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

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 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]. PACs increase complications
and have not been shown to improve outcome [15-17]. (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 [18,19]. 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 [14,20,21]. 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) to guide fluid
resuscitation rather than static hemodynamic measures (ie, CVP, pulmonary
artery occlusion pressure) [18,19]. There is increasing evidence that dynamic
measures are more accurate predictors of fluid responsiveness that static
measures, as long as the patients are in sinus rhythm and passively ventilated
with a sufficient tidal volume [14,20,21]. It seems likely that dynamic
measures will become increasingly common and be used to identify patients
who are likely to increase organ perfusion in response to intravenous fluids.

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) (figure 1).

Earlier studies of critically ill patients that used similar targets (SvO2 ≥70
percent) found no mortality benefit [22]. 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 [23]. 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) [24]. 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 offurosemide [25]. 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 [26,27]. 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 [28]. 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 [29].
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 [30]. 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 [7,31]. However, we findphenylephrine (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 [7,8,13,32,33]. 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 [34].
(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 [35]. 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 [36].
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 [37,38]. But, gastric tonometry is not widely
available and it is uncertain whether it can successfully guide therapy.
Additional studies and clinical experience are needed.

The American Thoracic Society (ATS) statement on the detection, correction,

and prevention of tissue hypoxia, as well as other ATS guidelines, can be
accessed through the ATS web site atwww.thoracic.org.

CONTROL OF THE SEPTIC FOCUS — Prompt identification and treatment of

the primary site or sites of infection are essential [39-41]. 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]:

 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 [42-44]. In a small trial,
increased TREM-1 levels were both sensitive and specific for the
diagnosis of bacterial sepsis (96 and 89 percent, respectively) [42].
Serial monitoring of TREM-1 may also provide prognostic information
in patients with established sepsis [43,44].
 Elevated serum procalcitonin levels are associated with bacterial
infection and sepsis [45-47]. But, 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) [46].

Evaluation of the clinical usefulness of both TREM-1 and procalcitonin 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 [48].
Antimicrobial regimen — Intravenous antibiotic therapy should be initiated
immediately after obtaining appropriate cultures, since early initiation of
antibiotic therapy is associated with lower mortality [49]. The choice of
antibiotics can be complex and should consider the patient's history (eg,
recent antibiotics received), comorbidities, clinical context (eg, community- or
hospital-acquired), Gram stain data, and local resistance patterns [7,50,51].

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) [52-58]. 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) [55]. 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 [56].

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 or 4th 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 [59]. 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 [60,61]. Many of these staphylococci have the Panton-
Valentine leukocidin virulence factor, which causes severe, necrotizing
infections [62]. For these reasons, we recommend that severely ill patients
presenting with sepsis of unclear etiology be treated with
intravenousvancomycin (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 [55,63-67]. Furthermore, one meta-analysis found double
coverage was associated with an increased incidence of adverse events
[66,67]. 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 [7,65]. (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 [68]. 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

Recombinant human activated protein C — Recombinant human activated

protein C (rhAPC, also called drotrecogin alfa) promotes fibrinolysis and
inhibits thrombosis. It has been hypothesized that rhAPC may be beneficial in
sepsis because it can modulate the procoagulant response that is believed to
contribute to multisystem organ dysfunction. The role of rhAPC in the
management of severe sepsis or septic shock is discussed separately.
(See "Recombinant human activated protein C in severe sepsis and septic
shock".)

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 "Nutritional 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
[69]. 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 that incorporate early empiric

antibiotics, restoration of tissue perfusion, glucocorticoids, glucose control,
and recombinant human activated protein C may improve outcome [70-72].
This was illustrated by an observational cohort study of 120 patients with
septic shock [72]. 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.

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 (figure 1). 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.)
 Recombinant human activated protein C therapy, 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 "Recombinant
human activated protein C in severe sepsis and septic
shock" and "Corticosteroid therapy in septic shock" and"Nutritional
support in critically ill patients: An overview" and "Glycemic control
and intensive insulin therapy in critical illness".)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe

sepsis in the United States: analysis of incidence, outcome, and associated
costs of care. Crit Care Med 2001; 29:1303.
2. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on
the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis
Study Group. N Engl J Med 1997; 336:912.
3. McCloskey RV, Straube RC, Sanders C, et al. Treatment of septic shock
with human monoclonal antibody HA-1A. A randomized, double-blind,
placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med 1994;
121:1.
4. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat
sepsis and septic shock: a reassessment. Crit Care Med 1997; 25:1095.
5. Sasse KC, Nauenberg E, Long A, et al. Long-term survival after
intensive care unit admission with sepsis. Crit Care Med 1995; 23:1040.
6. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005;
365:63.
7. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
international guidelines for management of severe sepsis and septic shock:
2008. Crit Care Med 2008; 36:296.
8. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for
hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med
2004; 32:1928.
9. Practice parameters for hemodynamic support of sepsis in adult
patients in sepsis. Task Force of the American College of Critical Care
Medicine, Society of Critical Care Medicine. Crit Care Med 1999; 27:639.
10. Sessler CN, Perry JC, Varney KL. Management of severe sepsis and
septic shock. Curr Opin Crit Care 2004; 10:354.
11. Luce JM. Pathogenesis and management of septic shock. Chest 1987;
91:883.
12. Ghosh S, Latimer RD, Gray BM, et al. Endotoxin-induced organ injury.
Crit Care Med 1993; 21:S19.
13. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in
the treatment of severe sepsis and septic shock. N Engl J Med 2001;
345:1368.
14. Michard F, Boussat S, Chemla D, et al. Relation between respiratory
changes in arterial pulse pressure and fluid responsiveness in septic patients
with acute circulatory failure. Am J Respir Crit Care Med 2000; 162:134.
15. Harvey S, Harrison DA, Singer M, et al. Assessment of the clinical
effectiveness of pulmonary artery catheters in management of patients in
intensive care (PAC-Man): a randomised controlled trial. Lancet 2005;
366:472.
16. Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary
artery catheter and outcomes in patients with shock and acute respiratory
distress syndrome: a randomized controlled trial. JAMA 2003; 290:2713.
17. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials Network, Wheeler AP, Bernard GR, et al.
Pulmonary-artery versus central venous catheter to guide treatment of acute
lung injury. N Engl J Med 2006; 354:2213.
18. Brennan JM, Blair JE, Hampole C, et al. Radial artery pulse pressure
variation correlates with brachial artery peak velocity variation in ventilated
subjects when measured by internal medicine residents using hand-carried
ultrasound devices. Chest 2007; 131:1301.
19. Eikermann M, Magder S, Malhotra A. Is brachial artery peak velocity
variation ready for prime time? Chest 2007; 131:1279.
20. Monnet X, Rienzo M, Osman D, et al. Esophageal Doppler monitoring
predicts fluid responsiveness in critically ill ventilated patients. Intensive Care
Med 2005; 31:1195.
21. Reuter DA, Bayerlein J, Goepfert MS, et al. Influence of tidal volume on
left ventricular stroke volume variation measured by pulse contour analysis in
mechanically ventilated patients. Intensive Care Med 2003; 29:476.
22. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented
hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N
Engl J Med 1995; 333:1025.
23. Jones AE, Brown MD, Trzeciak S, et al. The effect of a quantitative
resuscitation strategy on mortality in patients with sepsis: a meta-analysis.
Crit Care Med 2008; 36:2734.
24. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central
venous oxygen saturation as goals of early sepsis therapy: a randomized
clinical trial. JAMA 2010; 303:739.
25. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al.
Comparison of two fluid-management strategies in acute lung injury. N Engl J
Med 2006; 354:2564.
26. Wilkes MM, Navickis RJ. Patient survival after human albumin
administration. A meta-analysis of randomized, controlled trials. Ann Intern
Med 2001; 135:149.
27. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid
resuscitation: a systematic review. Crit Care Med 1999; 27:200.
28. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline
for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247.
29. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and
pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125.
30. Reinhart, K, Bloos, F, Spies, C. Vasoactive drug therapy in sepsis. In:
Clinical Trials for the treatment of sepsis, Sibbald, WJ, Vincent, JL (Eds),
Springer Verlag, Berlin, 1995, p.207.
31. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and
norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779.
32. Rhodes A, Bennett ED. Early goal-directed therapy: an evidence-based
review. Crit Care Med 2004; 32:S448.
33. Bersten AD, Hersch M, Cheung H, et al. The effect of various
sympathomimetics on the regional circulations in hyperdynamic sepsis.
Surgery 1992; 112:549.
34. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized,
controlled clinical trial of transfusion requirements in critical care. Transfusion
Requirements in Critical Care Investigators, Canadian Critical Care Trials
Group. N Engl J Med 1999; 340:409.
35. Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of
lactic acidosis. Chest 2000; 117:260.
36. Third European Consensus Conference in Intensive Care Medicine.
Tissue hypoxia: How to detect, how to correct, how to prevent. Société de
Réanimation de Langue Française. The American Thoracic Society. European
Society of Intensive Care Medicine. Am J Respir Crit Care Med 1996;
154:1573.
37. Gutierrez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a
therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992;
339:195.
38. Poeze M, Solberg BC, Greve JW, Ramsay G. Monitoring global volume-
related hemodynamic or regional variables after initial resuscitation: What is a
better predictor of outcome in critically ill septic patients? Crit Care Med 2005;
33:2494.
39. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of
the systemic inflammatory response syndrome (SIRS). A prospective study.
JAMA 1995; 273:117.
40. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and
outcome of severe sepsis and septic shock in adults. A multicenter prospective
study in intensive care units. French ICU Group for Severe Sepsis. JAMA
1995; 274:968.
41. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J
Med 1999; 340:207.
42. Gibot S, Kolopp-Sarda MN, Béné MC, et al. Plasma level of a triggering
receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with
suspected sepsis. Ann Intern Med 2004; 141:9.
43. Gibot S, Cravoisy A, Kolopp-Sarda MN, et al. Time-course of sTREM
(soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and
C-reactive protein plasma concentrations during sepsis. Crit Care Med 2005;
33:792.
44. Gibot S, Le Renard PE, Bollaert PE, et al. Surface triggering receptor
expressed on myeloid cells 1 expression patterns in septic shock. Intensive
Care Med 2005; 31:594.
45. Clec'h C, Fosse JP, Karoubi P, et al. Differential diagnostic value of
procalcitonin in surgical and medical patients with septic shock. Crit Care Med
2006; 34:102.
46. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for
sepsis diagnosis in critically ill patients: systematic review and meta-analysis.
Lancet Infect Dis 2007; 7:210.
47. Ruiz-Alvarez MJ, García-Valdecasas S, De Pablo R, et al. Diagnostic
efficacy and prognostic value of serum procalcitonin concentration in patients
with suspected sepsis. J Intensive Care Med 2009; 24:63.
48. Seder CW, Villalba MR Jr, Robbins J, et al. Early colectomy may be
associated with improved survival in fulminant Clostridium difficile colitis: an
8-year experience. Am J Surg 2009; 197:302.
49. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics
on survival in patients with severe sepsis or septic shock in whom early goal-
directed therapy was initiated in the emergency department. Crit Care Med
2010; 38:1045.
50. Verhoef J, Hustinx WM, Frasa H, Hoepelman AI. Issues in the adjunct
therapy of severe sepsis. J Antimicrob Chemother 1996; 38:167.
51. Sibbald WJ, Vincent JL. Round table conference on clinical trials for the
treatment of sepsis. Crit Care Med 1995; 23:394.
52. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al.
Impact of adequate empirical antibiotic therapy on the outcome of patients
admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31:2742.
53. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate
antimicrobial treatment of bloodstream infections on patient outcomes in the
ICU setting. Chest 2000; 118:146.
54. Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial
therapy and its effect on survival in a clinical trial of immunomodulating
therapy for severe sepsis. Am J Med 2003; 115:529.
55. Leibovici L, Paul M, Poznanski O, et al. Monotherapy versus beta-
lactam-aminoglycoside combination treatment for gram-negative bacteremia:
a prospective, observational study. Antimicrob Agents Chemother 1997;
41:1127.
56. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before
initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med 2006; 34:1589.
57. Schramm GE, Johnson JA, Doherty JA, et al. Methicillin-resistant
Staphylococcus aureus sterile-site infection: The importance of appropriate
initial antimicrobial treatment. Crit Care Med 2006; 34:2069.
58. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial
therapy results in a fivefold reduction of survival in human septic shock. Chest
2009; 136:1237.
59. McDonald JR, Friedman ND, Stout JE, et al. Risk factors for ineffective
therapy in patients with bloodstream infection. Arch Intern Med 2005;
165:308.
60. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis
caused by community-associated methicillin-resistant Staphylococcus aureus
in Los Angeles. N Engl J Med 2005; 352:1445.
61. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant
Staphylococcus aureus disease in three communities. N Engl J Med 2005;
352:1436.
62. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset
pneumonia in healthy adults caused by methicillin-resistant Staphylococcus
aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis 2005;
40:100.
63. Rubinstein E, Lode H, Grassi C. Ceftazidime monotherapy vs.
ceftriaxone/tobramycin for serious hospital-acquired gram-negative infections.
Antibiotic Study Group. Clin Infect Dis 1995; 20:1217.
64. Cometta A, Calandra T, Gaya H, et al. Monotherapy with meropenem
versus combination therapy with ceftazidime plus amikacin as empiric therapy
for fever in granulocytopenic patients with cancer. The International
Antimicrobial Therapy Cooperative Group of the European Organization for
Research and Treatment of Cancer and the Gruppo Italiano Malattie
Ematologiche Maligne dell'Adulto Infection Program. Antimicrob Agents
Chemother 1996; 40:1108.
65. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial
therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis.
Lancet Infect Dis 2004; 4:519.
66. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam
monotherapy versus beta lactam-aminoglycoside combination therapy for
sepsis in immunocompetent patients: systematic review and meta-analysis of
randomised trials. BMJ 2004; 328:668.
67. Paul M, Silbiger I, Grozinsky S, et al. Beta lactam antibiotic
monotherapy versus beta lactam-aminoglycoside antibiotic combination
therapy for sepsis. Cochrane Database Syst Rev 2006; :CD003344.
68. Marshall, J, Lowry, S. Evaluation of the adequacy of source control. In:
Clinical Trials for the treatment of sepsis, Sibbald, WJ, Vincent, JL (Eds),
Springer Verlag, Berlin, 1995, p. 329.
69. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia.
Crit Care Clin 2001; 17:107.
70. Kortgen A, Niederprüm P, Bauer M. Implementation of an evidence-
based "standard operating procedure" and outcome in septic shock. Crit Care
Med 2006; 34:943.
71. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes
of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;
34:1025.
72. Micek ST, Roubinian N, Heuring T, et al. Before-after study of a
standardized hospital order set for the management of septic shock. Crit Care
Med 2006; 34:2707.