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Management of severe sepsis and septic shock in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Oct 25, 2011.

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 750,000 cases of sepsis occur in the United States each year, resulting in approximately 200,000 fatalities [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 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".)

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 [6-9].
  • Distinguishing sepsis from systemic inflammatory response syndrome (SIRS) (table 1 and table 2) because, if an infection exists, it must be identified and treated as soon as possible (table 3). 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 [7,10].

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 [11,12].

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 lung injury (ALI) or acute respiratory distress syndrome (ARDS), which frequently complicate sepsis. (See "Acute respiratory distress syndrome: Definition; 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. 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), obtundation or restlessness, oliguria or anuria, and lactic acidosis. 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).

Catheters — 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 [13]. (See "Indications for and complications of central venous catheters".)

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 [14,15]. PACs increase complications and have not been shown to improve outcome [16-18]. (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 [19,20]. 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 [14,21,22]. 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 [23]. 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.

Restore perfusion — 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.

Central or mixed venous oxyhemoglobin saturation — Resuscitation of the circulation should target a central or mixed venous oxyhemoglobin saturation (ScvO2 or SvO2, respectively) of ≥70 percent [7,13]. Other common goals include a 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, although these targets have not been well studied.

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) [19,20].

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 [13]. 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" (ie, administered within the first six hours of presentation).

Earlier studies of critically ill patients that used similar targets (SvO2 ≥70 percent) found no mortality benefit [24]. This might be because these studies were not conducted during the crucial initial hours. This is supported by a systemic review that compared resuscitation targeting specific physiologic endpoints to standard resuscitation [25]. 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).

Lactate clearance — Lactate clearance has been evaluated as a potential substitute for ScvO2 as the target of resuscitation. A trial 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) [26]. 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.

In our practice, we adhere to the principles of early goal-directed therapy; that is, we initiate early aggressive therapy in order to restore perfusion. We prefer to target an ScvO2 ≥70 percent because it is the more extensively studied resuscitation goal, although a lactate clearance ≥10 percent appears to be a reasonable alternative if ScvO2 monitoring is unavailable.

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 and need for more of a therapy.

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 [13]. 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, ALI, ARDS). In patients with ALI or 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 [27]. 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'.)

Clinical trials have failed to consistently demonstrate a difference between colloid and crystalloid in the treatment of septic shock [28,29]. In the saline versus albumin fluid evaluation (SAFE) trial, 6997 critically ill patients were randomly assigned to receive 4 percent albumin 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.

Another randomized trial compared pentastarch (a colloid) to modified Ringer's lactate (a crystalloid) in patients with severe sepsis — the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial [31]. There was no difference in 28-day mortality, but the trial was stopped early because there was a trend toward increased 90-day mortality among patients who received pentastarch.

In our clinical practice, we generally use crystalloid because of the higher cost of colloid. We believe that giving a sufficient quantity of intravenous fluids rapidly and targeting appropriate goals is more important than the type of fluid chosen.

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 [32]. However, intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema.

In severe septic shock, there is no definitive evidence of the superiority of one vasopressor over another (table 4). We prefer to use norepinephrine in most patients [7,33]. 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 myocardial dysfunction, a trial of inotropic therapy is warranted if ScvO2 remains <70 percent after all of the interventions discussed above [7,8,13,34,35]. Inotropic therapy should not be used to increase the cardiac index to supranormal levels [7]. Dobutamine is the usual inotropic agent. 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.
  • Red blood cell transfusions — Early goal-directed therapy aggressively utilizes red blood cell transfusions to raise the ScvO2. In the trial discussed above, nearly 70 percent of patients in the early goal-directed therapy group received transfusions, compared to 45 percent in the conventional therapy group [13]. However, other data support a more cautious approach to transfusion in critically ill patients [36]. (See "Use of blood products in the critically ill", section on 'Red blood cells'.) 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.

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 5). Gastric tonometry may also be helpful, if available. 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 [13]. 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 [37]. 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 [38]. 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 [39,40]. 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 [41-43]. 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 6). 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. (See "Blood cultures for the detection of bacteremia".)

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 [44-46]. 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) [45] 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 [47].
  • 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 [48-50]. In a small trial, increased TREM-1 levels were both sensitive and specific for the diagnosis of bacterial sepsis (96 and 89 percent, respectively) [48]. Serial monitoring of TREM-1 may also provide prognostic information in patients with established sepsis [49,50].

Evaluation of the clinical usefulness of both procalcitonin and TREM-1 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 either.

Eradication of infection — Effective treatment of the active infection is essential to the successful treatment of severe sepsis and septic shock. 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 3). 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 [51].

Antimicrobial regimen — Intravenous antibiotic therapy should be initiated immediately after obtaining appropriate cultures, since early initiation of antibiotic therapy is associated with lower mortality [52]. The choice of antibiotics can be complex and should consider the patient's history (eg, recent antibiotics received [53]), comorbidities, clinical context (eg, community- or hospital-acquired), Gram stain data, and local resistance patterns [7,54,55].

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) [56-62]. 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) [59]. 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 [60].

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

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

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.

Staphylococcus aureus is associated with significant morbidity if not treated early in the course of infection [63]. 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 [64,65]. Many of these staphylococci have the Panton-Valentine leukocidin virulence factor, which causes severe, necrotizing infections [66]. 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. Linezolid is a reasonable alternative if there are contraindications to vancomycin.

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 [59,67-71]. Furthermore, one meta-analysis found double coverage was associated with an increased incidence of adverse events [70,71]. 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 [7,69]. (See "Pseudomonas aeruginosa bacteremia and endocarditis" and "Treatment 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 [72]. 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. 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.

ADDITIONAL THERAPIES

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 [73]. 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".)

Protocols — Sepsis treatment protocols may improve outcome [74-76]. This was illustrated by an observational cohort study of 120 patients with septic shock [76]. 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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SUMMARY AND RECOMMENDATIONS

  • 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 (or mixed) venous oxygen saturation ≥70 percent within six hours of presentation (Grade 1B). (See '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. There are no data to support preferential administration of crystalloid or colloid. (See 'Intravenous fluids' above.)
  • We recommend vasopressors for patients who remain hypotensive following intravascular volume repletion (Grade 1B). Although there is no definitive evidence of the superiority of one vasopressor over another, we suggest beginning with norepinephrine (Grade 2C). (See 'Vasopressors' above.)
  • For patients whose ScvO2 remains <70 percent after intravenous fluid and vasopressor therapy, it is reasonable to administer additional therapies, including blood transfusions or inotropic therapy. (See 'Additional therapies' above.)
  • 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 3). (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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