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 PCO 2 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 (ScvO2). 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 SvO 2 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 using pentastarch 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 Medicine guidelines [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 [18-20,44]. 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 Campaign guidelines 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 ScvO 2 [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 ScvO 2 70 percent in a protocolbased therapy, trials published since then (ProCESS, ARISE, ProMISe) have reported no
mortality benefit [18-20,44]. (See 'Protocol-directed 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 ScvO 2 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 [18-20,44,45,55-57]. Typically, they combine the EGDT targets (ScvO2, 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 [1820,44,45,57-59]:
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 ScvO 2, 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 60day 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 0.37-0.69) [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 broadspectrum 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 non-pulmonary
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 healthcareassociated 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 (eg, piperacillintazobactam, 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.
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 [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".)
Intensive insulin therapy Hyperglycemia and insulin resistance are common in critically ill
patients, independent of a history of diabetes mellitus [97]. 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 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 [98]. 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.
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".)
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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
albumin-containing 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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