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Disclosures: Gregory A Schmidt, MD Grant/Research/Clinical Trial Support: Spectral Diagnostics (septic shock). Jess Mandel, MD Nothing to disclose. Polly E Parsons, MD Nothing to disclose. Daniel J Sexton, MD Consultant/Advisory Boards: Johnson & Johnson (surgical infections); National Football League (infection control and prevention). Geraldine Finlay, MD Employee of UpToDate, Inc.

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Literature review current through: Mar 2014. | This topic last updated: Mar 19, 2014.

INTRODUCTION — Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a continuum of severity ranging from sepsis to severe sepsis and septic shock. Over 1,665,000 cases of sepsis occur in the United States each year, with a mortality rate of 20 to 50 percent [1]. Even with optimal treatment, mortality due to severe sepsis or septic shock is approximately 40 percent and can exceed 50 percent in the sickest patients [2-5].

Numerous interventions exist that decrease mortality due to sepsis. In this topic review, the management of severe sepsis and septic shock is discussed. Definitions, diagnosis, pathophysiology, and investigational therapies for sepsis, as well as management of sepsis in the asplenic patient are reviewed separately. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis" and "Pathophysiology of sepsis" and "Investigational and ineffective therapies for sepsis" and "Clinical features and management of sepsis in the asplenic patient".)

THERAPEUTIC PRIORITIES — Therapeutic priorities for patients with severe sepsis or septic shock include:

Early initiation of supportive care to correct physiologic abnormalities, such as hypoxemia and hypotension [6-10].

Distinguishing sepsis from systemic inflammatory response syndrome (SIRS) (table 1) because, if an infection exists, it must be identified and treated as soon as possible (table 2). This may require a surgical procedure (eg, drainage), as well as appropriate antibiotics.

EARLY MANAGEMENT — The first priority in any patient with severe sepsis or septic shock is stabilization of their airway and breathing. Next, perfusion to the peripheral tissues should be restored [10,11].

Stabilize respiration — Supplemental oxygen should be supplied to all patients with sepsis and oxygenation should be monitored continuously with pulse oximetry. Intubation and mechanical ventilation may be required to support the increased work of breathing that typically accompanies sepsis, or for airway protection since encephalopathy and a depressed level of consciousness frequently complicate sepsis [12,13].

Sedative and induction agents (eg, etomidate) used to intubate patients with severe sepsis or septic shock are discussed separately. Other aspects of intubation and mechanical ventilation are similarly described elsewhere. (See "Sedation or induction agents for rapid sequence intubation in adults" and "Advanced emergency airway management in adults" and "Rapid sequence intubation in adults" and "The decision to intubate" and "The difficult airway in adults".)

Chest radiographs and arterial blood analysis should be obtained following initial stabilization. These studies are used in combination with other clinical parameters to diagnose acute respiratory distress syndrome (ARDS), which frequently complicate sepsis. (See "Acute respiratory distress syndrome: Clinical features and diagnosis" and "Mechanical ventilation in acute respiratory distress syndrome".)

Assess perfusion — Once the patient's respiratory status has been stabilized, the adequacy of perfusion should be assessed. Hypotension is the most common indicator that perfusion is inadequate (eg, systolic blood pressure (SBP) <90 mmHg, mean arterial pressure <70 mmHg, decrease in SBP >40 mmHg). Therefore, it is important that the blood pressure be assessed early and often. An arterial catheter may be inserted if blood pressure is labile or restoration of arterial perfusion pressures is expected to be a protracted process, because a sphygmomanometer may be unreliable in hypotensive patients [8]. Attempts to insert an arterial line should not be allowed to delay the prompt management of shock. (See "Arterial catheterization techniques for invasive monitoring".)

Critical hypoperfusion can also occur in the absence of hypotension, especially during early sepsis. Thus, clinical evidence of impaired perfusion should be sought in all patients with sepsis. Common signs of hypoperfusion include cool, vasoconstricted skin due to redirection of blood flow to core organs (although warm, flushed skin may be present in the early phases of sepsis), tachycardia >90/min, obtundation or restlessness, and oliguria or anuria. These findings may be modified by preexisting disease or medications. As an example, elderly patients, diabetic patients, and patients who take beta-blockers may not exhibit an appropriate tachycardia as blood pressure falls. Patients with chronic hypertension may develop critical hypoperfusion at a higher blood pressure than healthy patients (ie, relative hypotension).

An elevated serum lactate (eg, >1 mmol/L) can be a manifestation of organ hypoperfusion in the absence of hypotension and is an important component of the initial evaluation [10]. A serum lactate level ≥4 mmol/L is consistent with severe sepsis. Additional laboratory studies that help characterize the severity of sepsis include the platelet count, international normalized ratio, creatinine, and bilirubin. Values for laboratory parameters that suggest severe sepsis are described separately. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis", section on 'Severe sepsis'.)

Establish central venous access — After initial assessment, a central venous catheter (CVC) should be inserted in most patients with severe sepsis or septic shock. A CVC can be used to infuse intravenous fluids, infuse medications, infuse blood products, and draw blood. In addition, it can be used for hemodynamic monitoring by measuring the central venous pressure (CVP) and the central venous oxyhemoglobin saturation (ScvO2). In one clinical trial, treatment of septic shock guided by the ScvO2 reduced mortality [14]. (See "Complications of central venous catheters and their prevention".)

We believe that pulmonary artery catheters (PACs) should not be used in the routine management of patients with severe sepsis or septic shock. PACs can measure the pulmonary artery occlusion pressure (PAOP) and mixed venous oxyhemoglobin saturation (SvO2). In theory, this may be helpful to guide circulatory resuscitation. However, the PAOP has proven to be a poor predictor of fluid responsiveness in sepsis and the SvO2 is similar to the ScvO2, which can be obtained from a CVC [15,16]. PACs increase complications and have not been shown to improve outcome [17-19]. (See "Pulmonary artery catheterization: Indications and complications".)

Respiratory changes in the radial artery pulse pressure, aortic blood flow peak velocity, and brachial artery blood flow velocity are considered dynamic hemodynamic measures, whereas CVP and PAOP are considered static hemodynamic measures [20,21]. There is increasing evidence that dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and passively ventilated with a sufficient tidal volume [15,22,23]. For actively breathing patients or those with irregular cardiac rhythms, an increase in the cardiac output in response to a passive leg-raising maneuver (measured by echocardiography, arterial pulse waveform analysis, or pulmonary artery catheterization) is a sensitive and specific predictor of fluid responsiveness [24]. It seems likely that dynamic measures will become more common and be used to identify patients who are likely to increase organ perfusion in response to intravenous fluids.

Goals of initial resuscitation — Once it has been established that hypoperfusion exists, early restoration of perfusion is necessary to prevent or limit multiple organ dysfunction, as well as reduce mortality. Hypoperfusion results from loss of plasma volume into the interstitial space, decreased vascular tone, and myocardial depression. The increase in the cardiac output that is necessary to compensate for the diminished vascular tone may be limited by the myocardial depression.

Goals during the first six hours of fluid resuscitation, as suggested by the Surviving Sepsis Campaign Guidelines, include the following [10]:

Central venous pressure 8 to 12 mmHg

Central venous (superior vena cava) or mixed venous oxygen saturation 70 or 65 percent, respectively

Mean arterial pressure ≥65 mmHg (MAP = [(2 x diastolic) + systolic]/3)

Urine output ≥0.5 mL/kg/hour

The best evidence favors targeting central venous oxygen saturation (ScVO2) ≥70 percent. However, following any or all of these goals, as valuable indicators of tissue perfusion, is reasonable. Ongoing large randomized studies should further validate the benefits of EGDT and select the optimal target to be followed.

Early goal-directed therapy-targeting venous oxygen saturation — Resuscitation of the circulation should target a central or mixed venous oxyhemoglobin saturation (ScvO2 or SvO2) of ≥70 or 65 percent, respectively [10,14]. The focus on the ScvO2 derives from a clinical trial in which 263 patients with severe sepsis or septic shock were randomly assigned to therapy targeting a ScvO2 ≥70 percent, or conventional therapy that did not target a ScvO2 [14]. Both groups initiated therapy within six hours of presentation and targeted the same CVP, MAP, and urine output. Mortality was lower in the group that targeted a ScvO2 ≥70 percent (31 versus 47 percent). This approach is known as "early goal-directed therapy" (EGDT) (ie, administered within the first six hours of presentation).

The mortality benefit of EGDT is derived from one single-center trial [14]. However, the general application of this mortality benefit from EGDT is unknown. Ongoing, are a number of large randomized trials (eg, Protocolized Care for Early Septic Shock [PROCESS] and Australasian Resuscitation In Sepsis Evaluation [ARISE]) designed to answer this question.

Earlier studies of critically ill patients that used similar targets (SvO2 ≥70 percent) found no mortality benefit [25]. This might be because these studies were not conducted during the crucial initial hours. This is supported by a systematic review that compared resuscitation targeting specific physiologic endpoints to standard resuscitation [26]. In a meta-analysis of randomized trials initiated within 24 hours of the onset of sepsis (6 trials, 740 patients), resuscitation targeting specific physiologic endpoints improved mortality compared to standard resuscitation (39 versus 57 percent, odds ratio 0.50, 95% CI 0.37-0.69). In contrast, a meta-analysis of randomized trials initiated more than 24 hours after the onset of sepsis (3 trials, 261 patients) found that resuscitation targeting specific physiologic endpoints did not improve mortality (64 versus 58 percent for standard resuscitation, odds ratio 1.16, 95% CI 0.60-2.22).

Early goal-directed therapy - other targets — The other goals outlined in the Surviving Sepsis Campaign, central venous pressure (CVP) 8 to 12 mmHg, a mean arterial pressure (MAP) ≥65 mmHg, and a urine output ≥0.5 mL/kg per hour have not been as well studied as the ScvO2 but are commonly used. Many clinicians prefer to use dynamic indices (eg, radial pulse pressure, aortic blood flow peak velocity, brachial artery blood flow velocity, or passive leg raising) to guide fluid resuscitation rather than static hemodynamic measures (ie, CVP, pulmonary artery occlusion pressure) [20,21]. We consider the numeric goals for CVP, MAP, and urine output to be guidelines and always consider additional clinical signs of hypoperfusion when assessing the patient's response to a therapy.

Lactate clearance — The lactate clearance is defined by the equation [(initial lactate - lactate >2 hours later)/initial lactate] x 100. The lactate clearance and interval change in lactate over the first 12 hours of resuscitation has been evaluated as a potential marker for effective resuscitation [27,28]. Best illustrating this was a trial that randomly assigned 300 patients with severe sepsis to undergo resuscitation targeting either a lactate clearance ≥10 percent or an ScvO2 ≥70 percent (other than these targets, the resuscitation protocols were identical) [27]. There was no difference in hospital mortality, length of stay, ventilator-free days, or incidence of multiorgan failure, suggesting that lactate clearance criteria may be an acceptable alternative to ScvO2 criteria.

Interventions to restore perfusion — Restoration of perfusion is predominantly focused on administration of intravenous fluids; additional modalities such as vasopressor therapy, inotropic therapy, and blood transfusion are added, depending on the response to fluid resuscitation, evidence for myocardial dysfunction, and presence of anemia.

Intravenous fluids — Relative intravascular hypovolemia is typical and may be severe. As an example, early goal-directed therapy required a mean infusion volume of approximately five liters within the initial six hours of therapy in the trial described above [14]. As a result, rapid, large volume infusions of intravenous fluids are indicated as initial therapy for severe sepsis or septic shock, unless there is coexisting clinical or radiographic evidence of heart failure.

Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses [8,9]. Volume status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be assessed before and after each bolus. Intravenous fluid challenges can be repeated until blood pressure is acceptable, tissue perfusion is acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.

Careful monitoring is essential in this approach because patients with sepsis typically develop noncardiogenic pulmonary edema (ie, ARDS). In patients with ARDS who are hemodynamically resuscitated, a liberal approach to intravenous fluid administration prolongs the duration of mechanical ventilation, compared to a more restrictive approach that typically requires large doses of furosemide [29]. Thus, while the early, aggressive fluid therapy is appropriate in severe sepsis and septic shock, fluids may be unhelpful or harmful when the circulation is no longer fluid-responsive. (See "Supportive care and oxygenation in acute respiratory distress syndrome", section on 'Fluid management'.)

Randomized trials have found no difference between using albumin solution and a crystalloid solution (eg, normal saline, Ringer’s lactate) in the treatment of severe sepsis or septic shock, but they have identified potential harm from using pentastarch or hydroxyethyl starch rather than a crystalloid solution:

Crystalloid versus albumin: In the saline versus albumin fluid evaluation (SAFE) trial, 6997 critically ill patients were randomly assigned to receive 4 percent albumin solution or normal saline for up to 28 days [30]. There were no differences between groups for any endpoint, including the primary endpoint, mortality. Among the patients with severe sepsis (18 percent of the total group), there were also no differences in outcome.

Crystalloid versus hydroxyethyl starch: In the Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, 804 patients with severe sepsis were randomly assigned to receive either 6 percent hydroxyethyl starch or Ringer’s acetate at a volume of up to 33 mL/kg of ideal body weight per day [31]. When assessed 90 days after randomization, mortality was increased in the hydroxyethyl starch group (51 versus 43 percent) and more patients in the hydroxyethyl starch group had required renal replacement therapy at some time during their illness (22 versus 16 percent).

Crystalloid versus pentastarch: The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial compared pentastarch to modified Ringer's lactate in patients with severe sepsis and found no difference in 28-day mortality [32]. The trial was stopped early because there was a trend toward increased 90-day mortality among patients who received pentastarch.

In our clinical practices, we generally use a crystalloid solution instead of albumin solution because of the higher cost of albumin. We believe that giving a sufficient quantity of intravenous fluids rapidly and targeting appropriate goals is more important than the type of fluid chosen. We do not use hydroxyethyl starch or pentastarch. These choices are consistent with current guidelines [10]. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Choice of replacement fluid'.)  

Vasopressors — Vasopressors are second line agents in the treatment of severe sepsis and septic shock; we prefer intravenous fluids as long as they increase perfusion without seriously impairing gas exchange [33]. However, intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema.

In severe septic shock, we prefer to use norepinephrine in most patients (table 3) [7,10,34]. However, we find phenylephrine (a pure alpha-adrenergic agonist) to be useful when tachycardia or arrhythmias preclude the use of agents with beta-adrenergic activity. Choosing a vasopressor agent is discussed in greater detail elsewhere. (See "Use of vasopressors and inotropes", section on 'Choice of agent in septic shock'.)

Additional therapies — When the ScvO2 remains <70 percent after optimization of intravenous fluid and vasopressor therapy, it is reasonable to consider additional therapies, such as inotropic therapy or red blood cell transfusion.

Inotropic therapy – For patients who have diminished cardiac output, a trial of inotropic therapy is warranted if ScvO2 remains <70 percent after all of the interventions discussed above [7,8,14,35,36]. Inotropic therapy should not be used to increase the cardiac index to supranormal levels [7]. Dobutamine is the usual inotropic agent [10]. At low doses, dobutamine may cause the blood pressure to decrease because it can dilate the systemic arteries. However, as the dose is increased, blood pressure usually rises because cardiac output increases out of proportion to the fall in vascular resistance. (See "Use of vasopressors and inotropes", section on 'Dobutamine'.)

Red blood cell transfusions – The ideal threshold for red blood cell transfusion in patients with sepsis is not known [37]. Early goal-directed therapy, as described above, aggressively utilized red blood cell transfusions to raise the ScvO2 [14]. Nearly 70 percent of patients in the early goal-directed therapy group received transfusions, compared to 45 percent in the conventional therapy group, suggesting a beneficial effect of transfusions [14]. In a separate observational study of 1054 patients with severe sepsis or septic shock, transfused patients had a lower risk of 7 and 28-day mortality (hazard ratio [HR] 0.42, 95% CI 0.19-0.50 and HR 0.43, 95% CI 0.29-0.62, respectively) [38].

However, other data support a more cautious approach to transfusion in critically ill patients [39]. There are several possible explanations for the conflicting data:

Outcome may be related to when a red blood cell transfusion is given. Transfusions administered as part of early goal-directed therapy were given early in the course of illness, whereas studies that support a more cautious approach typically gave transfusions later in the course of illness.

The apparent benefit of red blood cell transfusions may be due to other interventions. In other words, red blood cell transfusion was just one of several interventions during early goal-directed therapy and it is possible that the benefit was due to one or more of the other interventions, not the red blood cell transfusion per se [14].

The presence of underlying coronary artery disease may affect individual tolerance of restrictive blood transfusion policies [37].

The use of blood transfusions in critically-ill patients is discussed in detail separately. (See "Use of blood products in the critically ill", section on 'Red blood cells'.)

Ongoing management — There are two possible outcomes following the interventions described above:

Despite aggressive therapy, the patient may have persistent hypoperfusion and progressive organ failure. This should prompt reassessment of the adequacy of the above therapies, antimicrobial regimen, and control of the septic focus, as well as the accuracy of the diagnosis and the possibility that unexpected complications or coexisting problems have intervened (eg, pneumothorax following CVC insertion).

The patient may have responded to the above interventions with restored perfusion and a ScvO2 greater than 70 percent. Such patients should continue to have their clinical and laboratory parameters followed closely. These include blood pressure, arterial lactate, urine output, creatinine, platelet count, Glasgow coma scale score, serum bilirubin, liver enzymes, oxygenation (ie, arterial oxygen tension or oxyhemoglobin saturation), and gut function (table 4). Reevaluation is indicated if any of these parameters worsen or fail to improve.

In early sepsis, most lactate is probably a byproduct of anaerobic metabolism due to organ hypoperfusion. Supporting this view, early goal-directed therapy decreases lactate levels faster than conventional therapy [14]. After the restoration of perfusion, however, lactate is probably due to causes other than anaerobic metabolism and further increasing oxygen delivery to the peripheral tissues is unlikely to decrease its levels [40]. As a result, lactate values are generally unhelpful following restoration of perfusion, with one exception – a rising lactate level should prompt reevaluation of perfusion (see "Venous blood gases and other alternatives to arterial blood gases").

It would be ideal if hypoxia could be detected for individual organs, because tests that combine output from many organs (eg, arterial lactate) may obscure the presence of significant ischemia in an individual organ [41]. Gastric tonometry indirectly measures perfusion to the gut by estimating the gastric mucosal PCO2. It can be used to detect gut hypoxia by calculating the gastric to arterial PCO2 gap [42,43]. But, gastric tonometry is not widely available and it is uncertain whether it can successfully guide therapy. Additional studies and clinical experience are needed.

CONTROL OF THE SEPTIC FOCUS — Prompt identification and treatment of the primary site or sites of infection are essential [44-46]. This is the primary therapeutic intervention, with most other interventions being purely supportive.

Identification of the septic focus — A careful history and physical examination may yield clues to the source of sepsis and help guide microbiologic evaluation (table 5). As an example, sepsis arising after trauma or surgery is often due to infection at the site of injury or surgery. The presence of a urinary or vascular catheter increases the chances that these are the source of sepsis.

Gram stain of material from sites of possible infection may give early clues to the etiology of infection while cultures are incubating. As examples, urine should be routinely Gram stained and cultured, sputum should be examined in a patient with a productive cough, and an intra-abdominal collection in a postoperative patient should be percutaneously sampled under ultrasound or radiologic guidance.

Blood should be taken from two distinct venipuncture sites and inoculated into standard blood culture media (aerobic and anaerobic). For patients with a vascular catheter, blood should be obtained through the catheter and from another site [10]. (See "Blood cultures for the detection of bacteremia".)

If invasive candida or aspergillus infection is suspected, serologic assays for 1,3 beta-D-glucan, galactomannan, and anti-mannan antibodies, if available, may provide early evidence of these fungal infections [10]. The limitations of these assays and their role in the diagnosis of fungal infection are discussed separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Non-culture methods' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

There is no single test that immediately confirms the diagnosis of severe sepsis or septic shock. However, several laboratory tests, all of which are still investigational, have been studied as diagnostic markers of active bacterial infection [6]:

Elevated serum procalcitonin levels are associated with bacterial infection and sepsis [47-49]. Despite this, a meta-analysis of 18 studies found that procalcitonin distinguished sepsis from nonseptic systemic inflammation poorly (sensitivity of 71 percent and specificity of 71 percent) [48] and another meta-analysis of six trials (four in patients with sepsis and two in patients with other infections) found that using clinical algorithms based upon procalcitonin levels did not affect mortality [50].

The plasma concentration of soluble TREM-1 (triggering receptor expressed on myeloid cells), a member of the immunoglobulin superfamily that is specifically upregulated in the presence of bacterial products, is increased in patients with sepsis [51-53]. In a small trial, increased TREM-1 levels were both sensitive and specific for the diagnosis of bacterial sepsis (96 and 89 percent, respectively) [51]. However, a subsequent prospective cohort study found that increased TREM-1 levels predicted sepsis with a sensitivity and specificity of only 53 and 86 percent, respectively [54]. Serial monitoring of TREM-1 may also provide prognostic information in patients with established sepsis [52,53].

Increased expression of CD64 on polymorphonuclear leukocytes indicates cellular activation and has been shown to occur in patients with sepsis [55,56]. In a prospective cohort study of 300 consecutive critically ill patients, increased CD64 expression predicted sepsis with a sensitivity of 84 percent and a specificity of 95 percent [54]. In this study, the sensitivity and specificity of increased CD64 expression were superior to that of increased procalcitonin or TREM-1 levels.

The combination of procalcitonin levels, TREM-1 levels, and CD64 expression appears to be superior to the use of any of these markers alone. However, evaluation of the clinical usefulness of such biomarkers is still in its earliest stages and should be considered preliminary. Until additional clinical investigations have been performed, we do not suggest the routine use of such biomarkers to identify sepsis.

Eradication of infection — Prompt and effective treatment of the active infection is essential to the successful treatment of severe sepsis and septic shock [10]. Source control (physical measures undertaken to eradicate a focus of infection and eliminate or treat ongoing microbial proliferation and infection) should be undertaken since undrained foci of infection may not respond to antibiotics alone (table 2). As examples, potentially infected foreign bodies (eg, vascular access devices) should be removed when possible, and abscesses should undergo percutaneous or surgical drainage. Some patients require extensive soft tissue debridement or amputation; in severe cases, fulminant Clostridium difficile-associated colitis may necessitate colectomy [57].

Antimicrobial regimen — Intravenous antibiotic therapy should be initiated immediately after obtaining appropriate cultures, since early initiation of antibiotic therapy is associated with lower mortality [58]. The choice of antibiotics can be complex and should consider the patient's history (eg, recent antibiotics received [59]), comorbidities, clinical context (eg, community- or hospital-acquired), Gram stain data, and local resistance patterns [7,60,61].

Poor outcomes are associated with inadequate or inappropriate antimicrobial therapy (ie, treatment with antibiotics to which the pathogen was later shown to be resistant in vitro) [62-68]. They are also associated with delays in initiating antimicrobial therapy, even short delays (eg, an hour).

A prospective cohort study of 2124 patients demonstrated that inappropriate antibiotic selection was surprisingly common (32 percent) [65]. Mortality was markedly increased in these patients compared to those who had received appropriate antibiotics (34 versus 18 percent).

A retrospective analysis of 2731 patients with septic shock demonstrated that the time to initiation of appropriate antimicrobial therapy was the strongest predictor of mortality [66].

When the potential pathogen or infection source is not immediately obvious, we favor broad-spectrum antibiotic coverage directed against both gram-positive and gram-negative bacteria. Few guidelines exist for the initial selection of empiric antibiotics in severe sepsis or septic shock.

Staphylococcus aureus is associated with significant morbidity if not treated early in the course of infection [69]. There is growing recognition that methicillin-resistant S. aureus (MRSA) is a cause of sepsis not only in hospitalized patients, but also in community dwelling individuals without recent hospitalization [70,71].  For these reasons, we recommend that severely ill patients presenting with sepsis of unclear etiology be treated with intravenous vancomycin (adjusted for renal function) until the possibility of MRSA sepsis has been excluded. Potential alternative agents to vancomycin (eg, daptomycin for non-pulmonary MRSA, linezolid, ceftaroline) should be considered for patients with refractory or virulent MRSA, or a contraindication to vancomycin. These agents are discussed separately. (See "Treatment of invasive methicillin-resistant Staphylococcus aureus infections in adults", section on 'Bacteremia' and "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Methicillin-resistant Staphylococcus aureus'.)

In our practice, if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with one of the following:

Cephalosporin, 3rd generation (eg, ceftriaxone or cefotaxime), or

Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or

Carbapenem (eg, imipenem or meropenem)

Alternatively, if Pseudomonas is a possible pathogen, we favor combining vancomycin with two of the following (see "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections"):

Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or

Antipseudomonal carbapenem (eg, imipenem, meropenem), or

Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or

Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or

Aminoglycoside (eg, gentamicin, amikacin), or

Monobactam (eg, aztreonam)

Selection of two agents from the same class, for example, two beta-lactams, should be avoided. We emphasize the importance of considering local susceptibility patterns when choosing an empiric antibiotic regimen.

After culture results and antimicrobial susceptibility data return, we recommend that therapy be pathogen- and susceptibility-directed, even if there has been clinical improvement while on the initial antimicrobial regimen. Gram-negative pathogens have historically been covered with two agents from different antibiotic classes. However, several clinical trials and two meta-analyses have failed to demonstrate superior overall efficacy of combination therapy compared to monotherapy with a third generation cephalosporin or a carbapenem [65,72-76]. Furthermore, one meta-analysis found double coverage that included an aminoglycoside was associated with an increased incidence of adverse events (nephrotoxicity) [75,76]. For this reason, we recommend use of a single agent with proven efficacy and the least possible toxicity, except in patients who are either neutropenic or whose severe sepsis is due to a known or suspected Pseudomonas infection [7,74]. (See "Pseudomonas aeruginosa bacteremia and endocarditis" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Regardless of the antibiotic regimen selected, patients should be observed closely for toxicity, evidence of response, and the development of nosocomial superinfection [77]. There are no published randomized controlled trials testing safety of de-escalation of antibiotic therapy in adult patients with sepsis or septic shock [78]. The duration of therapy is typically 7 to 10 days, although longer courses may be appropriate in patients who have a slow clinical response, an undrainable focus of infection, or immunologic deficiencies [7]. In patients who are neutropenic, antibiotic treatment should continue until the neutropenia has resolved or the planned antibiotic course is complete, whichever is longer. In non-neutropenic patients in whom infection is thoroughly excluded, antibiotics should be discontinued to minimize colonization or infection with drug-resistant microorganisms and superinfection with other pathogens.


Glucocorticoids — Glucocorticoids have long been investigated as therapeutic agents in sepsis because the pathogenesis of sepsis involves an intense and potentially deleterious host inflammatory response. This topic is discussed in detail separately. (See "Corticosteroid therapy in septic shock".)

Nutrition — There is consensus that nutritional support improves nutritional outcomes in critically ill patients, such as body weight and mid-arm muscle mass. However, it is uncertain whether nutritional support improves important clinical outcomes (eg, duration of mechanical ventilation, length of stay, mortality), or when nutritional support should be initiated. This topic is reviewed in detail elsewhere. (See "Nutrition support in critically ill patients: An overview".)

Intensive insulin therapy — Hyperglycemia and insulin resistance are common in critically ill patients, independent of a history of diabetes mellitus [79]. As a result, intensive glycemic control has been studied and a body of evidence has accumulated. This topic is discussed separately. (See "Glycemic control and intensive insulin therapy in critical illness".)

External cooling — Controlling fever during severe sepsis and septic shock has potential benefits and adverse effects, the net effects of which are uncertain. A trial was performed to compare the effects of external cooling with no external cooling. External cooling consists of using either an automatic cooling blanket, or ice-cold bed sheets and ice packs, to achieve a core body temperature of 36.5 to 37°C for 48 hours. It decreases the time to fever control without exposing the patient to potential adverse effects of antipyretic drugs.

The trial randomly assigned 200 patients with septic shock (the patients were requiring vasopressors, mechanically ventilated, and sedated) to receive either external cooling or no external cooling [80]. Patients in the external cooling group had lower 14-day mortality (19 versus 34 percent) and were more likely to have their vasopressor dose lowered by 50 percent (54 versus 20 percent) and their shock reversed during their ICU stay (86 versus 73 percent). No antipyretic agents were received during the trial.

While these results are promising, we believe that the results need to be confirmed before external cooling is adopted as routine clinical practice. Among the limits of the trial, patients in the external cooling group may have been less severely ill (ie, they required a lower baseline vasopressor dose), the trial was not blinded so co-interventions cannot be excluded, and there were relatively few events (ie, deaths, patients with a 50 percent vasopressor dose decrease, and patients with shock reversal), which lowers confidence in the accuracy of the estimated effects. Moreover, the results suggest that external cooling is preferable to no cooling, but they do not provide guidance about whether external cooling is preferable to antipyretic medications.

Protocols — Sepsis treatment protocols may improve outcome [81-83]. This was illustrated by an observational cohort study of 120 patients with septic shock [83]. Implementation of a standardized hospital order set was associated with greater likelihood that the initial antibiotic regimen targeted the culprit microorganism (87 versus 72 percent), shorter hospital stay (9 versus 12 days), and lower 28-day mortality (30 versus 48 percent), compared to historical controls. It is impossible to determine which component or components of the protocol conferred the benefit.

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Basics topic (see "Patient information: Sepsis in adults (The Basics)")


Sepsis is a clinical syndrome characterized by systemic inflammation and widespread tissue injury due to infection. There is a continuum of illness severity ranging from sepsis to severe sepsis and septic shock. When infection is absent, the clinical syndrome is termed systemic inflammatory response syndrome (SIRS). (See 'Introduction' above.)

Initial management is aimed at securing the airway and correcting hypoxemia. Intubation and mechanical ventilation may be required. (See 'Stabilize respiration' above.)

Once the patient's respiratory status has been stabilized, the adequacy of perfusion should be assessed. Hypotension is the most common indicator that perfusion is inadequate. However, critical hypoperfusion can also occur in the absence of hypotension, especially during early sepsis. Common signs of hypoperfusion include cool, vasoconstricted skin due to redirection of blood flow to core organs (although warm, flushed skin may be present in the early phases of sepsis), obtundation or restlessness, oliguria or anuria, and lactic acidosis. (See 'Assess perfusion' above.)

Once it has been established that hypoperfusion exists, early restoration of perfusion is necessary to prevent or limit multiple organ dysfunction, as well as reduce mortality. Tissue perfusion should be promptly restored using intravenous fluids, vasopressors, inotropes, and, possibly, red blood cell transfusions. We recommend that patients be managed with therapy aimed at achieving a central venous oxygen saturation ≥70 percent, or mixed venous oxygen saturation ≥65 percent, within six hours of presentation, rather than being managed without specific therapeutic targets (Grade 1B). A strategy that targets a lactate clearance ≥10 percent is a reasonable alternative. (See 'Goals of initial resuscitation' above and 'Interventions to restore perfusion' above.)

We recommend boluses of intravenous fluids as first-line therapy in patients who demonstrate impaired perfusion (Grade 1B). Fluid boluses are repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or there is no further response. These parameters should be assessed before and after each fluid bolus. For initial fluid replacement, we recommend using a crystalloid solution rather than a hyperoncotic starch solution (Grade 1A), and we suggest using a crystalloid rather than albumin-containing solution (Grade 2B). (See 'Intravenous fluids' above and "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Choice of replacement fluid'.)

We recommend vasopressors for patients who remain hypotensive following intravascular volume repletion (Grade 1B); the preferred initial agent is norepinephrine. (See 'Vasopressors' above and "Use of vasopressors and inotropes", section on 'Choice of agent in septic shock'.)

For patients whose ScvO2 remains <70 percent after intravenous fluid and vasopressor therapy, additional therapies, such as inotropic therapy or blood transfusions, are administered based on individual assessment. (See 'Additional therapies' above and "Use of vasopressors and inotropes", section on 'Choice of agent in septic shock'.)

Prompt identification and treatment of the site of infection are essential. Sputum and urine should be collected for Gram stain and culture. Intra-abdominal fluid collections should be percutaneously sampled. Blood should be taken from two distinct venipuncture sites and from indwelling vascular access devices and cultured aerobically and anaerobically. (See 'Identification of the septic focus' above.)

Antibiotics should be administered immediately after appropriate cultures have been obtained. We recommend empiric broad spectrum antibiotics when a definite source of infection can not be identified (Grade 1B). (See 'Antimicrobial regimen' above.)

Potentially infected vascular access devices should be removed (if possible), abscesses should be drained, and extensive soft tissue infections should be debrided or amputated (table 2). (See 'Eradication of infection' above.)

Glucocorticoid therapy, nutritional support, and glucose control are additional issues that are important in the management of patients with severe sepsis or septic shock. Each is discussed separately. (See "Corticosteroid therapy in septic shock" and "Nutrition support in critically ill patients: An overview" and "Glycemic control and intensive insulin therapy in critical illness".)

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