruits capillaries that may be collapsed due to volume depletion. 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)

Clinical Context:  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.

Class Summary

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)

Clinical Context:  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.

Class Summary

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)

Clinical Context:  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.

Piperacillin and tazobactam (Zosyn)

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

Ceftriaxone (Rocephin)

Clinical Context:  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; however, susceptible to ESBL-producing organisms. Adjunct to fluoroquinolone or macrolide for pulmonary infection. Excellent CNS penetration for suspected meningitis. Does not have antipseudomonal activity.

Cefotaxime (Claforan)

Clinical Context:  Third-generation cephalosporin with enhanced gram-negative coverage (especially Escherichia coli, Proteus species, and Klebsiella species; has variable activity against Pseudomonas species. May be active against ESBL-producing organisms. Similar coverage to that of ceftriaxone.

Cefepime (Maxipime)

Clinical Context:  Fourth-generation cephalosporin. Gram-negative coverage comparable to ceftazidime but has better gram-positive coverage (comparable to ceftriaxone). Active against Pseudomonas species. Increased effectiveness against ESBL-producing organisms. Poor capacity to cross blood-brain barrier precludes use for treatment of meningitis.

Ciprofloxacin (Cipro)

Clinical Context:  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.

Levofloxacin (Levaquin)

Clinical Context:  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.

Clindamycin (Cleocin)

Clinical Context:  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.

Metronidazole (Flagyl)

Clinical Context:  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.

Vancomycin (Vancocin)

Clinical Context:  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.

Imipenem and cilastatin (Primaxin)

Clinical Context:  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. Agent of choice if ESBL-producing organism is suspected. Has been used as single-drug therapy for sepsis.

Meropenem (Merrem)

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

Class Summary

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. 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)

Clinical Context:  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.

Dopamine (Intropin)

Clinical Context:  Naturally occurring endogenous catecholamine that stimulates beta1- and alpha1-adrenergic and dopaminergic receptors in a dose-dependent fashion; stimulates release of norepinephrine.

At lower 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.

Epinephrine (Adrenalin, Bronitin, EpiPen)

Clinical Context:  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.

Phenylephrine (Neo-Synephrine)

Clinical Context:  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. First-line agent in patients with hypotension and extreme tachycardia. Can be used as adjunct to norepinephrine or dopamine to augment peripheral vasoconstriction.

Vasopressin (Pitressin)

Clinical Context:  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.

Class Summary

These agents may maintain vascular tone in states of shock.

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

Clinical Context:  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.

Class Summary

These agents may improve mortality.

Drotrecogin alfa (Xigris)

Clinical Context:  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.

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.


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.


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.


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 breakdown 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.[51]

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.


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%. Sepsis mortality is high, but its effect on the quality of life of survivors was previously not well characterized. New evidence shows that septic shock in elderly persons leads to significant long-term cognitive and functional disability compared with those hospitalized with nonsepsis conditions. Septic shock is often a major sentinel event that has lasting effects on the patient's independence, reliance on family support, and need for chronic nursing home or institutionalized care.[52]

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.


  1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. Apr 2003;31(4):1250-6.[View Abstract]
  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.[View Abstract]
  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.[View Abstract]
  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.[View Abstract]
  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.[View Abstract]
  6. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. Jan 21 1999;340(3):207-14.[View Abstract]
  7. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. Jan 9 2003;348(2):138-50.[View Abstract]
  8. 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.[View Abstract]
  9. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. Aug 23 2001;345(8):588-95.[View Abstract]
  10. Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit Care. 2005;9 Suppl 4:S20-6.[View Abstract]
  11. 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.[View Abstract]
  12. 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.[View Abstract]
  13. 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.[View Abstract]
  14. 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.[View Abstract]
  15. 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.[View Abstract]
  16. Mayr FB, Yende S, Linde-Zwirble WT, Peck-Palmer OM, Barnato AE, Weissfeld LA, et al. Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis. JAMA. Jun 2010;303(24):2495-2503.
  17. [Guideline] 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.[View Abstract]
  18. Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. Mar 5-11 2005;365(9462):871-5.[View Abstract]
  19. 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.[View Abstract]
  20. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. Aug 2004;32(8):1637-42.[View Abstract]
  21. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. Feb 24 2010;303(8):739-46.[View Abstract]
  22. 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.[View Abstract]
  23. 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.[View Abstract]
  24. 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.[View Abstract]
  25. Crowe CA, Mistry CD, Rzechula K, Kulstad CE. Evaluation of a modified early goal-directed therapy protocol. Am J Emerg Med. Jul 2010;28(6):689-93.[View Abstract]
  26. 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.[View Abstract]
  27. 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.[View Abstract]
  28. 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.[View Abstract]
  29. Micek ST, Roubinian N, Heuring T, Bode M, Williams J, Harrison C, et al. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med. Nov 2006;34(11):2707-13.[View Abstract]
  30. Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest. Feb 2006;129(2):225-32.[View Abstract]
  31. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest. Aug 2007;132(2):425-32.[View Abstract]
  32. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. May 21 2008;299(19):2294-303.[View Abstract]
  33. [Guideline] Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. Feb 2010;38(2):367-74.[View Abstract]
  34. [Guideline] Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. Mar 2004;32(3):858-73.[View Abstract]
  35. [Guideline] 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.[View Abstract]
  36. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. Jul 2008;134(1):172-8.[View Abstract]
  37. Nagdev AD, Merchant RC, Tirado-Gonzalez A, Sisson CA, Murphy MC. Emergency department bedside ultrasonographic measurement of the caval index for noninvasive determination of low central venous pressure. Ann Emerg Med. Mar 2010;55(3):290-5.[View Abstract]
  38. 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.[View Abstract]
  39. 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.[View Abstract]
  40. Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. Mar 2008;8(3):159-66.[View Abstract]
  41. 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.[View Abstract]
  42. 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.[View Abstract]
  43. Russell JA. Vasopressin in septic shock. Crit Care Med. Sep 2007;35(9 Suppl):S609-15.[View Abstract]
  44. 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.[View Abstract]
  45. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. Feb 20 2003;348(8):727-34.[View Abstract]
  46. 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.[View Abstract]
  47. 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.[View Abstract]
  48. 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.[View Abstract]
  49. 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.[View Abstract]
  50. 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.[View Abstract]
  51. 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.[View Abstract]
  52. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. Oct 27 2010;304(16):1787-94.[View Abstract]
  53. Russell JA. Vasopressin in septic shock. Crit Care Med. Sep 2007;35(9 Suppl):S609-15.[View Abstract]