INTRODUCTION Sepsis is a clinical syndrome characterized by systemic inflammation due to

infection. There is a continuum of severity ranging from sepsis to severe sepsis and septic shock. Over
1,665,000 cases of sepsis occur in the United States each year, with a mortality rate up to 50 percent [ 1].
Even with optimal treatment, mortality due to severe sepsis or septic shock is approximately 40 percent
and can exceed 50 percent in the sickest patients [2-5].
In this topic review, the management of severe sepsis and septic shock is discussed. Definitions,
diagnosis, pathophysiology, and investigational therapies for sepsis, as well as management of sepsis in
the asplenic patient are reviewed separately. (See "Sepsis and the systemic inflammatory response
syndrome: Definitions, epidemiology, and prognosis" and "Pathophysiology of sepsis" and "Investigational
and ineffective therapies for sepsis" and "Clinical features and management of sepsis in the asplenic
patient".)
THERAPEUTIC PRIORITIES The early administration of fluids and antibiotics is the cornerstone of
management for patients with severe sepsis and septic shock.
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) because, if
an infection exists, it must be identified and treated as soon as possible (table 2). This may require
appropriate antibiotics as well as a surgical procedure (eg, drainage).
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 and
antibiotics administered [9,10].
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].
The choice and use of sedative and induction agents (eg, etomidate, ketamine) 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 gas analysis should be obtained following initial stabilization. These
studies are used in combination with other clinical parameters to diagnose acute respiratory distress
syndrome (ARDS), which frequently complicates sepsis. (See "Acute respiratory distress syndrome:
Clinical features and diagnosis in adults" and "Mechanical ventilation of adults 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 sign but critical hypoperfusion can also occur in

the absence of hypotension, especially during early sepsis. Clinical signs of impaired perfusion include
the following:
Hypotension Hypotension is the most common indicator that perfusion is inadequate (eg,
systolic blood pressure [SBP] <90 mmHg, mean arterial pressure <70 mmHg, decrease in SBP >40
mmHg). Therefore, it is important that the blood pressure be assessed early and often. Because a
sphygmomanometer may be unreliable in hypotensive patients, an arterial catheter may be inserted
if blood pressure is labile or restoration of arterial perfusion pressures is expected to be a protracted
process [8]. Attempts to insert an arterial line should not delay the prompt management of shock.
(See"Arterial catheterization techniques for invasive monitoring".)
Signs of poor end-organ perfusion Warm, flushed skin may be present in the early phases of
sepsis. As sepsis progresses to shock, the skin may become cool due to redirection of blood flow to
core organs. Additional signs of hypoperfusion include tachycardia >90 per min, obtundation or
restlessness,
and
oliguria
or
anuria.
These findings may be modified by preexisting disease or medications. As examples, older patients,
diabetic patients, and patients who take beta-blockers may not exhibit an appropriate tachycardia as
blood pressure falls. In contrast, younger patients frequently develop a severe and prolonged
tachycardia and fail to become hypotensive until acute decompensation later occurs, often suddenly.
Patients with chronic hypertension may develop critical hypoperfusion at a higher blood pressure
than healthy patients (ie, relative hypotension).
Elevated lactate An elevated serum lactate (eg, >2 mmol/L) can be a manifestation of organ
hypoperfusion in the presence or absence of hypotension and is an important component of the
initial evaluation [9,13,14]. A serum lactate level 4 mmol/L is consistent with, but not diagnostic of,
severe sepsis. Additional laboratory studies that help characterize the severity of sepsis include a
low platelet count, and elevated international normalized ratio, creatinine, and bilirubin. Values for
laboratory parameters that suggest severe sepsis are described separately. (See "Sepsis and the
systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis", section on
'Severe sepsis'.)
Other Tests that combine output from many organs (eg, arterial lactate) may obscure the
presence of significant ischemia in an individual organ [15]. Gastric tonometry indirectly measures
perfusion to the gut by estimating the gastric mucosal PCO 2. It can be used to detect gut hypoxia by
calculating the gastric to arterial PCO2 gap [15-17]. But, gastric tonometry is not widely available and
it is uncertain whether it can successfully guide therapy. Additional studies and clinical experience
are needed.
Establish venous access Venous access should be established as soon as possible in patients with
suspected sepsis. While peripheral venous access may be sufficient in some patients, particularly for
initial resuscitation, the majority will require central venous access at some point during their course. A
central venous catheter (CVC) can be used to infuse intravenous fluids, medications (particularly
vasopressors), and blood products, as well as to draw blood for frequent laboratory studies. In addition,
this access can be used for hemodynamic monitoring by measuring the central venous pressure (CVP)
and the central venous oxyhemoglobin saturation (ScvO 2). While in the past, a major purpose of a CVC
was the measurement of ScVO2 and CVP, evidence from randomized trials on the value these targets to
follow therapeutic effect is conflicting [18-20]. (See 'Goals of initial resuscitation' below
and "Complications of central venous catheters and their prevention".)

We believe that pulmonary artery catheters (PACs) should not be used in the routine management of
patients with severe sepsis or septic shock. PACs can measure the pulmonary artery occlusion pressure
(PAOP) and mixed venous oxyhemoglobin saturation (SvO 2). 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 [21,22]. PACs increase
complications and have not been shown to improve outcome [23-25]. (See "Pulmonary artery
catheterization: Indications, contraindications, and complications in adults".)
Interventions to restore perfusion The rapid restoration of perfusion is predominantly achieved by
the administration of intravenous fluids, usually crystalloids. Modalities such as vasopressor therapy,
inotropic therapy, and blood transfusion are added, depending on the response to fluid resuscitation,
evidence for myocardial dysfunction, and presence of anemia. (See "Treatment of severe hypovolemia or
hypovolemic shock in adults".)
Intravenous fluids In patients with sepsis, intravascular hypovolemia is typical and may be severe,
requiring rapid fluid resuscitation.
Volume The optimal volume of resuscitative fluid is unknown. Several studies of early goal directed
therapy reported intravenous fluid infusions targeted to physiologic endpoints and resulted in volumes
ranging from 3 to 5 liters [18-20]. The volume of fluid that was administered within the initial six hours of
presentation was targeted to set physiologic endpoints (eg, mean arterial pressure). While an early study
of early goal-directed therapy (EGDT) reported mean infusion volume in the first six hours of 3 to 5 liters
[18], later trials reporting mean infusion volumes of 2 to 3 liters [19,20]. Thus, 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. Suggested targets for fluid
resuscitation are discussed separately. (See 'Goals of initial resuscitation' below.)
Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses [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
and tissue perfusion are acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.
Careful monitoring is essential because patients with sepsis may develop noncardiogenic pulmonary
edema (ie, ARDS). Once patients with ARDS have been fluid resuscitated a liberal approach to
intravenous fluid administration has been shown to prolong the duration of mechanical ventilation,
compared to a more restrictive approach that also typically requires large doses of furosemide [26]. In
addition, small retrospective studies have reported that fluid overload is common in patients with sepsis
and is associated with the increased performance of medical interventions (eg, diuresis, thoracentesis);
the effect of fluid overload and such interventions on mortality is unclear [27,28]. 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 "Acute respiratory distress syndrome:
Supportive care and oxygenation in adults", section on 'Fluid management'.)
Choice of fluid Evidence from randomized trials and meta-analyses have found no convincing
difference between using albumin solutions and crystalloid solutions (eg, normal saline, Ringers lactate)
in the treatment of severe sepsis or septic shock, but they have identified potential harm from
usingpentastarch or hydroxyethyl starch rather than a crystalloid solution [29-35]:

Crystalloid versus albumin: In the Saline versus Albumin Fluid Evaluation (SAFE) trial, 6997
critically ill patients were randomly assigned to receive 4 percent albumin solution or normal saline
for up to 28 days [29]. 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. In another multicenter open-label randomized trial of
patients with severe sepsis or septic shock, the addition of albumin to crystalloid did not improve
survival compared to crystalloid alone (31 versus 32 percent) [30].
Crystalloid versus hydroxyethyl starch: In the Scandinavian Starch for Severe Sepsis and
Septic Shock (6S) trial, 804 patients with severe sepsis were randomly assigned to receive either 6
percent hydroxyethyl starch or Ringers acetate at a volume of up to 33 mL/kg of ideal body weight
per day [31]. When assessed 90 days after randomization, mortality was increased in the
hydroxyethyl starch group (51 versus 43 percent) and more patients in the hydroxyethyl starch
group had required renal replacement therapy at some time during their illness (22 versus 16
percent).
Crystalloid versus pentastarch: The Efficacy of Volume Substitution and Insulin Therapy in
Severe Sepsis (VISEP) trial compared pentastarch to modified Ringer's lactate in patients with
severe sepsis and found no difference in 28-day mortality [32]. The trial was stopped early because
there was a trend toward increased 90-day mortality among patients who received pentastarch.
In our clinical practice, we generally use a crystalloid solution instead of albumin solution because of the
lack of clear benefit and higher cost of albumin. We believe that giving a sufficient quantity of intravenous
fluids rapidly and targeting appropriate goals is more important than the type of fluid chosen. We do not
use hydroxyethyl starch or pentastarch. These choices are consistent with the Society of Critical Care
Medicineguidelines [9]. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section
on 'Choice of replacement fluid'.)
Vasopressors Vasopressors are second line agents in the treatment of severe sepsis and septic
shock; we prefer intravenous fluids as long as they increase perfusion without seriously impairing gas
exchange [36]. However, intravenous vasopressors are useful in patients who remain hypotensive despite
adequate fluid resuscitation or who develop cardiogenic pulmonary edema.
In most patients with severe septic shock, we prefer to use norepinephrine (table 3) [7,9,37]. 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 (eg, norepinephrine). 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 There is conflicting evidence on the use of additional therapies, such as
inotropic therapy or red blood cell transfusion. Such therapies are targeted at increasing the cardiac
output to improve tissue perfusion and thereby raise the central venous (superior vena cava)
oxyhemoglobin saturation toward normal (ScvO 2 70 percent). We prefer that their use be limited to those
with refractory shock in whom the ScvO 2 remains <70 percent after optimization of intravenous fluid and
vasopressor therapy.
Inotropic therapy A trial of inotropic therapy may be warranted in patients who have refractory shock
who also have diminished cardiac output [7,8,18,38,39]. Inotropic therapy should not be used to increase
the cardiac index to supranormal levels [7]. Dobutamine is the usual inotropic agent [9]. At low doses,
dobutamine may cause the blood pressure to decrease because its peripheral effects 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 peripheral vascular resistance. (See "Use of vasopressors
and inotropes", section on 'Dobutamine'.)
Red blood cell transfusions Based upon clinical experience, randomized studies, and guidelines on
transfusion of blood products in critically ill patients, we typically reserve red blood cell transfusion for
patients with a hemoglobin level 7 g per deciliter. Exceptions include suspicion of concurrent
hemorrhagic shock or active myocardial ischemia.
Support for a restrictive transfusion strategy (goal hemoglobin >7 g/dL) is derived from direct and
indirect evidence from randomized studies of patients with septic shock:
One multicenter randomized study of 998 patients with septic shock reported no difference in
28 day mortality between patients who were transfused when the hemoglobin was
7 g/dL(restrictive strategy) and patients who were transfused when the hemoglobin was
9 g/dL (liberal strategy) [40]. The restrictive strategy resulted in 50 percent fewer red blood
cell transfusions (1545 versus 3088 transfusions) and did not have any adverse effect on the
rate of ischemic events (7 versus 8 percent).
Data from randomized studies of early goal directed therapy (EGDT) that use red blood cell
transfusion as part of the protocol for treating patients with sepsis are conflicting. While one
trial initially reported a mortality benefit from EGDT that included transfusing patients to a goal
hematocrit >30 (hemoglobin level 10 g/dL) [18], two similarly designed studies published since
then reported no benefit to this strategy [19,20]. These studies are discussed below.
(See'Protocol-directed therapy' below.)
In further support of a restrictive approach to transfusion in patients with septic shock is the
consensus among experts that transfusing to a goal of >7 g/dL is also preferred in critically ill
patients without sepsis [41-43]. The use of blood transfusions in critically-ill patients is discussed in
detail separately. (See "Use of blood products in the critically ill", section on 'Red blood cells'.)
Goals of initial resuscitation The goal of fluid resuscitation is early restoration of perfusion to prevent
or limit multiple organ dysfunction, as well as to reduce mortality.
The term "early goal-directed therapy" (EGDT) refers to the administration of intravenous fluids within the
first six hours of presentation using physiologic targets to guide fluid management. EGDT has gained
widespread acceptance in clinical practice but the optimal targets are unknown.
Early goal-directed therapy targets Although evidence is conflicting regarding the routine
measurement of early goal-directed therapy targets, we suggest measuring the following targets for fluid
management in patients with sepsis:
Mean arterial pressure (MAP) 65 mmHg (MAP = [(2 x diastolic) + systolic]/3) (calculator 1)
Urine output 0.5 mL/kg/hour
Static or dynamic predictors of fluid responsiveness, eg, central venous pressure (CVP) 8 to 12
mmHg when central access is available (static measurement) or respiratory changes in the radial
artery pulse pressure (dynamic measurement).
Central venous (superior vena cava) oxyhemoglobin saturation (ScvO 2) 70 percent (when central
access is available) or mixed venous oxyhemoglobin saturation (SvO 2) 65 percent (if a pulmonary
artery catheter is being used).

Lactate clearance is not readily available at the bedside, making it a less useful target to follow acutely in
EGDT. Nonetheless, it should be followed as a target in patients with sepsis to ensure a trend that
demonstrates adequate clearance with therapy.
The optimal physiologic target(s) of EGDT is unknown. There is also conflicting evidence on the value of
measuring such targets, particularly CVP and ScVO 2, which require central catheter placement [1820,44]. In addition, the generalizability of a standard targeted approach to both resource-poor and
resource-rich facilities is unknown. We prefer measuring MAP and urine output as universal targets that
can be readily measured in all patients with sepsis, with the addition of CVP and/or ScVO2 in those in
whom central access is otherwise required. This approach differs slightly from that of The Surviving
Sepsis Campaignguidelines that recommend central venous access for CVP/ScvO2 measurement
together with MAP and urine output in all patients with severe sepsis [9]. However, these guidelines were
created before the results of three major randomized trials (ProCESS, ARISE, ProMISe), that showed no
mortality benefit to an EGDT-based approach, were published [19,20,44,45].
Evidence that supports the use of EGDT targets is described below:
CVP, MAP and urine output CVP 8 to 12 mmHg, MAP 65 mmHg (calculator 1), and urine
output 0.5 mL/kg per hour are common EGDT targets used in clinical practice. Support for their use
is derived from clinical experience and their use in the single randomized trial that studied them with
and without ScvO2 [18]. They have not been compared to each other nor have they been proven to
be superior to any other target or to clinical assessment.
The ideal targets for MAP, CVP, and urine output are unknown. One trial that randomized patients to
a target MAP of 65 to 70 mmHg (low target MAP) or 80 to 85 mmHg (high target MAP) reported no
mortality benefit to targeting a higher MAP [46]. Patients with a higher MAP had a greater incidence
of atrial fibrillation (7 versus 3 percent), suggesting that targeting a MAP >80 mmHg is potentially
harmful.
ScvO2 Evidence from randomized trials that study the value of central venous oxyhemoglobin
saturation (ScvO2) report mixed results. While one early trial of patients with septic shock reported a
mortality benefit to targeting ScvO2 70 percent in a protocol-based therapy, trials published since
then (ProCESS, ARISE, ProMISe) have reported no mortality benefit [18-20,44]. (See 'Protocoldirected therapy' below.)
Lactate clearance Although the optimal frequency is unknown, we follow serum lactate (eg,
every six hours), as an additional EGDT target in patients with sepsis until the lactate value has
clearly fallen.
The lactate clearance is defined by the equation [(initial lactate - lactate >2 hours later)/initial lactate]
x 100. The lactate clearance and interval change in lactate over the first 12 hours of resuscitation
has been evaluated as a potential marker for effective resuscitation [47,48]. One 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
that included MAP, CVP, and urine output targets were identical) [47]. 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 ScvO 2 criteria.
After the restoration of perfusion, lactate is a poor marker of tissue perfusion [49]. As a result, lactate
values are generally unhelpful following restoration of perfusion, with one exception a rising lactate

level should prompt reevaluation of perfusion (see "Venous blood gases and other alternatives to
arterial blood gases").
Other Dynamic indices have been studied as a potential target to guide fluid management in
sepsis. Respiratory changes in the vena caval diameter, radial artery pulse pressure, aortic blood
flow peak velocity, and brachial artery blood flow velocity are considered dynamic hemodynamic
measures, whereas CVP, MAP, ScvO 2 and pulmonary artery occlusion pressure are considered
static hemodynamic measures [50,51]. 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 [21,52,53]. 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 [54].
Large randomized studies will be needed proving the efficacy of assessing dynamic measurement in
response to intravenous fluids before they can be routinely applied to patients for the management
of sepsis.
Protocol-directed therapy Protocols targeted at the use of a combination of physiologic endpoints to
guide fluid management in patients with severe sepsis and septic shock are common practice [1820,44,45,55-57]. Typically, they combine the EGDT targets (ScvO 2, CVP, MAP (calculator 1) and urine
output, lactate) for fluid management with early administration of antibiotics, both within the first six hours
of presentation.
There is conflicting evidence regarding the value of protocol-based therapy for sepsis [18-20,44,45,5759]:
One single center randomized trial of 263 patients with severe sepsis or septic shock compared a
protocol that included targeting ScvO 2 70 percent, CVP 8 to 12 mmHg, MAP 65 mmHg, and urine
output 0.5 mL/kg/hour to conventional therapy that targeted CVP, MAP, and urine output only [18].
Both groups initiated therapy (including antibiotics) within six hours of presentation. Mortality was
lower in the group where all four targets were used (31 versus 47 percent), suggesting that targeting
ScvO2, CVP, MAP, and urine output was a superior strategy. There was a heavy emphasis on the
use of red cell transfusion (for a hematocrit >30) and dobutamine in order to reach the ScvO2 target
in this trial. In addition, the results of this trial may not be generalizable due to the inclusion of a
significant number of sick patients with liver and heart disease that may have potentially biased the
outcome favorably.
A multicenter randomized trial (ProCESS) of 1341 patients with septic shock reported no mortality
benefit with protocol-based therapies [19]. A protocol-based therapy that used all of the EGDT
targets (ScvO2, CVP, MAP and urine output; protocol-based EGDT; central access required) was
compared to a protocol that used some of the EGDT targets (MAP and urine output; protocol-based
standard therapy; central access not required) and to usual care (no protocol used to direct fluid
management). There were no differences in 60-day mortality between the groups (21 versus 18
versus
19
percent).
Two similarly designed multicenter randomized trials of 1600 (ARISE) and 2160 (ProMISe) patients
with septic shock also reported no mortality benefit from EGDT [20,44]. In ARISE, compared to
usual care, the 90 day mortality of 19 percent was similar in patients who received EGDT using the

traditional targets outlined in prior studies [20]. Similarly, in ProMISe, the 90 day mortality was no
different (29 percent) between the EGDT and usual care groups [44].
One explanation for the apparent negative results from these three trials may be that central line
placement was common (>50 percent) in patients receiving protocol-based standard therapy and
usual care; it is likely that CVP and ScvO 2 were measured and targeted in these patients as well.
Lack of benefit may also be attributed to overall better outcomes in these studies, perhaps due to
early administration of antibiotics (70 to 100 percent before randomization) in all groups, and to
improved clinical performance by highly trained clinicians in academic centers during an era that
follows an aggressive sepsis education and management campaign.
Timing and duration The early administration of fluid appears to be more important than volume or
type of fluid in reducing mortality associated with sepsis. Based upon evidence from randomized studies
and meta-analyses, we favor the initiation of fluid resuscitation within six hours of presentation. Once the
targets of resuscitation are met and perfusion is restored, fluids can be reduced or stopped, and
occasionally patients can be diuresed, when necessary. Resolution of severe sepsis and septic shock can
take as little as a few hours or can be protracted to days or weeks.
A 2008 meta-analysis of randomized trials that initiated resuscitation targeting specific physiologic
endpoints reported that compared to standard care, only trials that initiated resuscitation within 24 hours
of the onset of sepsis showed a mortality benefit (39 versus 57 percent, odds ratio 0.50, 95% CI 0.370.69) [60]. In contrast, analysis of randomized trials that initiated therapy more than 24 hours after the
onset of sepsis found no difference in mortality (64 versus 58 percent for standard resuscitation, odds
ratio 1.16, 95% CI 0.60-2.22).
There are two possible outcomes following the interventions described above:
Inadequate perfusion 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).
Adequate perfusion Patients who respond to therapy should have the rate of fluid
administration reduced or stopped, and vasopressor support weaned. Patients should also continue
to have their clinical and laboratory parameters followed closely. These include blood pressure,
arterial lactate, urine output, creatinine, platelet count, Glasgow coma scale score, serum bilirubin,
liver enzymes, oxygenation (ie, arterial oxygen tension or oxyhemoglobin saturation), and gut
function (table 4). Reevaluation is indicated if any of these parameters worsen or fail to improve.
CONTROL OF THE SEPTIC FOCUS Prompt identification and treatment of the primary site or sites of
infection are essential [61-63]. This is the primary therapeutic intervention, with most other interventions
being purely supportive. Antibiotics should be administered within the first six hours of presentation or
earlier.
Identification of the septic focus A careful history and physical examination may yield clues to the
source of sepsis and help guide microbiologic evaluation (table 5). As an example, sepsis arising after
trauma or surgery is often due to infection at the site of injury or surgery. The presence of a urinary or
vascular catheter increases the chances that these are the source of sepsis.

Gram stain of material from sites of possible infection may give early clues to the etiology of infection
while cultures are incubating. As examples, urine should be routinely analyzed via dipstick for leukocyte
esterase, 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 other radiologic guidance.
Blood should be drawn from two distinct venipuncture sites and inoculated into standard blood culture
media (aerobic and anaerobic). For patients with a vascular catheter, blood should be obtained both
through the catheter and from another site [9]. (See "Blood cultures for the detection of bacteremia".)
If invasive candida or aspergillus infection is suspected, serologic assays for 1,3 beta-D-glucan,
galactomannan, and anti-mannan antibodies, if available, may provide early evidence of these fungal
infections [9]. The limitations of these assays and their role in the diagnosis of fungal infection are
discussed separately. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis
in adults", section on 'Non-culture methods' and "Diagnosis of invasive aspergillosis", section on
'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan
assay'.)
There is no single test that immediately confirms the diagnosis of severe sepsis or septic shock. However,
several laboratory tests, all of which are still investigational, have been studied as diagnostic markers of
active bacterial infection [6]:
Elevated serum procalcitonin levels are associated with bacterial infection and sepsis [64-66].
Despite this, a meta-analysis of 18 studies found that procalcitonin did not readily distinguish sepsis
from nonseptic systemic inflammation (sensitivity of 71 percent and specificity of 71 percent) [65]. An
additional randomized trial and another meta-analysis found that using clinical algorithms based
upon procalcitonin levels did not affect mortality or duration of antibiotic treatment [67,68].
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 [69-71]. In a small trial, increased TREM-1
levels were both sensitive and specific for the diagnosis of bacterial sepsis (96 and 89 percent,
respectively) [69]. However, a subsequent prospective cohort study found that increased TREM-1
levels predicted sepsis with a sensitivity and specificity of only 53 and 86 percent, respectively [72].
Serial monitoring of TREM-1 may also provide prognostic information in patients with established
sepsis [70,71].
Increased expression of CD64 on polymorphonuclear leukocytes indicates cellular activation and
has been shown to occur in patients with sepsis [73,74]. In a prospective cohort study of 300
consecutive critically ill patients, increased CD64 expression predicted sepsis with a sensitivity of 84
percent and a specificity of 95 percent [72]. In this study, the sensitivity and specificity of increased
CD64 expression were superior to that of increased procalcitonin or TREM-1 levels.
The combination of procalcitonin levels, TREM-1 levels, and CD64 expression appears to be superior to
the use of any of these markers alone. However, evaluation of the clinical usefulness of such biomarkers
is still in its early stages and should be considered preliminary. Until additional clinical investigations have
been performed, we do not suggest the routine use of such biomarkers to identify sepsis.
Eradication of infection Prompt and effective treatment of the active infection is essential to the
successful treatment of severe sepsis and septic shock [9]. Source control (physical measures

undertaken to eradicate a focus of infection and eliminate or treat ongoing microbial proliferation and
infection) should be undertaken since undrained foci of infection may not respond to antibiotics alone
(table 2). As examples, potentially infected foreign bodies (eg, vascular access devices) should be
removed when possible, and abscesses should undergo percutaneous or surgical drainage. Some
patients require extensive soft tissue debridement or amputation; in severe cases, fulminant Clostridium
difficile-associated colitis may necessitate colectomy [75].
Antimicrobial regimen Intravenous antibiotic therapy should be initiated within the first six hours or
earlier (eg, within one hour), after obtaining appropriate cultures, since early initiation of antibiotic therapy
is associated with lower mortality [7,76]. The choice of antibiotics can be complex and should consider the
patient's history (eg, recent antibiotics received [77]), comorbidities, clinical context (eg, community- or
hospital-acquired), Gram stain data, and local resistance patterns [7,78,79].
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) [80-86]. 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) [83]. 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 [84].
When the potential pathogen or infection source is not immediately obvious, we favor broad-spectrum
antibiotic coverage directed against both gram-positive and gram-negative bacteria. Few guidelines exist
for the initial selection of empiric antibiotics in severe sepsis or septic shock.
Staphylococcus aureus is associated with significant morbidity if not treated early in the course of
infection [87]. 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 [88,89]. For these reasons, we recommend that severely ill patients presenting with sepsis
of unclear etiology be treated with intravenous vancomycin (adjusted for renal function) until the possibility
of MRSA sepsis has been excluded. Potential alternative agents to vancomycin (eg, daptomycin for nonpulmonary MRSA,linezolid, ceftaroline) should be considered for patients with refractory or virulent
MRSA, or a contraindication to vancomycin. These agents are discussed separately. (See "Treatment of
invasive
methicillin-resistant
Staphylococcus
aureus
infections in
adults",
section
on
'Bacteremia' and "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated
pneumonia in adults", section on 'Methicillin-resistant Staphylococcus aureus'.)
In our practice, if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with one of the
following:
Cephalosporin, 3rd generation (eg, ceftriaxone or cefotaxime) or 4th generation (cefepime), or
Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or
Carbapenem (eg, imipenem or meropenem)
Alternatively, if Pseudomonas is a possible pathogen, we favor combining vancomycin with two of the
following (see "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections"):

Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or

Antipseudomonal carbapenem (eg, imipenem, meropenem), or
Antipseudomonal beta-lactam/beta-lactamase inhibitor
clavulanate), or

(eg, piperacillin-tazobactam, ticarcillin-

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

Aminoglycoside (eg, gentamicin, amikacin), or
Monobactam (eg, aztreonam)
Selection of two agents from the same class, for example, two beta-lactams, should be avoided. We
emphasize the importance of considering local susceptibility patterns when choosing an empiric antibiotic
regimen.
After culture results and antimicrobial susceptibility data return, we recommend that therapy be pathogenand 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 [83,90-94]. Furthermore, one meta-analysis found double coverage that
included an aminoglycoside was associated with an increased incidence of adverse events
(nephrotoxicity) [93,94]. For this reason, in patients with gram negative pathogens, 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 [7,92].
(See "Pseudomonas aeruginosa bacteremia and endocarditis" and "Principles of antimicrobial therapy of
Pseudomonas aeruginosa infections".)
Regardless of the antibiotic regimen selected, patients should be observed closely for toxicity, evidence of
response, and the development of nosocomial superinfection [95]. There are no published randomized
controlled trials testing safety of de-escalation of antibiotic therapy in adult patients with sepsis or septic
shock [96]. The duration of therapy is typically 7 to 10 days, although longer courses may be appropriate
in patients who have a slow clinical response, an undrainable focus of infection, or immunologic
deficiencies [7]. In patients who are neutropenic, antibiotic treatment should continue until the neutropenia
has resolved or the planned antibiotic course is complete, whichever is longer. In non-neutropenic
patients in whom infection is thoroughly excluded, antibiotics should be discontinued to minimize
colonization or infection with drug-resistant microorganisms and superinfection with other pathogens.
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.
Evidence from randomized trials suggest that corticosteroid therapy is most likely to be beneficial in
patients who have severe septic shock (defined as a systolic blood pressure <90 mmHg) that is
unresponsive to adequate fluid resuscitation and vasopressor administration. Data from ongoing clinical
trials are needed to confirm that benefit. 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".)
Venous thromboembolism prophylaxis Patients with sepsis and septic shock are at increased risk
for venous thromboembolism such that patients should receive thromboprophylaxis [97], the details of
which are discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill
hospitalized medical adults".)
Intensive insulin therapy Hyperglycemia and insulin resistance are common in critically ill patients,
independent of a history of diabetes mellitus [98]. The optimal blood glucose range is controversial. Most
clinicians target blood glucose levels between 140 and 180 mg/dL (7.7 to 10 mmol/L). This topic is
discussed separately. (See "Glycemic control and intensive insulin therapy in critical illness".)
External cooling or antipyretics Controlling fever during severe sepsis and septic shock has
potential benefits and adverse effects, the net effects of which are uncertain.
A trial was performed to compare the effects of external cooling with no external cooling. External cooling
consists of using either an automatic cooling blanket, or ice-cold bed sheets and ice packs, to achieve a
core body temperature of 36.5 to 37C for 48 hours. It decreases the time to fever control without
exposing the patient to potential adverse effects of antipyretic drugs. The trial randomly assigned 200
patients with septic shock (the patients were requiring vasopressors, mechanically ventilated, and
sedated) to receive either external cooling or no external cooling [99]. Patients in the external cooling
group had lower 14-day mortality (19 versus 34 percent) and were more likely to have their vasopressor
dose lowered by 50 percent (54 versus 20 percent) and their shock reversed during their ICU stay (86
versus 73 percent). No antipyretic agents were received during the trial.
While these results are promising, we believe that the results need to be confirmed before external
cooling is adopted as routine clinical practice. Among the limits of the trial, patients in the external cooling
group may have been less severely ill (ie, they required a lower baseline vasopressor dose), the trial was
not blinded so co-interventions cannot be excluded, and there were relatively few events (ie, deaths,
patients with a 50 percent vasopressor dose decrease, and patients with shock reversal), which lowers
confidence in the accuracy of the estimated effects. Moreover, the results suggest that external cooling is
preferable to no cooling, but they do not provide guidance about whether external cooling is preferable to
antipyretic medications.
The role of antipyretics for fever control in critically ill patients is also of uncertain benefit and is discussed
separately. (See "Fever in the intensive care unit", section on 'Management'.)
Investigational therapies A variety of investigational therapies including cytokine and toxin
inactivation, as well as hemofiltration, statins, and beta blockade are discussed in detail separately.
(See"Investigational and ineffective therapies for sepsis".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The
Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at
the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10 th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on patient info and the keyword(s) of interest.)
Basics topic (see "Patient information: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
Therapeutic priorities for patients with sepsis and septic shock include securing the airway,
correcting hypoxemia, and administering fluids and antibiotics. Intubation and mechanical ventilation
are required in some patients. (See 'Therapeutic priorities' above and 'Stabilize respiration' above.)
The adequacy of perfusion should be assessed in patients with suspected severe sepsis and
septic shock. Hypotension is the most common indicator of inadequate perfusion. However, critical
hypoperfusion can also occur in the absence of hypotension, especially during early sepsis.
Common signs of hypoperfusion include warm, vasodilated skin in early sepsis that progresses to
cool, vasoconstricted skin in late sepsis, tachycardia >90 per min, obtundation or restlessness,
oliguria or anuria, and lactic acidosis. (See 'Assess perfusion' above.)
For patients with severe sepsis and septic shock, we recommend intravenous fluids, rather than
vasopressors, inotropes, or red blood cell transfusions as first-line therapy for the restoration of
tissue perfusion (Grade 1B). Therapy should be initiated as early as possible, within six hours of
presentation. Fluid boluses are the preferred method of administration and should be 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
(See 'Interventions to restore perfusion' above.)
For initial fluid replacement, we suggest using a crystalloid solution rather than albumincontaining solution (Grade 2B) and recommend that a hyperoncotic starch solution NOT be
administered (Grade 1A). (See 'Choice of fluid' above and "Treatment of severe hypovolemia
or hypovolemic shock in adults", section on 'Choice of replacement fluid'.)
For patients who remain hypotensive following intravascular volume repletion, we recommend
vasopressors
(Grade
1B);
the
preferred
initial
agent
is norepinephrine.
(See 'Vasopressors'above and "Use of vasopressors and inotropes", section on 'Choice of
agent in septic shock'.)
For patients with severe sepsis and septic shock that are refractory to intravenous fluid and
vasopressor therapy, additional therapies, such as inotropic therapy and blood transfusions,
are administered based on individual assessment. We typically reserve red blood cell
transfusion for patients with a hemoglobin level <7 g per deciliter. (See 'Additional
therapies' above and "Use of vasopressors and inotropes", section on 'Choice of agent in
septic shock'.)
For most patients with sepsis and septic shock, we suggest fluid management be guided using
specific targets (early goal-directed therapy [EGDT]), rather than being managed without specific
therapeutic targets. The optimal target to guide fluid management is unknown. For most patients,
we target mean arterial pressure 65 mmHg (calculator 1) and urine output 0.5 mL/kg/hour and
integrate it with static measures of determining adequacy of fluid administration (eg, central venous
pressure [CVP] 8 to 12 mmHg), or dynamic predictors of fluid responsiveness (eg, respiratory
changes in the radial artery pulse pressure) or central venous oxygen saturation 70 percent. In

addition, we follow serum lactate (eg, every six hours), until there is a clear clinical response.
(See 'Goals of initial resuscitation' 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 within six hours of presentation, preferably after appropriate
cultures have been obtained. We recommend empiric broad spectrum antibiotics when a definite
source of infection can not be identified (Grade 1B). (See 'Antimicrobial regimen' above.)
Potentially infected vascular access devices should be removed (if possible), abscesses should be
drained, and extensive soft tissue infections should be debrided or amputated (table 2).
(See'Eradication of infection' above.)
Glucocorticoid therapy, nutritional support, glucose control, and investigational therapies are
additional considerations 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" and"Investigational and ineffective therapies for sepsis".)
Use of UpToDate is subject to the Subscription and License Agreement.
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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.

93.

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.

94.

Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus

beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev
2014; 1:CD003344.

95.

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treatment of sepsis, Sibbald WJ, Vincent JL (Eds), Springer Verlag, Berlin 1995. p.329.

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with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev 2013; 3:CD007934.

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Sepsis is one of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis ()
was the process by which flesh rots, swamps generate foul airs, and wounds fester.1 Galen later considered
sepsis a laudable event, necessary for wound healing. 2 With the confirmation of germ theory by Semmelweis,
Pasteur, and others, sepsis was recast as a systemic infection, often described as blood poisoning, and
assumed to be the result of the host's invasion by pathogenic organisms that then spread in the bloodstream.
However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of sepsis:
many patients with sepsis died despite successful eradication of the inciting pathogen. Thus, researchers
suggested that it was the host, not the germ, that drove the pathogenesis of sepsis. 3
In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection,
noting that sepsis could arise in response to multiple infectious causes and that septicemia was neither a
necessary condition nor a helpful term.4 Instead, the panel proposed the term severe sepsis to describe
instances in which sepsis is complicated by acute organ dysfunction, and they codified septic shock as sepsis
complicated by either hypotension that is refractory to fluid resuscitation or by hyperlactatemia. In 2003, a
second consensus panel endorsed most of these concepts, with the caveat that signs of a systemic
inflammatory response, such as tachycardia or an elevated white-cell count, occur in many infectious and
noninfectious conditions and therefore are not helpful in distinguishing sepsis from other conditions. 5 Thus,
severe sepsis and sepsis are sometimes used interchangeably to describe the syndrome of infection
complicated by acute organ dysfunction.

INCIDENCE AND CAUSES

The incidence of severe sepsis depends on how acute organ dysfunction is defined and on whether that
dysfunction is attributed to an underlying infection. Organ dysfunction is often defined by the provision of
supportive therapy (e.g., mechanical ventilation), and epidemiologic studies thus count the treated incidence
rather than the actual incidence. In the United States, severe sepsis is recorded in 2% of patients admitted to
the hospital. Of these patients, half are treated in the intensive care unit (ICU), representing 10% of all ICU
admissions.6,7 The number of cases in the United States exceeds 750,000 per year 7 and was recently
reported to be rising.8 However, several factors new International Classification of Diseases, 9th

Revision (ICD-9) coding rules, confusion over the distinction between septicemia and severe sepsis, the
increasing capacity to provide intensive care, and increased awareness and surveillance confound the
interpretation of temporal trends.

Studies from other high-income countries show similar rates of sepsis in the ICU. 9 The incidence of severe
sepsis outside modern ICUs, especially in parts of the world in which ICU care is scarce, is largely unknown.
Extrapolating from treated incidence rates in the United States, Adhikari et al. estimated up to 19 million cases
worldwide per year.10 The true incidence is presumably far higher.

Severe sepsis occurs as a result of both community-acquired and health careassociated infections.
Pneumonia is the most common cause, accounting for about half of all cases, followed by intraabdominal
and urinary tract infections. 7,8,11,12 Blood cultures are typically positive in only one third of cases, and in
up to a third of cases, cultures from all sites are negative. 7,11,13,14Staphylococcus
aureus and Streptococcus pneumoniae are the most common gram-positive isolates, whereas Escherichia
coli, klebsiella species, and Pseudomonas aeruginosa predominate among gram-negative isolates.11,14 An
epidemiologic study of sepsis showed that during the period from 1979 to 2000, gram-positive infections
overtook gram-negative infections.15 However, in a more recent study involving 14,000 ICU patients in 75
countries, gram-negative bacteria were isolated in 62% of patients with severe sepsis who had positive
cultures, gram-positive bacteria in 47%, and fungi in 19%.12
Risk factors for severe sepsis are related both to a patient's predisposition for infection and to the likelihood of
acute organ dysfunction if infection develops. There are many well-known risk factors for the infections that
most commonly precipitate severe sepsis and septic shock, including chronic diseases (e.g., the acquired
immunodeficiency syndrome, chronic obstructive pulmonary disease, and many cancers) and the use of
immunosuppressive agents.7 Among patients with such infections, however, the risk factors for organ
dysfunction are less well studied but probably include the causative organism and the patient's genetic
composition, underlying health status, and preexisting organ function, along with the timeliness of therapeutic
intervention.16 Age, sex, and race or ethnic group all influence the incidence of severe sepsis, which is higher
in infants and elderly persons than in other age groups, higher in males than in females, and higher in blacks
than in whites.7,17
There is considerable interest in the contribution of host genetic characteristics to the incidence and outcome of
sepsis, in part because of strong evidence of inherited risk factors. 18 Many studies have focused on
polymorphisms in genes encoding proteins implicated in the pathogenesis of sepsis, including cytokines and
other mediators involved in innate immunity, coagulation, and fibrinolysis. However, findings are often
inconsistent, owing at least in part to the heterogeneity of the patient populations studied. 19,20 Although a
recent genomewide association study21 explored drug responsiveness in sepsis, no such large-scale studies of
susceptibility to or outcome of sepsis have been performed.

CLINICAL FEATURES
The clinical manifestations of sepsis are highly variable, depending on the initial site of infection, the causative
organism, the pattern of acute organ dysfunction, the underlying health status of the patient, and the interval

before initiation of treatment. The signs of both infection and organ dysfunction may be subtle, and thus the
most recent international consensus guidelines provide a long list of warning signs of incipient sepsis ( Table

1TABLE 1

Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.).5 Acute organ

dysfunction most commonly affects the respiratory and cardiovascular systems. Respiratory compromise is
classically manifested as the acute respiratory distress syndrome (ARDS), which is defined as hypoxemia with
bilateral infiltrates of noncardiac origin.22 Cardiovascular compromise is manifested primarily as hypotension or
an elevated serum lactate level. After adequate volume expansion, hypotension frequently persists, requiring
the use of vasopressors, and myocardial dysfunction may occur.23
The brain and kidneys are also often affected. Central nervous system dysfunction is typically manifested as
obtundation or delirium. Imaging studies generally show no focal lesions, and findings on
electroencephalography are usually consistent with nonfocal encephalopathy. Critical illness polyneuropathy
and myopathy are also common, especially in patients with a prolonged ICU stay.24 Acute kidney injury is
manifested as decreasing urine output and an increasing serum creatinine level and frequently requires
treatment with renal-replacement therapy. Paralytic ileus, elevated aminotransferase levels, altered glycemic
control, thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and the euthyroid
sick syndrome are all common in patients with severe sepsis. 5

OUTCOME
Before the introduction of modern intensive care with the ability to provide vital-organ support, severe sepsis
and septic shock were typically lethal. Even with intensive care, rates of in-hospital death from septic shock
were often in excess of 80% as recently as 30 years ago. 25 However, with advances in training, better
surveillance and monitoring, and prompt initiation of therapy to treat the underlying infection and support failing
organs, mortality is now closer to 20 to 30% in many series.7,26 With decreasing death rates, attention has
focused on the trajectory of recovery among survivors. Numerous studies have suggested that patients who
survive to hospital discharge after sepsis remain at increased risk for death in the following months and years.
Those who survive often have impaired physical or neurocognitive functioning, mood disorders, and a low
quality of life.27 In most studies, determining the causal role of sepsis in such subsequent disorders has been
difficult. However, a recent analysis of the Health and Retirement Study, involving a large, longitudinal cohort of
aging Americans, suggested that severe sepsis significantly accelerated physical and neurocognitive decline. 28

PATHOPHYSIOLOGY
Host Response
As the concept of the host theory emerged, it was first assumed that the clinical features of sepsis were the
result of overly exuberant inflammation. Later, Bone et al.29 advanced the idea that the initial inflammatory
response gave way to a subsequent compensatory antiinflammatory response syndrome. However, it has
become apparent that infection triggers a much more complex, variable, and prolonged host response, in which
both proinflammatory and antiinflammatory mechanisms can contribute to clearance of infection and tissue
recovery on the one hand and organ injury and secondary infections on the other.30 The specific response in
any patient depends on the causative pathogen (load and virulence) and the host (genetic characteristics and
coexisting illnesses), with differential responses at local, regional, and systemic levels ( Figure 1FIGURE 1

The Host Response in Severe Sepsis.). The composition and direction of the host response

probably change over time in parallel with the clinical course. In general, proinflammatory reactions (directed at
eliminating invading pathogens) are thought to be responsible for collateral tissue damage in severe sepsis,
whereas antiinflammatory responses (important for limiting local and systemic tissue injury) are implicated in
the enhanced susceptibility to secondary infections.
Innate Immunity
Knowledge of pathogen recognition has increased tremendously in the past decade. Pathogens activate
immune cells through an interaction with pattern-recognition receptors, of which four main classes toll-like
receptors, C-type lectin receptors, retinoic acid inducible gene 1like receptors, and nucleotide-binding
oligomerization domainlike receptors have been identified, with the last group partially acting in protein
complexes called inflammasomes (Figure 1).31 These receptors recognize structures that are conserved
among microbial species, so-called pathogen-associated molecular patterns, resulting in the up-regulation of
inflammatory gene transcription and initiation of innate immunity. The same receptors also sense endogenous
molecules released from injured cells, so-called damage-associated molecular patterns, or alarmins, such as
high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. 32 Alarmins are also
released during sterile injury such as trauma, giving rise to the concept that the pathogenesis of multiple organ
failure in sepsis is not fundamentally different from that in noninfectious critical illness. 32
Coagulation Abnormalities
Severe sepsis is almost invariably associated with altered coagulation, frequently leading to disseminated
intravascular coagulation.33 Excess fibrin deposition is driven by coagulation through the action of tissue factor,
a transmembrane glycoprotein expressed by various cell types; by impaired anticoagulant mechanisms,
including the protein C system and antithrombin; and by compromised fibrin removal owing to depression of the

fibrinolytic system (Figure 2FIGURE 2

Organ Failure in Severe Sepsis and Dysfunction of the

Vascular Endothelium and Mitochondria.).33 Protease-activated receptors (PARs) form the molecular link

between coagulation and inflammation. Among the four subtypes that have been identified, PAR1 in particular
is implicated in sepsis.33 PAR1 exerts cytoprotective effects when stimulated by activated protein C or lowdose thrombin but exerts disruptive effects on endothelial-cell barrier function when activated by high-dose
thrombin.34 The protective effect of activated protein C in animal models of sepsis is dependent on its capacity
to activate PAR1 and not on its anticoagulant properties.34
Antiinflammatory Mechanisms and Immunosuppression
The immune system harbors humoral, cellular, and neural mechanisms that attenuate the potentially harmful
effects of the proinflammatory response (Figure 1).30 Phagocytes can switch to an antiinflammatory phenotype
that promotes tissue repair, and regulatory T cells and myeloid-derived suppressor cells further reduce
inflammation. In addition, neural mechanisms can inhibit inflammation.35 In the so-called neuroinflammatory
reflex, sensory input is relayed through the afferent vagus nerve to the brain stem, from which the efferent
vagus nerve activates the splenic nerve in the celiac plexus, resulting in norepinephrine release in the spleen
and acetylcholine secretion by a subset of CD4+ T cells. The acetylcholine release targets 7 cholinergic
receptors on macrophages, suppressing the release of proinflammatory cytokines. 36 In animal models of
sepsis,35 disruption of this neural-based system by vagotomy increases susceptibility to endotoxin shock,
whereas stimulation of the efferent vagus nerve or 7 cholinergic receptors attenuates systemic inflammation.
Patients who survive early sepsis but remain dependent on intensive care have evidence of
immunosuppression, in part reflected by reduced expression of HLA-DR on myeloid cells. 37 These patients
frequently have ongoing infectious foci, despite antimicrobial therapy, or reactivation of latent viral
infection.38,39 Multiple studies have documented reduced responsiveness of blood leukocytes to pathogens in
patients with sepsis,30 findings that were recently corroborated by postmortem studies revealing strong
functional impairments of splenocytes obtained from patients who had died of sepsis in the ICU. 37 Besides the
spleen, the lungs also showed evidence of immunosuppression; both organs had enhanced expression of
ligands for T-cell inhibitory receptors on parenchymal cells. 37 Enhanced apoptosis, especially of B cells, CD4+
T cells, and follicular dendritic cells, has been implicated in sepsis-associated immunosuppression and
death.40,41Epigenetic regulation of gene expression may also contribute to sepsis-associated
immunosuppression.42
Organ Dysfunction
Although the mechanisms that underlie organ failure in sepsis have been only partially elucidated, impaired
tissue oxygenation plays a key role (Figure 2). Several factors including hypotension, reduced red-cell

deformability, and microvascular thrombosis contribute to diminished oxygen delivery in septic shock.
Inflammation can cause dysfunction of the vascular endothelium, accompanied by cell death and loss of barrier
integrity, giving rise to subcutaneous and body-cavity edema.43 In addition, mitochondrial damage caused by
oxidative stress and other mechanisms impairs cellular oxygen use. 44 Moreover, injured mitochondria release
alarmins into the extracellular environment, including mitochondrial DNA and formyl peptides, which can
activate neutrophils and cause further tissue injury.45

TREATMENT
The Surviving Sepsis Campaign, an international consortium of professional societies involved in critical care,
treatment of infectious diseases, and emergency medicine, recently issued the third iteration of clinical

guidelines for the management of severe sepsis and septic shock ( Table 2TABLE 2

Guidelines

for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Campaign.).23The most important

elements of the guidelines are organized into two bundles of care: an initial management bundle to be
accomplished within 6 hours after the patient's presentation and a management bundle to be accomplished in
the ICU.23 Implementation of the bundles is associated with an improved outcome.46,47
The principles of the initial management bundle are to provide cardiorespiratory resuscitation and mitigate the
immediate threats of uncontrolled infection. Resuscitation requires the use of intravenous fluids and
vasopressors, with oxygen therapy and mechanical ventilation provided as necessary. The exact components
required to optimize resuscitation, such as the choice and amount of fluids, appropriate type and intensity of
hemodynamic monitoring, and role of adjunctive vasoactive agents, all remain the subject of ongoing debate
and clinical trials; many of these issues will be covered in this series. 23 Nonetheless, some form of
resuscitation is considered essential, and a standardized approach has been advocated to ensure prompt,
effective management.23 The initial management of infection requires forming a probable diagnosis, obtaining
cultures, and initiating appropriate and timely empirical antimicrobial therapy and source control (i.e., draining
pus, if appropriate).
The choice of empirical therapy depends on the suspected site of infection, the setting in which the infection
developed (i.e., home, nursing home, or hospital), medical history, and local microbial-susceptibility patterns.
Inappropriate or delayed antibiotic treatment is associated with increased mortality.48,49 Thus, intravenous
antibiotic therapy should be started as early as possible and should cover all likely pathogens. It has not been
determined whether combination antimicrobial therapy produces better outcomes than adequate single-agent
antibiotic therapy in patients with severe sepsis. 50-53 Current guidelines recommend combination antimicrobial

therapy only for neutropenic sepsis and sepsis caused by pseudomonas species. Empirical antifungal therapy
should be used only in patients at high risk for invasive candidiasis. 50
The patient should also be moved to an appropriate setting, such as an ICU, for ongoing care. After the first 6
hours, attention focuses on monitoring and support of organ function, avoidance of complications, and deescalation of care when possible. De-escalation of initial broad-spectrum therapy may prevent the emergence
of resistant organisms, minimize the risk of drug toxicity, and reduce costs, and evidence from observational
studies indicates that such an approach is safe. 54The only immunomodulatory therapy that is currently

advocated is a short course of hydrocortisone (200 to 300 mg per day for up to 7 days or until
vasopressor support is no longer required) for patients with refractory septic shock. 23 This
recommendation is supported by a meta-analysis, 55but the two largest studies had conflicting
results,56,57 and other clinical trials are ongoing. 58,59

SEARCH FOR NEW THERAPIES

Recent Failures
One of the great disappointments during the past 30 years has been the failure to convert advances in our
understanding of the underlying biologic features of sepsis into effective new therapies. 60 Researchers have
tested both highly specific agents and agents exerting more pleiotropic effects. The specific agents can be
divided into those designed to interrupt the initial cytokine cascade (e.g., antilipopolysaccharide or anti
proinflammatory cytokine strategies) and those designed to interfere with dysregulated coagulation (e.g.,
antithrombin or activated protein C).61 The only new agent that gained regulatory approval was activated

protein C.62 However, postapproval concern about the safety and efficacy of activated protein C prompted
a repeat study, which did not show a benefit and led the manufacturer, Eli Lilly, to withdraw the drug from
the market.11 All other strategies thus far have not shown efficacy. With the recent decision to stop further
clinical development of CytoFab, a polyclonal antitumor necrosis factor antibody (ClinicalTrials.gov
number, NCT01145560), there are no current large-scale trials of anticytokine strategies in the treatment
of sepsis.
Among the agents with broader immunomodulatory effects, glucocorticoids have received the most
attention. Intravenous immune globulin is also associated with a potential benefit, 63 but important
questions remain, and its use is not part of routine practice. 23 Despite a large number of observational
studies suggesting that the use of statins reduces the incidence or improves the outcome of sepsis and
severe infection,64 such findings have not been confirmed in randomized, controlled trials, so the use of
statins is not part of routine sepsis care. 23
Problems with Therapeutic Development
Faced with these disappointing results, many observers question the current approach to the development of
sepsis drugs. Preclinical studies commonly test drugs in young, healthy mice or rats exposed to a septic

challenge (e.g., bacteria or bacterial toxins) with limited or no ancillary treatment. In contrast, patients with
sepsis are often elderly or have serious coexisting illnesses, which may affect the host response and increase
the risk of acute organ dysfunction. Furthermore, death in the clinical setting often occurs despite the use of
antibiotics, resuscitation, and intensive life support, and the disease mechanisms in such cases are probably
very different from those underlying the early deterioration that typically occurs in animal models in the absence
of supportive care. There are also large between-species genetic differences in the inflammatory host
response.65
In clinical studies, the enrollment criteria are typically very broad, the agent is administered on the basis of a
standard formula for only a short period, there is little information on how the agent changes the host response
and hostpathogen interactions, and the primary end point is death from any cause. Such a research strategy
is probably overly simplistic in that it does not select patients who are most likely to benefit, cannot adjust
therapy on the basis of the evolving host response and clinical course, and does not capture potentially
important effects on nonfatal outcomes.
New Strategies
Consequently, hope is pinned on newer so-called precision-medicine strategies with better preclinical models,
more targeted drug development, and clinical trials that incorporate better patient selection, drug delivery, and
outcome measurement. For example, options to enrich the preclinical portfolio include the study of animals that
are more genetically diverse, are older, or have preexisting disease. Longer experiments with more advanced
supportive care would allow better mimicry of the later stages of sepsis and multiorgan failure, permitting the
testing of drugs in a more realistic setting and perhaps facilitating the measurement of outcomes such as
cognitive and physical functioning. In addition, preclinical studies could be used to screen for potential
biomarkers of a therapeutic response for which there are human homologues.
Activated protein C mutants that lack anticoagulant properties are examples of more targeted drug
development and were shown to provide protection from sepsis-induced death in animals, without an increased
risk of bleeding.66 Biomarkers such as whole-genome expression patterns in peripheral-blood leukocytes may
aid in stratifying patients into more homogeneous subgroups or in developing more targeted therapeutic
interventions.67 The insight that severe sepsis can cause immunosuppression raises the possibility of using
immune-stimulatory therapy (e.g., interleukin-7, granulocytemacrophage colony-stimulating factor,68 or
interferon-69), but ideally, such therapy would be used only in patients in whom immunosuppression is
identified or predicted. Thus, such therapies could be deployed on the basis of laboratory measures, such as
monocyte HLA-DR expression. In addition, concern about accelerated neurocognitive decline in survivors of
sepsis opens up avenues to explore agents currently being tested in patients with dementia and related
conditions.

The designs of trials could be modified to more easily incorporate these ideas. For example, the considerable
uncertainty at the beginning of a trial with regard to the appropriate selection of patients and drugadministration strategy and the possibility of treatment interactions may be better handled with the use of a
Bayesian design. A trial could commence with multiple study groups that reflect the various uncertainties to be
tested but then automatically narrow assignments to the best-performing groups on the basis of predefinedresponse adaptive randomization rules. Such designs could be particularly helpful when testing combination
therapy or incorporating potential biomarkers of drug responsiveness.

CONCLUSIONS
Severe sepsis and septic shock represent one of the oldest and most pressing problems in medicine. With
advances in intensive care, increased awareness, and dissemination of evidence-based guidelines, clinicians
have taken large strides in reducing the risk of imminent death associated with sepsis. However, as more
patients survive sepsis, concern mounts over the lingering sequelae of what was previously a lethal event.
Strategies are also needed to reach the many millions of patients with sepsis who are far from modern
intensive care. At the same time, advances in molecular biology have provided keen insight into the complexity
of pathogen and alarm recognition by the human host and important clues to a host response that has gone
awry. However, harnessing that information to provide effective new therapies has proved to be difficult. To
further improve the outcome of patients with sepsis through the development of new therapeutic agents, newer,
smarter approaches to clinical-trial design and execution are essential.
Dr. Angus reports receiving grant support through his institution from Eisai, consulting fees from Idaho Technology, Pfizer,
Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli Lilly for serving as a member of a clinical-trial data and safety
monitoring board. Dr. van der Poll reports receiving grant support through his institution from Sirtris Pharmaceuticals and
consulting fees from Eisai. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was updated on November 21, 2013, at NEJM.org.

SOURCE INFORMATION
From the CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical
Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh (D.C.A.); and the Center for Experimental and
Molecular Medicine, Division of Infectious Diseases, and Center for Infection and Immunity Amsterdam, Academic Medical
Center, University of Amsterdam, Amsterdam (T.P.).
Address reprint requests to Dr. Angus at the Department of Critical Care Medicine, University of Pittsburgh, 614 Scaife Hall,
3550 Terrace St., Pittsburgh, PA 15261, or at angusdc@upmc.edu; or to Dr. van der Poll at the Division of Infectious
Diseases, Academic Medical Center, Meibergdreef 9, Rm. G2-130, 1105 AZ Amsterdam, the Netherlands, or
at t.vanderpoll@amc.uva.nl.

http://www.nejm.org/doi/full/10.1056/NEJMra1208623