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
Last literature review version 18.1: Janeiro 2010 | This topic last updated:
Fevereiro 3, 2010 (More)
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 [25].
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".)
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 "Swan-Ganz 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.
Resuscitation of the circulation should target a ScvO2 or SvO2 70 percent
[7,13]. Other reasonable goals include a central venous pressure 8 to 12
mmHg, a mean arterial pressure (MAP) 65 mmHg, and a urine output 0.5
mL/kg per hour.
These goals derive 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 goaldirected therapy" (ie, administered within the first six hours of presentation)
(algorithm 1).

Earlier studies of critically ill patients that used similar targets (SvO2 70
percent) found no mortality benefit [22]. This is probably 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 (39
versus 57 percent for standard resuscitation, odds ratio 0.50, 95% CI 0.370.69). 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).
In our clinical practice, we adhere to the principles of early goal-directed
therapy; that is, we initiate aggressive therapy early to restore perfusion and we
target a ScvO2 70 percent. However, we consider the numeric goals for CVP,
MAP, and urine output 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 [24]. 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'.)

Crystalloid versus colloid Clinical trials have failed to consistently

demonstrate a difference between colloid and crystalloid in the treatment of
septic shock [25,26].
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 [27]. 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 [28]. 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 [29]. 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 norepinephrine, although
dopamine is also a reasonable first-choice among vasopressors [7].
Phenylephrine, a pure alpha-adrenergic agonist, may be particularly useful
when tachycardia or arrhythmias preclude the use of agents with betaadrenergic activity. Limited experience with vasopressin (antidiuretic hormone)
suggests that this agent may be useful in vasodilatory septic shock. (See "Use
of vasopressors and inotropes".)
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 [7,8,13,30,31]. 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 [32]. (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 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 [33]. 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 [34]. 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 [35,36]. 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

at

www.thoracic.org/sections/publications/statements/index.html.
CONTROL OF THE SEPTIC FOCUS Prompt identification and treatment of
the primary site or sites of infection are essential [37-39]. 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 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 [40-42]. In a small trial, increased TREM-1 levels were both sensitive
and specific for the diagnosis of bacterial sepsis (96 and 89 percent,
respectively) [40]. Serial monitoring of TREM-1 may also provide prognostic
information in patients with established sepsis [41,42].
Elevated serum procalcitonin levels are associated with bacterial infection and
sepsis [43-45]. 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) [44].
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 rare cases, fulminant Clostridium difficileassociated colitis may necessitate colectomy [46].
Antimicrobial regimen Intravenous antibiotic therapy should be initiated
immediately after obtaining appropriate cultures. 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 [7,47,48].
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) [49-55]. 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) [52]. 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 [53].
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, ticarcillinclavulanate), or
Carbapenem (eg, imipenem or meropenem).
Alternatively, if Pseudomonas is a possible pathogen, we combine 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 [56]. There is growing recognition that methicillinresistant S. aureus (MRSA) is a cause of sepsis not only in hospitalized
patients,

but

also

in

community

dwelling

individuals

without

recent

hospitalization [57,58]. Many of these staphylococci have the Panton-Valentine

leukocidin virulence factor, which causes severe, necrotizing infections [59]. 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 [52,6064]. Furthermore, one meta-analysis found double coverage was associated
with an increased incidence of adverse events [63,64]. 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

known

or

suspected

Pseudomonas infection

[7,62].

(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 [65]. 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
Efficacy Numerous coagulation abnormalities have been detected in severe
sepsis and septic shock (table 1). In addition, several reports have suggested
that protein C supplementation may produce clinical benefit, particularly in the
setting of purpura fulminans [66-69].
These observations provided the rationale for the multicenter PROWESS trial
that supported the efficacy of recombinant human activated protein C
(drotrecogin alfa, Xigris) [70]. The trial randomly assigned 1690 patients to
receive a 96-hour infusion of drotrecogin alfa or placebo, beginning within 24
hours of presentation. Patients with acute renal failure were included, but not
those with chronic renal failure. The full inclusion and exclusion criteria are
shown in the table (table 7A-B).
The following findings were noted:

The 28-day mortality rate was significantly lower in the drotrecogin-treated

group (24.7 versus 30.8 percent).
There was a nonstatistically significant increase in the incidence of serious
bleeding (including fatal intracranial hemorrhage) in patients receiving
drotrecogin alfa (3.5 versus 2.0 percent).
Based upon post-hoc analyses of the study data, drotrecogin alfa was of
greater benefit in the most severely ill patients, including those with an APACHE

II score 25 (calculator 1) or multiple organ dysfunction. (See "Predictive

scoring systems in the intensive care unit".)

An analysis of secondary endpoints suggested that the incidence of multiple

organ dysfunction was lower in patients treated with drotrecogin alfa and that
therapy was associated with more rapid recovery of cardiac and pulmonary
function [71].
Interpretation of these results is complicated by the fact that the study protocol
was modified after the enrollment of 720 patients, excluding those with
metastatic cancer, pancreatitis, and most organ transplant recipients [72].
A subsequent open-label, single arm study of patients with severe sepsis (the
ENHANCE trial) noted that the 28-day all cause mortality for patients treated
with drotrecogin alfa (24 mcg/kg per hour for 96 hours) was similar to that
observed in PROWESS. However, the incidence of intracranial hemorrhage in
this trial was higher than in the PROWESS trial, both during the infusion (0.6
versus 0.2 percent) and at 28 days (1.5 versus 0.2 percent) [73]. In addition, the
ENHANCE trial found that patients treated within 0 to 24 hours from their first
sepsis-induced organ dysfunction had significantly lower mortality than those
treated after 24 hours (22.9 versus 27.4 percent).
Indications We believe that drotrecogin alfa is indicated for patients who
have septic shock or severe sepsis and a high risk of death, defined as an
APACHE II score >25 (calculator 1), multiple organ dysfunction, or sepsisinduced acute respiratory distress syndrome. Effort should be made to initiate
the infusion within 24 hours from the first-sepsis induced organ dysfunction.
Contraindications Patients with certain risk factors for bleeding were
excluded from the PROWESS trial (table 7A-B), since bleeding is the major
adverse effect of drotrecogin alfa. However, many of these risk factors are not
listed as contraindications on the product label.

Whether patients who have risk factors for bleeding as defined by the
PROWESS trial are actually at increased risk for bleeding was evaluated by a
retrospective cohort study of 73 patients who received drotrecogin alfa [74]. The
incidence of serious bleeding was significantly higher among patients with one
or more risk factors for bleeding, compared to patients without any risk factors
(35 versus 4 percent). Serious bleeding was defined as a hemoglobin fall of 2
g/dL over <48 hours, a transfusion requirement of 4 units over 48 hours,
objective evidence of bleeding, and clinician documentation of clinical
consequences of the bleeding.
This study suggests that extra caution is warranted when deciding whether to
administer drotrecogin alfa to patients who have one or more of the risk factors
for bleeding that were used as exclusion criteria during the PROWESS trial,
even if those risk factors are not listed as contraindications on the product label.
Administration The suggested dosing regimen of drotrecogin alfa is 24
mcg/kg per hour for 96 hours. Extending the duration of the infusion in patients
who are still vasopressor dependent at the end of the infusion does not improve
outcomes [75]. There is no suggested dose adjustment for patients with renal
failure [76,77].
VTE prophylaxis The importance of venous thromboembolism (VTE)
prophylaxis with heparin during the infusion of drotrecogin alfa has been studied
since, theoretically, heparin may be unnecessary (drotrecogin alfa has
antithrombotic and profibrinolytic properties) or harmful (heparin increases the
clearance of drotrecogin alfa in vitro) [78,79].
The Xigris and Prophylactic HeparRin Evaluation in Severe Sepsis (XPRESS)
trial randomly assigned patients with severe sepsis or septic shock to receive
subcutaneous unfractionated heparin (n = 511), subcutaneous low molecular
weight heparin (n = 493), or placebo (n = 990) during their 96-hour drotrecogin
alfa infusion [78]. Compared to patients who received placebo, those who
received unfractionated or low molecular weight heparin had significantly more
bleeding complications (10.8 versus 8.1 percent) and fewer ischemic strokes

(0.3 versus 1.3 percent), as well as a nonstatistically significant reduction in 28day mortality (28 versus 32 percent). Despite the increase in total bleeding
complications among those who received heparin, the rate of serious bleeding
events (intracranial hemorrhage, retinal hemorrhage, hemarthrosis, spinal
hemorrhage, or other life threatening bleeding) did not increase [80].
Recognizing that many patients would receive heparin VTE prophylaxis prior to
deciding whether to administer drotrecogin alfa infusion, the investigators
prospectively defined four subgroups [78]:

Patients who received heparin both before and during the infusion
Patients who received heparin before the infusion, but placebo during the
infusion
Patients who received no prophylaxis before the infusion, but heparin during
the infusion
Patients who received no prophylaxis before the infusion and placebo during
the infusion
The 28-day mortality increased among patients whose heparin was replaced by
placebo (36 percent), but was similar among the other groups (27 to 29
percent). This trial suggests that heparin VTE prophylaxis should not be
discontinued during infusion of drotrecogin alfa, unless the potential risks of
heparin outweigh the potential benefits.
Cost-effectiveness The economic impact and cost effectiveness of
drotrecogin alfa therapy have been assessed using two separate decisionanalysis models [81,82]. These studies found that, for patients with APACHE II
scores 25, the cost per year of life saved with drotrecogin alfa is a costeffective therapy in patients with severe sepsis and septic shock (calculator 1).
Other patient groups The role of drotrecogin alfa has been studied in several
additional populations of patients, including adults with severe sepsis or septic
shock and a low risk of death, children with severe sepsis or septic shock, and

adults with the systemic inflammatory response syndrome. Drotrecogin alfa

appears to have little role in these patient populations.

Less severe disease The role of drotrecogin alfa in the treatment of adults
with less severe disease was the subject of several trials [83-86]. The largest of
these trials, the ADDRESS trial, evaluated patients with severe sepsis and a
low risk of death (defined as an APACHE II score <25 or single organ
dysfunction). It was designed to randomly assign 11,000 adult patients to
treatment with drotrecogin alfa (24 mcg/kg per hour for 96 hours) or placebo
within 48 hours of presentation [85]. However, it was stopped after 2600
patients completed the protocol because an interim analysis suggested that,
despite its massive size, the trial was unlikely to demonstrate a significant
difference in mortality. While the 28-day and in-hospital mortality rates were
similar in both groups, there was a significantly increased risk of serious
bleeding among patients treated with drotrecogin alfa (3.9 versus 2.2 percent).
Children A large clinical trial of drotrecogin alfa in pediatric patients with
sepsis (RESOLVE trial) was stopped early when interim analysis suggested that
this intervention did not improve mortality and was associated with an increased
risk of intracranial hemorrhage, particularly in infants 60 days [87]. (See
"Septic shock: Initial evaluation and management in children".)

SIRS The value of drotrecogin alfa in patients with severe systemic

inflammatory response syndrome (SIRS) is unclear. As an example, there are
case reports of patients with severe acute pancreatitis, without evidence of
infection, who have been treated with drotrecogin alfa [88]. However, larger
dedicated trials to demonstrate therapeutic efficacy in SIRS patients will be
needed before this approach can be recommended.
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 [89]. As a
result, intensive insulin therapy 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 [90-92]. This
was illustrated by an observational cohort study of 120 patients with septic
shock [92]. 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, red blood cell transfusions, and inotropes
(algorithm 1). We recommend patients be managed with therapy aimed at
achieving a central (or mixed) venous oxygen saturation 70 percent within six
hours of presentation (Grade 1B). It is reasonable to simultaneously aim for a
central venous pressure 8 to 12 mmHg, mean arterial pressure (MAP) 65
mmHg, and urine output 0.5 mL per kg per hour. (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. Intraabdominal 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.)

We suggest recombinant human activated protein C (rhAPC) for patients with

severe sepsis or septic shock, a high risk of death, and no risk factors for
bleeding (Grade 2B). The decision to initiate rhAPC should be carefully
contemplated in the context of the patient's goals, values, and preferences. If
the decision is made to initiate rhAPC, it should be administered with caution
because rhAPC increases the risk of serious bleeding complications. (See
'Recombinant human activated protein C' above.)
Recombinant human activated protein C appears to confer no benefit in
children or in patients with severe sepsis and a low risk of death (defined as an
APACHE II score <25 or single organ dysfunction) and is associated with
increasing bleeding. We suggest that recombinant human activated protein C
not be administered to these patient populations (Grade 2B). Its impact in SIRS
is unclear. (See 'Recombinant human activated protein C' 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 in detail in separate topic reviews. (See
"Corticosteroid therapy in septic shock" and "Nutritional support in critically ill
patients: An overview" and "Glycemic control and intensive insulin therapy in
critical illness".)
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