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Management of severe sepsis and septic shock in adults Authors

Gregory A Schmidt, MD

Jess Mandel, MD

Section Editors

Polly E Parsons, MD

Daniel J Sexton, MD

Deputy Editor

Kevin C Wilson, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is

complete.

Literature review current through: Feb 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 "Arterial and mixed venous

blood gases in lactic acidosis").

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:

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 "Treatment 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.

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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Here are the patient education articles that are relevant to this topic. We encourage you to

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

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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Topic 1613 Version 11.0

GRAPHICS

Definitions of systemic inflammatory response syndrome (SIRS) and different degrees of severity of sepsis

Condition Description

Systemic inflammatory response syndrome

Two or more of the following conditions: temperature >38.5°C or <35.0°C; heart rate of >90 beats/min; respiratory rate of >20 breaths/min or PaCO2 of <32 mm Hg; and WBC count of >12,000 cells/mL, <4000 cells/mL, or >10 percent immature (band) forms

Sepsis SIRS in response to documented infection (culture or Gram stain of blood, sputum, urine, or normally sterile body fluid positive for pathogenic

microorganism; or focus of infection identified by visual inspection, eg, ruptured bowel with free air or bowel contents found in abdomen at surgery, wound with purulent discharge)

Severe sepsis Sepsis and at least one of the following signs of organ hypoperfusion or organ dysfunction: areas of mottled skin; capillary refilling of ≥3 s; urinary output of <0.5 mL/kg for at least 1 h or renal replacement therapy; lactate >2 mmol/L; abrupt change in mental status or abnormal EEG findings; platelet count of <100,000 cells/mL or disseminated intravascular coagulation; acute lung injury/ARDS; and cardiac dysfunction (echocardiography)

Septic shock Severe sepsis and one of the following conditions: systemic mean BP of <60 mm Hg (<80 mm Hg if previous hypertension) after 20 to 30 mL/kg starch or

40 to 60 mL/kg saline solution, or PCWP between 12 and 20 mm Hg; and need for dopamine of >5 mcg/kg/min, or norepinephrine or epinephrine of <0.25 mcg/kg/min to maintain mean BP at >60 mm Hg (80 mm Hg if previous hypertension)

Refractory septic shock

Need for dopamine at >15 mcg/kg/min, or norepinephrine or epinephrine at >0.25 mcg/kg/min to maintain mean BP at >60 mm Hg (80 mm Hg if previous hypertension)

WBC count: white blood cell count; BP: blood pressure. Data from: Annane, D, Bellissant, E, Cavaillon, JM. Septic shock. Lancet 2005; 365:63.

Noninfectious mimics of sepsis

Acute myocardial infarction

Acute pulmonary embolus

Acute pancreatitis

Fat emboli syndrome

Acute adrenal insufficiency

Acute gastrointestinal hemorrhage

Overzealous diuresis

Transfusion reactions

Adverse drug reactions

Procedure-related transient bacteremia

Amniotic fluid embolism

Adapted from Cuhna, BA, Crit Care Clin 1998; 14:1

Source control methods for common ICU infections

Site Interventions

Sinusitis Surgical decompression of the sinuses

Pneumonia Chest physiotherapy, suctioning

Empyema thoracis Drainage, decortication

Mediastinitis Drainage, debridement, diversion

Peritonitis Resection, repair, or diversion of ongoing sources of contamination, drainage of abscesses, debridement of necrotic tissue

Cholangitis Bile duct decompression

Pancreatic infection Drainage or debridement

Urinary tract Drainage of abscesses, relief of obstruction, removal or changing of infected catheters

Catheter-related bacteremia

Removal of catheter

Endocarditis Valve replacement

Septic arthritis Joint drainage and debridement

Soft tissue infection Debridement of necrotic tissue and drainage of discrete abscesses

Prosthetic device

infection

Device removal

Adapted from Marshall, JC, Lowry, SF. Evaluation of the adequacy of source control. In: Sibbald, WJ, Vincent, JL, Clinical Trials for the Treatment of Sepsis. Springer-Verlag, Berlin, 1995 p 329.

Vasoactive agents in septic shock

Drug Effect on heart

rate Effect on

contractility Arterial constriction

effects

Dobutamine + +++ - (dilates)

Dopamine ++ ++ ++

Epinephrine +++ +++ ++

Norepinephrine ++ ++ +++

Phenylephrine 0 0 +++

Amrinone + +++ -- (dilates)

Parameters for monitoring organ system function in patients with sepsis

Organ system Parameter

Respiratory system PaO2/FiO2 ratio

Renal system Urine output and serum creatinine

Hematologic system Platelet count

Central nervous system Glasgow coma score

Hepatobiliary system Serum bilirubin and liver enzymes

Cardiovascular system Blood pressure, arterial lactate

Gastrointestinal system Gastric intramucosal pH (pHi), ileus, blood in nasogastric aspirate

Evaluation of common sources of sepsis

Suspected site Symptoms/signs Microbiologic evaluation

Upper respiratory tract

Pharyngeal inflammation plus exudate ± swelling and

lymphadenopathy

Throat swab for aerobic culture

Lower respiratory tract

Productive cough, pleuritic chest pain, consolidative auscultatory findings

Sputum of good quality, quantitative culture of protected brush or bronchoalveolar lavage

Urinary tract Fever, urgency, dysuria, loin pain Urine microscopy >50 WBC/hpf plus:

midstream urine >100,000 cfu/mL

catheter urine >100,000 cfu/mL

Suprapubic aspirate >1000 cfu/mL

Wound or burn Inflammation, edema, erythema, discharge of pus

Gram stain and culture of draining pus, wound culture not reliable

Skin/soft tissue Erythema, edema, lymphangitis Culture blister fluid or draining pus;

role of tissue aspirates not proven

Central nervous system

Signs of meningeal irritation CSF microscopy, protein, glucose, culture, bacterial antigen test

Gastrointestinal Abdominal pain, distension,

diarrhea, and vomiting

Stool culture for Salmonella, Shigella,

and Campylobacter

Intraabdominal Specific abdominal symptoms/signs Aerobic and anaerobic culture of percutaneously or surgically drained abdominal fluid collections

Peritoneal dialysis (PD) infections

Cloudy PD fluid, abdominal pain, fever

Cell count and culture of PD fluid

Genital tract Low abdominal pain, vaginal discharge

Endocervical and high vaginal swabs onto selective media

Adapted from Cohen, J, Microbiologic requirements for studies of sepsis. In: Sibbald, WJ, Vincent, JL (eds), Clinical Trials for the Treatment of Sepsis, Springer-Verlag, Berlin, 1995, p 73.

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