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Official reprint from UpToDate®

[Link] © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation and management of suspected sepsis and

septic shock in adults
Authors: Gregory A Schmidt, MD, Jess Mandel, MD, MACP, ATSF, FRCP
Section Editors: Polly E Parsons, MD, Daniel J Sexton, MD, Korilyn S Zachrison, MD, MSc
Deputy Editor: Geraldine Finlay, MD

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

Literature review current through: Feb 2023. | This topic last updated: Mar 06, 2023.

INTRODUCTION

Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a

continuum of severity ranging from sepsis to septic shock. Although wide-ranging and
dependent upon the population studied, mortality has been estimated to be ≥10 percent and
≥40 percent when shock is present [1,2].

In this topic review, the management of sepsis and septic shock is discussed. Our approach is
consistent with 2021 guidelines issued by the Surviving Sepsis Campaign [3,4].

While we use the Society of Critical Care Medicine (SCCM)/European Society of Intensive Care
Medicine (ESICM) definitions, such definitions are not unanimously accepted. For example, the
Center for Medicare and Medicaid Services (CMS) still continues to support the previous
definition of systemic inflammatory response syndrome, sepsis, and severe sepsis. In addition,
the Infectious Diseases Society of America (IDSA) has pointed out that use of such definitions,
while lifesaving for those with shock, may lead to overtreatment with broad-spectrum
antibiotics for those with milder variants of sepsis [5].

Definitions, diagnosis, pathophysiology, and investigational therapies for sepsis, as well as

management of sepsis in the asplenic patient are reviewed separately. (See "Sepsis syndromes
in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and
"Pathophysiology of sepsis" and "Investigational and ineffective therapies for sepsis" and

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"Clinical features, evaluation, and management of fever in patients with impaired splenic
function".)

IMMEDIATE EVALUATION AND MANAGEMENT

Securing the airway (if indicated) and correcting hypoxemia, and establishing venous access for
the early administration of fluids and antibiotics are priorities in the management of patients
with sepsis and septic shock [3,4].

Stabilize respiration — Supplemental oxygen should be supplied to all patients with sepsis
who have indications for oxygenation, and oxygenation should be monitored continuously with
pulse oximetry. Ideal target values for peripheral saturation are unknown, but we typically
target values between 90 and 96 percent. Intubation and mechanical ventilation may be
required to support the increased work of breathing that frequently accompanies sepsis or for
airway protection since encephalopathy and a depressed level of consciousness frequently
complicate sepsis [6,7]. Target values for oxygenation, techniques and sedative and induction
agents for intubation are discussed separately. (See "Overview of initiating invasive mechanical
ventilation in adults in the intensive care unit", section on 'Fraction of inspired oxygen' and
"Induction agents for rapid sequence intubation in adults for emergency medicine and critical
care" and "Overview of advanced airway management in adults for emergency medicine and
critical care" and "Rapid sequence intubation for adults outside the operating room" and "The
decision to intubate" and "Direct laryngoscopy and endotracheal intubation in adults".)

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. However, the insertion of a central line should not delay the
administration of resuscitative fluids and antibiotics. 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. While a CVC can be used to monitor
the therapeutic response by measuring the central venous pressure (CVP) and the central
venous oxyhemoglobin saturation (ScvO2), evidence from randomized trials suggest that their
value is limited [8-13]. (See "Overview of complications of central venous catheters and their
prevention in adults" and 'Monitor response' below.)

Initial investigations — An initial brief history and examination, as well as laboratory,

microbiologic (including blood cultures), and imaging studies are often obtained simultaneously
while access is being established and the airway stabilized. This brief assessment yields clues to

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the suspected source and complications of sepsis, and therefore, helps guide empiric therapy
and additional testing ( table 1). (See "Sepsis syndromes in adults: Epidemiology, definitions,
clinical presentation, diagnosis, and prognosis", section on 'Clinical presentation' and 'Empiric
antibiotic therapy (first hour)' below.)

Quickly obtaining the following is preferable (within 45 minutes of presentation) but should not
delay the administration of fluids and antibiotics:

● Complete blood counts with differential, chemistries, liver function tests, and coagulation
studies including D-dimer level. Results from these studies may support the diagnosis,
indicate the severity of sepsis, and provide baseline to follow the therapeutic response.

● Serum lactate – An elevated serum lactate (eg, >2 mmol/L or greater than the laboratory
upper limit of normal) may indicate the severity of sepsis and is used to follow the
therapeutic response [3,4,14-16].

● Peripheral blood cultures (aerobic and anaerobic cultures from at least two different sites),
urinalysis, and microbiologic cultures from suspected sources (eg, sputum, urine,
intravascular catheter, wound or surgical site, body fluids) from readily accessible sites.
Drawing blood for cultures through an indwelling or central intravascular catheter should
be avoided whenever possible, since ports are frequently colonized with skin flora, thereby
increasing the likelihood of a false-positive blood culture. If blood cultures are drawn from
an intravenous line, a second specimen should be drawn from a peripheral venipuncture
site.

The importance of early blood cultures was best illustrated in a multicenter randomized
trial of 325 patients with a presumed or confirmed source of infection and hypotension or
elevated lactate >4 mmol/L [17]. All patients had two sets of blood cultures drawn from
two separate sites before antimicrobial administration and a second set of blood cultures
was obtained from zero to four hours after antimicrobial administration. Pre-antimicrobial
cultures were positive in 31.4 percent compared with 19.4 percent post-antimicrobial
administration. When pre-antimicrobial cultures were considered the reference gold
standard, the sensitivity of post-antimicrobial blood cultures was 53 percent. When other
cultures were included with post-antimicrobial blood cultures, pathogens were identified
in approximately two-thirds of patients. Although some methodologic issues (eg, in some
patients only one blood culture or one venipuncture was obtained instead of two), this
study nonetheless highlights the importance of taking blood cultures prior to
antimicrobial administration. Importantly, both the collection of cultures and the initiation
of antimicrobial therapy should be prompt in those with the signs of severe sepsis.

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● Arterial blood gas (ABG) analysis – ABGs may reveal acidosis, hypoxemia, or hypercapnia.

● Imaging targeted at the suspected site of infection is warranted (eg, chest radiography,
computed tomography of chest and/or abdomen).

● Procalcitonin – While the diagnostic value of procalcitonin in patients with sepsis is poorly
supported by evidence, its value in de-escalating antibiotic therapy is well established in
populations, in particular, those with community acquired pneumonia and respiratory
tract infections; measurement of procalcitonin to guide duration of antibiotic use is
appropriate in those populations with sepsis, while its role in other groups is unclear.
While one meta-analysis of 5158 critically ill patients reported a mortality benefit
associated with procalcitonin use a survival benefit was not noted in the subset of patients
with sepsis [18]. In contrast, a randomized trial of 266 patients with sepsis from lower
respiratory tract infections, acute pyelonephritis, or primary bloodstream infection,
procalcitonin guided therapy was associated with a reduction in 28-day mortality (28
versus 15 percent) and length of antibiotic therapy (5 versus 10 days) [19]. While
encouraging, additional data from well-conducted randomized trials in patients with
sepsis are required before we can routinely recommend procalcitonin use all patients with
sepsis. Detailed evidence to support the use of procalcitonin is provided separately. (See
"Procalcitonin use in lower respiratory tract infections" and "Clinical evaluation and
diagnostic testing for community-acquired pneumonia in adults", section on 'Serum
biomarkers'.)

INITIAL RESUSCITATIVE THERAPY

The cornerstone of initial resuscitation is the rapid restoration of perfusion and the early
administration of antibiotics.

● Tissue perfusion is predominantly achieved by the aggressive administration of

intravenous fluids (IVF), usually crystalloids (balanced crystalloids or normal saline) given
at 30 mL/kg (actual body weight), started by one hour and completed within the first three
hours following presentation.

● Empiric antibiotic therapy is targeted at the suspected organism(s) and site(s) of infection
and preferably administered within the first hour.

Our approach is based upon several major randomized trials that used a protocol-based
approach (ie, early goal-directed therapy [EGDT]) to treating sepsis [8-13]. Components of the
protocols usually included the early administration of fluids and antibiotics (within one to six
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hours) using the following targets to measure the response: central venous oxyhemoglobin
saturation (ScvO2) ≥70 percent, central venous pressure (CVP) 8 to 12 mmHg, mean arterial
pressure (MAP) ≥65 mmHg, and urine output ≥0.5 mL/kg/hour. Although all trials [9-11] (except
for one [8]) did not show a mortality benefit to EGDT, it is thought that the lack of benefit was
explained by an overall improved outcome in both control and treatment groups and to
improved clinical performance by trained clinicians in academic centers during an era that
followed an aggressive sepsis education and management campaign. In support of this
hypothesis is that central line placement was common (>50 percent) in control groups so it is
likely that CVP, ScvO2, and/or lactate clearance were targeted in these patients. Furthermore,
the mortality in studies that did not report a benefit to EGDT [9-11] approximated that of the
treatment arm in the only study that reported benefit [8].

● One single center randomized trial of 263 patients with suspected sepsis reported a lower
mortality in patients when ScvO2, CVP, MAP, and urine output were used to direct therapy
compared with those in whom only CVP, MAP, and urine output were targeted (31 versus
47 percent) [8]. Both groups initiated therapy, including antibiotics, within six hours of
presentation. There was a heavy emphasis on the use of red cell transfusion (for a
hematocrit >30) and dobutamine to reach the ScvO2 target in this trial.

● Three subsequent multicenter randomized trials of patients with septic shock, ProCESS [9],
ARISE [10], and ProMISE [11] and two meta-analyses [12,13] all reported no mortality
benefit (mortality ranged from 20 to 30 percent), associated with an identical protocol
compared with protocols that used some of these targets or usual care. In contrast, one
meta-analysis of 13 trials reported a mortality benefit from early-goal directed therapy
within the first six hours [20].

● A lack of benefit of resuscitation protocols has also been reported in resource-limited

settings. As an example, in a randomized trial of 212 patients with sepsis (defined as
suspected infection plus two systemic inflammatory response syndrome criteria) and
hypotension (systolic blood pressure ≤90 mmHg or MAP <65 mmHg) in Zambia, a
protocolized approach of aggressive fluid resuscitation, monitoring, blood, and
vasopressor transfusion within the first six hours of presentation resulted in a higher rate
of death (48 versus 33 percent) when compared with usual care [21]. However, several
flaws including crude measurements of monitoring, lower than usual rates of lactate
elevation, larger than typical volumes of fluid resuscitation, and use of dopamine (as
opposed to norepinephrine) in a population with a high percentage of patients with
human immunodeficiency virus may have biased the results.

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● Another analysis from a cohort of 1871 Canadian patients reported that prehospital
administration of fluids by paramedics to patients with hypotension from sepsis may be of
benefit, although it was associated with increased prehospital time [22].

The importance of timely treatment, particularly with antibiotics, was illustrated in a database
study of nearly 50,000 patients with sepsis and septic shock who were treated with various
types of protocolized treatment bundles (that included fluids and antibiotics, blood cultures,
and serum lactate measurements) [23]. Compared with those in whom a three-hour bundle
(blood cultures before broad spectrum antibiotics, serum lactate level) was completed within
the three-hour time frame, a higher in-hospital mortality was reported when a three-hour
bundle was completed later than three hours (odds ratio [OR] 1.04 per hour). Increased
mortality was associated with the delayed administration of antibiotics but not with a longer
time to completion of a fluid bolus (as part of a six hour bundle) (OR 1.04 per hour versus 1.10
per hour).

Intravenous fluids (first three hours) — In patients with sepsis, intravascular hypovolemia is
typical and may be severe, requiring rapid fluid resuscitation. (See "Treatment of severe
hypovolemia or hypovolemic shock in adults".)

Volume — Intravascular hypovolemia is typical and may be severe in sepsis. Rapid, large
volume infusions of IVF (30 mL/kg) are indicated as initial therapy for severe sepsis or septic
shock, unless there is convincing evidence of significant pulmonary edema. This approach is
based upon several randomized trials that reported no difference in mortality when mean
infusion volumes of 2 to 3 liters were administered in the first three hours [9-11] compared with
larger volumes of three to five liters, which was considered standard therapy at the time [8].
However, some patients may require higher than recommended volumes, particularly those
who demonstrate clinical and/or hemodynamic indicators of fluid-responsiveness. (See 'Monitor
response' below.)

Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses. The
clinical and hemodynamic response 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.

In one trial, over 1500 patients with sepsis-induced hypotension refractory to initial
resuscitation with 1 to 3 L of IVF were randomized to receive either a restrictive fluid regimen
(prioritizing vasopressors and lower intravenous fluid volumes) or liberal fluid regimen
(prioritizing higher volumes of intravenous fluids before vasopressor use). The restrictive

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strategy entailed early administration of vasopressors after infusion of up to 2 L of fluid

including prerandomization fluid, if needed. The liberal regimen prioritized infusion of an
additional 2 L at randomization in addition to prerandomized fluid and additional boluses as
needed [24]. Despite more fluid administration in the liberal group compared with the
restrictive group (3400 versus 1267mL at 24 hours), there was no difference in 90-day mortality
(15 versus 14 percent) or any other outcome measured. Vasopressors were administered earlier
and for longer periods in those who received the restrictive regimen but did not appear to be
associated with excess adverse effects. However, results may have been impacted by greater
than intended fluid volumes administered in some patients in the restrictive group and lower
than intended volumes in some patients in the liberal group, perhaps limiting the ability of the
study to detect a meaningful difference between the interventions. In addition, the median
volume administered in the liberal group is reasonably close to that which is widely practiced
and both arms of this trial led to administration of significantly less fluid than would have been
typical a decade ago; this suggests that adopting a more aggressive restrictive approach than
currently practiced may not be associated with additional benefit.

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, Ringer's lactate) in the treatment of sepsis or septic shock, but they have identified
potential harm from using pentastarch or hydroxyethyl starch [25-34]. There is no role for
hypertonic saline [35].

In our practice, we generally use a balanced crystalloid solution or normal saline instead of an
albumin solution because of the lack of clear benefit and higher cost of albumin. Balanced
crystalloid may be preferred if there is a perceived need to avoid or treat the hyperchloremia
that occurs when large volumes of nonbuffered crystalloid (eg, normal saline) are administered,
although the data to support this practice are weak (and discussed separately). (See "Treatment
of severe hypovolemia or hypovolemic shock in adults", section on 'Choice of replacement
fluid'.)

Data discussing IVF choice among patients with sepsis include the following:

● Crystalloid versus albumin – Among patients with sepsis, several randomized trials and
meta-analyses have reported no difference in mortality when albumin was compared with
crystalloids, although one meta-analysis suggested benefit in those with septic shock
[26,33,34]. In the Saline versus Albumin Fluid Evaluation (SAFE) trial performed in critically
ill patients, there was no benefit to albumin compared with saline even in the subgroup
with severe sepsis, who comprised 18 percent of the total group [25]. Among the

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crystalloids, there are no guidelines to suggest that one form is more beneficial than the
other.

● Crystalloid versus hydroxyethyl starch (HES) – In the Scandinavian Starch for Severe
Sepsis and Septic Shock (6S) trial, compared with Ringer’s acetate, use of HES resulted in
increased mortality (51 versus 43 percent) and renal replacement therapy (22 versus 16
percent) [27]. Similar results were found in additional trials of patients without sepsis.

● 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 [28]. The trial was stopped
early because there was a trend toward increased 90-day mortality among patients who
received pentastarch.

● Balanced salt solutions – Evidence to support the use of a balanced crystalloid solution
or 0.9 percent saline in patients with sepsis is indirect and mostly derived from studies
performed in a mixed population of critically ill patients. Further details are provided
separately. (See "Treatment of severe hypovolemia or hypovolemic shock in adults",
section on 'Choosing between 0.9 percent saline and buffered crystalloid'.)

Treating metabolic acidosis — Whether metabolic acidosis associated with sepsis should be
treated with bicarbonate is discussed separately. (See "Bicarbonate therapy in lactic acidosis".)

Empiric antibiotic therapy (first hour) — Prompt identification and treatment of the site(s) of
infection is the primary therapeutic intervention, with most other interventions being purely
supportive.

Identification of suspected source — Empiric antibiotics should be targeted at the suspected

source(s) of infection which is typically identified from the initial history, physical examination,
and preliminary laboratory findings and imaging ( table 1) (see 'Initial investigations' above).
However, additional diagnostic testing or interventions may be required to identify the
anatomic site(s) of infection. In particular, in addition to antibiotics, closed-space infections
should be promptly drained or debrided (eg, empyema, abscess) for effective source control.
(See 'Septic focus identification and source control' below.)

Timing — Once a presumed diagnosis of sepsis or septic shock has been made, optimal doses
of appropriate intravenous antibiotic therapy should be initiated, preferably within one hour of
presentation and after cultures have been obtained (see 'Initial investigations' above). The early
administration of antimicrobials is often challenging because various patient- and institutional-
related factors may lead to delays in timely treatment [36]. Institutional protocols should
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address timeliness as a quality improvement measure [37]. However, several clinician groups
including the Infectious Diseases Society of America (IDSA) criticized the Society of Critical Care
Medicine (SCCM) for promoting standards defining rigid time frames for initiation of antibiotics
as it is often difficult to determine the actual onset of sepsis in individual patients; in addition,
the one hour time frame could lead to overuse and inappropriate administration of
unwarranted antimicrobials [5,38]. The IDSA favors removal of a recommendation for specific
minimum time frames for initiating antibiotic therapy and instead advocates replacing these
recommendations with the statement that prompt administration of antibiotics is
recommended once a presumed diagnosis of sepsis or shock has been made by the treating
clinician [5].

Although the feasibility of a one hour target for initiating antibiotics has not been assessed, the
rationale for choosing it is based upon observational studies that report poor outcomes with
delayed (even beyond one hour), inadequately dosed, or inappropriate (ie, treatment with
antibiotics to which the pathogen was later shown to be resistant in vitro) antimicrobial therapy
[39-49].

● In a retrospective analysis of over 17,000 patient with sepsis and septic shock, delay in first
antibiotic administration was associated with increased in-hospital mortality with a linear
increase in the risk of mortality for each hour delay in antibiotic administration [47].
Similar results were reported in an emergency department cohort of 35,000 patients [49].

● A prospective cohort study of 2124 patients demonstrated that inappropriate antibiotic

selection was surprisingly common (32 percent) [43]. Mortality was markedly increased in
these patients compared with those who had received appropriate antibiotics (34 versus
18 percent).

Choosing a regimen — The choice of antimicrobials can be complex and should consider the
patient's history (eg, recent antibiotics received, previous organisms), comorbidities (eg,
diabetes, organ failures), immune defects (eg, human immune deficiency virus), clinical context
(eg, community- or hospital-acquired), suspected site of infection, presence of invasive devices,
Gram stain data, and local prevalence and resistance patterns [50-54]. The general principles
and examples of potential empiric regimens are given in this section but antimicrobial choice
should be tailored to each individual.

For most patients with sepsis without shock, we recommend empiric broad spectrum therapy
with one or more antimicrobials to cover all likely pathogens. Coverage should be directed
against both gram-positive and gram-negative bacteria and, if indicated, against fungi (eg,
Candida) and rarely viruses (eg, influenza). Broad spectrum is defined as therapeutic agent(s)

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with sufficient activity to cover a range of gram-negative and gram-positive organisms (eg,
carbapenem, piperacillin-tazobactam). In order to ensure treatment with an effective antibiotic,
many patients with septic shock suspected to be due to gram-negative organisms may require
initial therapy with two antimicrobials from two different classes (ie, combination therapy),
although this practice depends upon the organisms that are considered likely pathogens and
local antibiotic susceptibilities.

Empiric therapy for patients with sepsis should be directed at the most common organisms
causing sepsis in specific patient populations. Among organisms isolated from patients with
sepsis, the most common include Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae,
and Streptococcus pneumoniae, such that coverage of these organisms should be kept in mind
when choosing an agent [55].

However, when the organism is unknown, the clinician should be mindful of other potential
pathogens when risk factors are present and consider the following:

● Methicillin-resistant S. aureus – Methicillin-resistant S. aureus (MRSA) is a cause of sepsis

not only in hospitalized patients but also in community dwelling individuals without recent
hospitalization [56,57]. For these reasons, we suggest empiric intravenous vancomycin
(adjusted for renal function) be added to empiric regimens, particularly in those with
shock or those at risk for MRSA. Potential alternative agents to vancomycin (eg,
daptomycin for nonpulmonary MRSA, linezolid) should be considered for patients with
refractory or virulent MRSA or with a contraindication to vancomycin. (See "Treatment of
hospital-acquired and ventilator-associated pneumonia in adults", section on 'MRSA risk
factors only' and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment
of bacteremia".)

In our practice, if Pseudomonas is an unlikely pathogen, we favor combining vancomycin

with one of the following:

• A third generation (eg, ceftriaxone or cefotaxime) or fourth generation cephalosporin

(cefepime), or

• A beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam), or

• A carbapenem (eg, imipenem or meropenem)

● Pseudomonas – Alternatively, if Pseudomonas is a likely pathogen, we favor combining

vancomycin with one to two of the following, depending on local antibiotic susceptibility
patterns (see "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections"):

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• Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or

• Antipseudomonal carbapenem (eg, imipenem, meropenem), or

• Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam),

or

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

• Aminoglycoside (eg, gentamicin, amikacin), or

• Monobactam (eg, aztreonam)

● Non pseudomonal gram-negative organisms (eg, E. coli, K. pneumoniae) – In the past,

gram-negative pathogens routinely were covered with two agents from different antibiotic
classes. However, several clinical trials and two meta-analyses failed to demonstrate
superior overall efficacy of combination therapy compared to monotherapy with a third
generation cephalosporin or a carbapenem [43,58-62]. Furthermore, one meta-analysis
found double coverage that included an aminoglycoside was associated with an increased
incidence of adverse events (nephrotoxicity) [61,62]. For this reason, in patients with
suspected 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 sepsis is due to a known or suspected Pseudomonas infection, where combination
therapy can be considered [60]. (See "Pseudomonas aeruginosa bacteremia and
endocarditis" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa
infections".)

● Invasive fungal infections – The routine administration of empirical antifungal therapy is

not generally warranted in nonneutropenic critically ill patients. Invasive fungal infections
occasionally complicate the course of critical illness, especially when the following risk
factors are present: surgery, parenteral nutrition, prolonged antimicrobial treatment or
hospitalization (especially in the intensive care unit [ICU]), chemotherapy, transplant,
chronic liver or renal failure, diabetes, major abdominal surgery, vascular devices, septic
shock or multisite colonization with Candida spp. However, studies do not support the
routine use of empiric antifungals in this population:

• In a meta-analysis of 22 studies (most often comparing fluconazole to placebo, but also

using ketoconazole, anidulafungin, caspofungin, micafungin, and amphotericin B),
untargeted empiric antifungal therapy possibly reduced fungal colonization and the
risk of invasive fungal infection but did not reduce all-cause mortality [63].

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• In a study of critically ill patients ventilated at least five days, empiric antifungal
treatment (mostly fluconazole) was not associated with a decreased risk of mortality or
occurrence of invasive candidiasis [64].

• In a multicenter randomized trial (EMPIRICUS) of 260 nonneutropenic critically ill

patients with Candida colonization (at multiple sites), multiple organ failure, and ICU-
acquired sepsis, empiric treatment for 14 days with micafungin did not result in
improved infection-free survival at 28 days but did decrease the rate of new fungal
infection [65].

However, if Candida or Aspergillus is strongly suspected or if neutropenia is present, an

echinocandin (for Candida) or voriconazole (for Aspergillus) are often appropriate. (See
"Treatment and prevention of invasive aspergillosis" and "Management of candidemia and
invasive candidiasis in adults".)

● Other – Other regimens should consider the inclusion of agents for specific organisms
such as Legionella (macrolide or fluoroquinolone) or difficult to treat organisms (eg,
Stenotrophomonas), or for specific conditions (eg, neutropenic bacteremia)

Dosing — Clinicians should pay attention to maximizing the dose in patients with sepsis and
septic shock using a full "high-end" loading dose where possible. This strategy is based upon
the known increased volume of distribution that can occur in patients with sepsis due to the
administration of fluid [66-68] and that higher clinical success rates have been reported in
patients with higher peak concentrations of antimicrobials [69-71]. Continuous infusions of
antibiotics as compared with intermittent dosing regimens remains investigational at this time
[72].

Location of admission — Whether patients should be admitted to an ICU or ward is unclear

and likely varies with the individual presenting characteristics as well as available institutional
services and policy, which also may vary from state to state and country to country. For
example, patients with septic shock who require mechanical ventilation and vasopressors
clearly require ICU admission while those without shock who quickly respond to fluid and
antibiotics may be safely transferred to the floor. For those in between these extremes, close
observation and a low threshold to admit to the ICU is prudent.

Use of a systematic approach to ICU admission has been studied. One study of 3037 critically ill
French patients aged 75 years or older, randomized patients to hospitals that promoted a
systematic approach to ICU admission (interventional group) or to hospitals that did not use
this approach (usual care) [73]. Despite a doubling of the admission rate to the ICU and an
increased risk of in-hospital death, there was no difference in mortality at six months after
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adjustment for age, illness severity, initial clinical diagnosis, seniority of the emergency
department clinician, time of ICU admission, baseline functional status, living situation, and
type of home support. However, several flaws including, higher severity of illness in the
intervention group, lack of blinding, and a strategy that was underpowered to detect a
mortality difference may have influenced these results. In addition, international differences in
the care of patients with sepsis may also explain an opposing outcome reported by a United
States cohort [74].

MONITOR RESPONSE

After fluids and empiric antibiotics have been administered, the therapeutic response should be
assessed frequently. We suggest that clinical, hemodynamic, and laboratory parameters be
followed as outlined in the sections below. In our experience, most patients respond within the
first 6 to 24 hours to initial fluid therapy, however, resolution can be protracted and take days or
weeks. The response mostly influences further fluid management but can also affect
antimicrobial therapy and source control.

Monitoring catheters — For many patients, a central venous catheter (CVC) and an arterial
catheter are placed, although they are not always necessary. For example, an arterial catheter
may be inserted if blood pressure is labile, sphygmomanometer readings are unreliable,
restoration of perfusion is expected to be protracted (especially when vasopressors are
administered), or dynamic measures of fluid responsiveness are selected to follow the
hemodynamic response. A CVC may be placed if the infusion of large volumes of fluids or
vasopressors are anticipated, peripheral access is poor, or the central venous pressure (CVP) or
the central venous oxyhemoglobin saturation (ScvO2) are chosen as methods of monitoring the
hemodynamic response. (See "Intra-arterial catheterization for invasive monitoring: Indications,
insertion techniques, and interpretation" and "Novel tools for hemodynamic monitoring in
critically ill patients with shock" and "Central venous access in adults: General principles".)

We believe that pulmonary artery catheters (PACs) should not be used in the routine
management of patients with sepsis or septic shock since they have not been shown to improve
outcome [75-77]. PACs can measure the pulmonary artery occlusion pressure (PAOP) and mixed
venous oxyhemoglobin saturation (SvO2). 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 [78,79]. (See "Pulmonary artery catheterization: Indications, contraindications, and
complications in adults".)

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Clinical — All patients should be followed clinically for improved mean arterial pressure (MAP),
urine output, heart rate, respiratory rate, skin color, temperature, pulse oximetry, and mental
status. Among these, a MAP ≥65 mmHg (MAP = [(2 x diastolic) + systolic]/3) (calculator 1), and
urine output ≥0.5 mL/kg per hour are common targets used in clinical practice. They have not
been compared to each other nor have they been proven to be superior to any other target or
to clinical assessment. Data supporting the use of these clinical parameters are discussed
above. (See 'Initial resuscitative therapy' above.)

Most clinicians target a MAP ≥65 mmHg based upon data from large randomized trials that
demonstrated benefit when using this target MAP (see 'Initial resuscitative therapy' above).
However, the ideal target for MAP, is unknown. Furthermore, data since then suggest that
higher MAPs (eg, ≥70 mmHg) may be harmful, while targeting lower MAPs (eg, 60 to 65 mmHg)
may be appropriate. Thus, a reasonable goal may be to individualize targets within a range (eg,
60 to 70 mmHg) rather than targeting one specific numeric goal. Further trials are pending that
should help elucidate an optimal range for a target MAP for patients with hypotension from
sepsis.

● 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
[80]. 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.

● A pilot randomized trial reported that among patients aged 75 years or older, a higher
MAP target (75 to 80 mmHg) was associated with increased hospital mortality compared
with a lower MAP target (60 to 65 mmHg; 60 versus 13 percent) [81]. The same group
subsequently reported outcomes in a nonblinded randomized trial of 2600 volume-
repleted patients with vasodilatory shock who were older than 65 years and 80 percent of
whom had sepsis (the "65 trial") [82]. Patients in whom vasopressors were used to target a
MAP 60 to 65 mmHg ("permissive hypotension"; median mean MAP 66.7 mmHg) were
compared with patients who received "usual care" (MAP at the discretion of the treating
clinician; median MAP 72.6 mmHg). Fluid balance, rates of corticosteroid use (roughly one-
third), and urine output were similar among the groups. Although the 90 day mortality
was no different, the point estimate favored the permissive hypotension treatment
strategy (41 versus 44 percent; adjusted odds ratio 0.82, 95% CI 0.68-0.98) and patients in
the permissive hypotension group received lower doses of vasopressors for shorter
duration. Importantly, there were no differences in the rates of cognitive dysfunction,
cardiac arrhythmias, or acute renal failure. Although the prespecified outcome of
superiority was not met, this trial suggests that at minimum, permissive hypotension was

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not harmful and supports the use of lower than usual target MAPs. It also suggests that
similar to observations in other trials, clinicians tend to "overshoot" the target when a
target MAP is set. However, several flaws including bias due to lack of blinding and a
higher than usual mortality in the usual care group may limit interpretation of this study.

● Two meta-analyses that did not include the "65 trial" above [82] reported increased
mortality in patients in whom a higher MAP was targeted with vasopressor use for greater
than six hours [83] and a greater risk of supraventricular cardiac arrhythmias [84]. Another
meta-analysis found no difference in mortality or the need for renal replacement therapy
when higher versus lower MAP targets were used [85].

Hemodynamic — Static or dynamic predictors of fluid responsiveness should be employed in

order to determine further fluid management. Guidelines state a preference for dynamic
measures [3] since they are more accurate than static measures (eg, CVP) at predicting fluid
responsiveness. However whether the use of dynamic predictors improve clinically impactful
outcomes such as mortality remains unproven.

● Static – Traditionally, in addition to MAP, the following static CVC measurements were
used to determine adequate fluid management:

• CVP at a target of 8 to 12 mmHg

• ScvO2 ≥70 percent (≥65 percent if sample is drawn off a PAC)

While one early trial of patients with septic shock reported a mortality benefit to these
static parameters in a protocol-based therapy, trials published since then (ProCESS, ARISE,
ProMISe) have reported no mortality benefit in association with their use [8-11]. (See
'Initial resuscitative therapy' above.)

● Dynamic – Respiratory changes in the vena caval diameter, radial artery pulse pressure,
aortic blood flow peak velocity, left ventricular outflow tract velocity-time integral, and
brachial artery blood flow velocity are considered dynamic measures of fluid
responsiveness. 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. 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) also predicts fluid
responsiveness. Choosing among these is dependent upon availability and technical
expertise, but a passive leg raising maneuver may be the most accurate and broadly
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available. Future studies that report improved outcomes (eg, mortality, ventilator free
days) in association with their use are needed. Further details are provided separately.
(See "Novel tools for hemodynamic monitoring in critically ill patients with shock".)

Laboratory

● Lactate clearance – Although the optimal frequency of measuring serum lactate is

unknown, we follow serum lactate (eg, every six hours) in patients with sepsis until the
lactate value has clearly fallen. While guidelines promote normalization of lactate [3],
lactate-guided resuscitation has not been convincingly associated with improved
outcomes.

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 [14,86-90]. One meta-analysis of five low quality trials reported that lactate–
guided resuscitation resulted in a reduction in mortality compared with resuscitation
without lactate [3]. Other meta-analyses reported modest mortality benefit when lactate
clearance strategies were used compared with usual care or ScvO2 normalization [89,90].
However, many of the trials included in these meta-analyses studied heterogeneous
populations and used varying definitions of lactate clearance as well as additional
variables that potentially affected the outcome.

In addition, lactate is a poor marker of tissue perfusion after the restoration of perfusion
[91]. As a result, lactate values are generally unhelpful following restoration of perfusion,
with one exception: a rising serum lactate level should prompt reevaluation of the
adequacy of perfusion. (See "Venous blood gases and other alternatives to arterial blood
gases".)

Devices that allow measurement of serum lactate levels at the bedside are now available
and their use may increase the practicality and utility of serial monitoring of serum lactate
levels [92-94].

● Routine laboratories – Follow up laboratory studies, in particular platelet count, serum

chemistries, and liver function tests are often performed (eg, every six hours) until values
have reached normal or baseline. Hyperchloremia should be avoided, but if it is occurs,
switching to low chloride-containing (ie, buffered) solutions may be indicated. (See
"Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Buffered
crystalloid'.)

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● Microbiology – Follow up indices of infection are also indicated, including complete blood
count and additional cultures. Results should prompt alteration of antibiotic choice if a
better and safer regimen can be substituted and/or investigations directed toward source
control. (See 'Septic focus identification and source control' below.)

● Arterial blood gases – It is prudent to follow worsening or resolution of gas exchange

abnormalities, as well as the severity and type of acidosis (eg, resolution of metabolic
acidosis and development of hyperchloremic acidosis). Worsening gas exchange may be a
clue to the presence of pulmonary edema from excessive fluid resuscitation and also help
detect other complications including pneumothorax from central catheter placement,
acute respiratory distress syndrome, or venous thromboembolism.

SEPTIC FOCUS IDENTIFICATION AND SOURCE CONTROL

In our experience, a focused history and physical examination is the most valuable method for
source detection. Following initial investigations and empiric antimicrobial therapy, further
efforts aimed at identifying and controlling the source(s) of infection should be performed in all
patients with sepsis. In addition, for those who fail despite therapy or those who fail having
initially responded to therapy, further investigations aimed at adequacy of the antimicrobial
regimen or nosocomial super infection should be considered.

● Identification – Additional investigations targeted at the suspected source(s) should be

considered in patients with sepsis as promptly as is feasible (eg, within the first 12 hours).
This investigation may include imaging (eg, computed tomography, ultrasonography) and
sample acquisition (cultures or further diagnostic samples [eg, bronchoalveolar lavage,
aspirating fluid collections or joints]); performing additional investigations depends upon
the risk, if an intervention is involved, and patient stability. 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. These assays are discussed separately. (See "Clinical manifestations and
diagnosis of candidemia and invasive candidiasis in adults", section on 'Nonculture
methods' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen
detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

● Source control – Source control (ie, physical measures to eradicate a focus of infection
and eliminate or treat microbial proliferation and infection) should be undertaken in
timely manner when they feasible since undrained foci of infection may not respond to
antibiotics alone ( table 2). As examples, potentially infected vascular access devices

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should be removed (after other vascular access has been established). Other examples
include removing other infected implantable devices/hardware, when feasible, abscess
drainage (including thoracic empyema and joint), percutaneous nephrostomy, soft tissue
debridement or amputation, colectomy (eg, for fulminant Clostridium difficile-associated
colitis), and cholecystostomy.

The optimal timing of source control is unknown but guidelines suggest no more than 6 to
12 hours after diagnosis since survival is negatively impacted by inadequate source
control [3]. Although the general rule of thumb is that source control should occur as soon
as possible [95-97], this is not always practical or feasible. In addition, decisions about the
type and timing of source control should take into consideration the risk of a specific
intervention and its potential risk of complications (eg, death, fistula formation) and the
likelihood of success, particularly when there is diagnostic uncertainty regarding the
source.

PATIENTS WHO FAIL INITIAL THERAPY

Patients having persistent hypoperfusion despite adequate fluid resuscitation and antimicrobial
treatment should be reassessed for fluid responsiveness (see 'Hemodynamic' above) adequacy
of the antimicrobial regimen and septic focus control (see 'Septic focus identification and source
control' above) as well as the accuracy of the diagnosis of sepsis and/or its source and the
possibility that unexpected complications or coexisting problems have occurred (eg,
pneumothorax following central venous catheter insertion) (see "Evaluation of and initial
approach to the adult patient with undifferentiated hypotension and shock"). Other options for
treatment of persistent hypoperfusion such as the use of vasopressors, glucocorticoids,
inotropic therapy, and blood transfusion are discussed in this section.

Vasopressors — Intravenous vasopressors are useful in patients who remain hypotensive

despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. Based
upon meta-analyses of small randomized trials and observational studies, a paradigm shift in
practice has occurred such that most experts prefer to avoid dopamine in this population and
favor norepinephrine as the first-choice agent ( table 3 and table 4). Although guidelines
suggest additional agents including vasopressin (up to 0.03 units/minute to reduce the dose of
norepinephrine) or epinephrine (for refractory hypotension), practice varies considerably.
Guidelines state a preference for central venous and arterial access especially when
vasopressor administration is prolonged or high dose, or multiple vasopressors are
administered through the same catheter [3]; while this is appropriate, waiting for placement

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should not delay their administration and the risks of catheter placement should also be taken
into account.

● First agent – Data that support norepinephrine as the first-line single agent in septic shock
are derived from numerous trials that compared the use of one vasopressor to another
[98-104]. These trials studied norepinephrine versus phenylephrine [105], norepinephrine
versus vasopressin [106-109], norepinephrine versus terlipressin [110-112],
norepinephrine versus epinephrine [113], and vasopressin versus terlipressin [114]. While
some of the comparisons found no convincing difference in mortality, length of stay in the
intensive care unit or hospital, or incidence of kidney failure [109,115], two meta-analyses
reported increased mortality among patients who received dopamine during septic shock
compared with those who received norepinephrine (53 to 54 percent versus 48 to 49
percent) [101,116]. Although the causes of death in the two groups were not directly
compared, both meta-analyses identified arrhythmic events about twice as often with
dopamine than with norepinephrine.

However, we believe the initial choice of vasopressor in patients with sepsis is often
individualized and determined by additional factors including the presence of coexistent
conditions contributing shock (eg, heart failure), arrhythmias, organ ischemia, or agent
availability. For example, in patients with significant tachycardia (eg, fast atrial fibrillation,
sinus tachycardia >160/minute), agents that completely lack beta adrenergic effects (eg,
vasopressin) may be preferred if it is believed that worsening tachycardia may prompt
further decompensation. Similarly, dopamine (DA) may be acceptable in those with
significant bradycardia; but low dose DA should not be used for the purposes of "renal
protection."

The impact of agent availability was highlighted by one study of nearly 28,000 patients
from 26 hospitals, which reported that during periods of norepinephrine shortages,
phenylephrine was the most frequent alternative agent chosen by intensivists (use rose
from 36 to 54 percent) [117]. During the same period, mortality rates from septic shock
rose from 36 to 40 percent. Whether this was directly related to phenylephrine use
remains unknown.

● Additional agents – The addition of a second or third agent to norepinephrine may be

required (eg, epinephrine, dobutamine, or vasopressin).

• For patients with distributive shock from sepsis, vasopressin may be added. In a meta-
analysis of 23 trials, the addition of vasopressin to catecholamine vasopressors (eg,
epinephrine, norepinephrine) resulted in a lower rate of atrial fibrillation (relative risk

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0.77, 95% CI 0.67-0.88) [118]. However, when including only studies at low risk of bias,
no mortality benefit, reduced requirement for renal replacement therapy, or rate of
myocardial injury, stroke, ventricular arrhythmias or length of hospital stay was
reported. Although not studied, this effect is likely due to a reduced need for
catecholamines which increase the risk of cardiac arrhythmias. This analysis is
consistent with other trials and meta-analyses that have demonstrated no mortality
benefit from vasopressin and selepressin in patients with septic shock [119-123].

• For patients with refractory septic shock associated with a low cardiac output, addition
of an inotropic agent may be useful. In a retrospective series of 234 patients with septic
shock, among several vasopressor agents added to norepinephrine (dobutamine,
dopamine, phenylephrine, vasopressin), inotropic support with dobutamine was
associated with a survival advantage (epinephrine was not studied) [124]. (See "Use of
vasopressors and inotropes", section on 'Epinephrine' and "Use of vasopressors and
inotropes", section on 'Dobutamine'.)

Whether lower vasopressor use is associated with lower mortality is unclear [125].

Additional information regarding vasopressor use including angiotensin II is provided

separately. (See "Use of vasopressors and inotropes".)

Additional therapies — Most clinicians agree that additional therapies such as glucocorticoids,
inotropic agents, or red blood cell (RBC) transfusion are not routinely warranted in patients with
sepsis or septic shock but the use of these therapies maybe useful in refractory cases of septic
shock or in special circumstances.

Glucocorticoids — Guidelines recommend against the routine use of glucocorticoids in

patients with sepsis. However, corticosteroid therapy may be appropriate in patients with septic
shock that is refractory to adequate fluid resuscitation and vasopressor administration. This
topic is discussed in detail separately. (See "Glucocorticoid therapy in septic shock in adults".)

Inotropic therapy — A trial of inotropic therapy may be warranted in patients who fail to
respond to adequate fluids and vasopressors, particularly those who also have diminished
cardiac output ( table 4) [8,126-128]. Inotropic therapy should not be used to increase the
cardiac index to supranormal levels [129]. Dobutamine is a suitable first-choice agent;
epinephrine is a suitable alternative. (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
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blood cell transfusion for patients with a hemoglobin level ≤7 g/dL. 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) [130]. 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).

● One randomized trial initially reported a mortality benefit from a protocol that included
transfusing patients to a hematocrit goal >30 (hemoglobin level 10 g/dL) [8]. However,
similarly designed studies published since then reported no benefit to this strategy [9-11].
These studies are discussed 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 [131-133], the details of which are provided separately. (See "Use of
blood products in the critically ill", section on 'Red blood cells'.)

PATIENTS WHO RESPOND TO THERAPY

Once patients have demonstrated a response to therapy, attention should be directed towards
continuing to control the septic focus, and de-escalation of fluids and antibiotics, as
appropriate. This may occur within hours or days, depending upon the indicators of response
and the individual patient. (See 'Clinical' above and 'Hemodynamic' above and 'Laboratory'
above.)

Identification and control of the septic focus — Further efforts aimed at identifying and
controlling the source of infection should be done if the initial evaluation and investigations fail
to identify a source. (See 'Septic focus identification and source control' above.)

De-escalation fluids — In patients who respond to initial fluid therapy (ie, clinical
hemodynamic and laboratory targets are met; usually hours to one to two days), we reduce the
rate of or stop fluids, wean vasopressor support, and, if necessary, administer diuretics. While
early fluid therapy is appropriate in sepsis, fluids may be unhelpful or harmful when the

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circulation is no longer fluid responsive. Careful and frequent monitoring is essential because
patients with sepsis may develop cardiogenic and noncardiogenic pulmonary edema (ie, acute
respiratory distress syndrome [ARDS]).

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 and functional
recovery in sepsis is unclear [134-136]. Data that support fluid restriction in this population
include the following:

● In patients with ARDS or sepsis, a restrictive approach to intravenous fluid administration

has been shown to decrease the duration of mechanical ventilation and ICU stay,
compared with a more liberal approach [137-139].

● Another trial has shown no difference in mortality when fluid restriction was compared
with a more liberal approach [139]. In this trial of 1554 patients with sepsis who had
received at least 1 liter of fluid and were within 12 hours of the onset of shock, patients
were randomized to receive either restricted intravenous fluid (ie, infusion stopped, small
boluses given when needed for organ perfusion, low urine output, or insensible losses) or
standard intravenous fluid therapy. There was no difference in the 90-day mortality or
adverse effects. Cumulatively, at 90 days, patients in the restrictive group received
approximately 2 liters less of fluids than patients in the standard group. While these data
are encouraging and support safety of a restrictive approach to fluid de-escalation, both
groups had received a median of 3 liters of fluid before randomization, the intervention
was not blinded, and there were more violations in the restrictive group (22 versus 13
percent). Interestingly, the standard fluids group received less fluid than patients in some
of the original sepsis trials [8], suggesting that practice has swung in favor of
implementing a fluid-restricted approach to sepsis resuscitation. More studies are needed
to guide de-escalation in patients with sepsis. (See "Acute respiratory distress syndrome:
Fluid management, pharmacotherapy, and supportive care in adults", section on
'Conservative fluid management'.)

De-escalation and duration of antibiotics — It is appropriate that de-escalation and duration

of antimicrobial agents be assessed daily [140,141]. When uncertain, it is also appropriate to
obtain an infectious diseases consultation to facilitate good antimicrobial stewardship.

● De-escalation – After culture and susceptibility results return and/or after patients
clinically improve, we recommend that antimicrobial therapy be narrowed (typically a few
days). When possible, antimicrobial therapy should also be pathogen and susceptibility

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directed (also known as targeted/definitive therapy). However, since no pathogen is

identified in approximately 50 percent of patients, de-escalation of empiric therapy
requires a component of clinical judgement. For example, vancomycin typically is
discontinued if no methicillin-resistant Staphylococcus is cultured.

While there is no consensus on de-escalation criteria, most experts use follow-up clinical
(improved vital signs), laboratory and imaging data, and a fixed course of broad-spectrum
therapy (eg, three to five days).

There are no high quality trials testing safety of de-escalation of antibiotic therapy in adult
patients with sepsis or septic shock [142-146]. However, most observational trials report
equivalent or improved outcomes with these fixed strategies of de-escalation.

● Duration – The duration of antibiotics should be individualized. For most patients, the
duration of therapy is typically three to eight days [147-150]. However, longer courses are
appropriate in patients who have a slow clinical response, an undrainable focus of
infection, bacteremia with S. aureus, some fungal (eg, deep Candida infections) or viral
infections (eg, herpes or cytomegalovirus), endocarditis, osteomyelitis, large abscesses,
highly resistant gram-negative pathogens with marginal or limited sensitivities,
neutropenia, or immunologic deficiencies [151-156]. Similarly, shorter courses may be
acceptable in patients with negative cultures and rapid resolution of sepsis and laboratory
studies. 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 nonneutropenic patients in whom infection is thoroughly excluded, antibiotics
should be discontinued as early as is feasible to minimize colonization or infection with
drug-resistant microorganisms and superinfection with other pathogens. Occasionally,
shorter courses may be appropriate (eg, patients with pyelonephritis, urinary sepsis, or
peritonitis who have rapid resolution of source control) [157-160].

● Role of procalcitonin – Although many institutions and guidelines support the use of
procalcitonin to limit antibiotic (empiric or therapeutic) use in critically ill patients with
suspected infection or documented infection, the evidence to support this practice is
limited. While one randomized open-label trial of critically ill patients with infection
reported a mortality benefit when the duration of antibiotic use was guided by
normalization of procalcitonin levels [161], several randomized trials and meta-analyses
found that using procalcitonin-guided algorithms to guide antimicrobial de-escalation did
not result in any mortality benefit [162-168]. However, most trials report a reduction in the
duration of antibiotic therapy (on average one day). One retrospective analysis suggested
that use of procalcitonin was associated with lower hospital and ICU length of stay, but no
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clinically meaningful outcomes were measured in this study [169]. Other studies suggest
that procalcitonin may distinguish infectious from noninfectious conditions and may
therefore facilitate the decision to de-escalate empiric therapy [162,170-172]. However,
procalcitonin's greatest utility is in guiding antibiotic discontinuation in patients with
known community-acquired pneumonia and acute bronchitis; thus measuring
procalcitonin in these populations is appropriate. (See "Procalcitonin use in lower
respiratory tract infections".)

SUPPORTIVE THERAPIES

Details regarding supportive therapies needed for the care of critically ill patients, including
those with sepsis are provided separately:

● Blood product infusion (see "Use of blood products in the critically ill")

● Nutrition (see "Nutrition support in critically ill patients: An overview")

● Stress ulcer prophylaxis (see "Stress ulcers in the intensive care unit: Diagnosis,
management, and prevention")

● Neuromuscular blocking agents (see "Neuromuscular blocking agents in critically ill

patients: Use, agent selection, administration, and adverse effects")

● Venous thromboembolism prophylaxis (see "Prevention of venous thromboembolic

disease in acutely ill hospitalized medical adults")

● Intensive insulin therapy (see "Glycemic control in critically ill adult and pediatric patients")

● External cooling or antipyretics (see "Fever in the intensive care unit", section on
'Management')

● Mechanical ventilation, sedation, weaning (see "Ventilator management strategies for

adults with acute respiratory distress syndrome" and "Sedative-analgesic medications in
critically ill adults: Selection, initiation, maintenance, and withdrawal" and "Initial weaning
strategy in mechanically ventilated adults")

● Investigational therapies for sepsis and acute respiratory distress syndrome (eg,
intravenous immune globulin, antithrombin, thrombomodulin, heparin, cytokine and toxin
inactivators, as well as hemofiltration, statins, beta-2 agonists, beta blockade, and vitamin

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C) (see "Investigational and ineffective therapies for sepsis" and "Acute respiratory distress
syndrome: Investigational or ineffective therapies in adults")

PREGNANCY

The optimal way to manage sepsis in pregnancy is unknown but most experts use the same
principles as outlined in this topic being cognizant of the altered hemodynamics of pregnancy.
Guidelines have been proposed but have not been validated [173]. Further details regarding the
management of critically ill pregnant patients are provided separately. (See "Critical illness
during pregnancy and the peripartum period".)

POST-SEPSIS CARE

For survivors of sepsis, attention should be paid to follow-up care and the recognition of post-
intensive care syndrome (PICS). Further details regarding PICS and prognosis of patients with
sepsis are provided separately. (See "Post-intensive care syndrome (PICS)" and "Sepsis
syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis",
section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sepsis in children and
adults".)

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 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

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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 education: Sepsis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Initial evaluation – For patients with sepsis and septic shock, therapeutic priorities
include securing the airway, correcting hypoxemia, and establishing appropriate vascular
access for the early administration of fluids and antibiotics. Simultaneously obtaining the
following is preferable (within 45 minutes) but should not delay the administration of
fluids and antibiotics (see 'Immediate evaluation and management' above):

• Routine laboratory studies

• Serum lactate
• Arterial blood gases
• Blood cultures (aerobic and anaerobic) from two distinct venipuncture sites and from
all indwelling vascular access devices; it is preferable that blood cultures be drawn
before the initiation of antibiotics
• Cultures from easily accessible sites (eg, sputum, urine)
• Imaging of suspected sources

● Initial resuscitation – For patients with sepsis and septic shock, we suggest the infusion
of intravenous fluids (30 mL/kg), commencing within the first hour and completed within
the first three hours of presentation, rather than vasopressors, inotropes, or red blood cell
transfusions (Grade 2B). (See 'Initial resuscitative therapy' above.)

• Intravenous fluids – 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. (See 'Intravenous fluids
(first three hours)' above.)

Crystalloid solutions (eg, normal saline or Ringer lactate) are our preferred
resuscitation fluid. Balanced crystalloid may be preferred if there is a perceived need to
avoid or treat the hyperchloremia that occurs when large volumes of nonbuffered
crystalloid (eg, normal saline) are administered. We recommend that a hyperoncotic
starch solution not be administered (Grade 1A). (See 'Choice of fluid' above.)

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• Antibiotics – For patients with sepsis, we recommend that optimal doses of empiric
broad spectrum intravenous therapy with one or more antimicrobials be administered
in a prompt fashion (eg, within one hour) of presentation (Grade 1B). Broad spectrum
is defined as therapeutic agent(s) with sufficient activity to cover a broad range of
gram-negative and positive organisms, and, if suspected, against fungi and viruses.
(See 'Empiric antibiotic therapy (first hour)' above and 'Initial resuscitative therapy'
above.)

For patients with septic shock associated with likely gram-negative sepsis, we suggest
consideration of the use of two antibiotics from different classes to ensure effective
treatment of resistant organisms.

Agent selection depends upon patient's history, comorbidities, immune defects, clinical
context, suspected site of infection, presence of invasive devices, Gram stain data, and
local prevalence and resistance patterns. The routine administration of antifungal
therapy is not warranted in nonneutropenic patients.

● Monitoring – For most patients with sepsis and septic shock, we recommend that fluid
management be guided using clinical targets including mean arterial pressure 60 to 70
mmHg (calculator 1) and urine output ≥0.5 mL/kg/hour (Grade 1B). (See 'Monitor
response' above and 'Clinical' above.)

• Hemodynamics – In addition, while dynamic measures of fluid responsiveness (eg,

respiratory changes in the radial artery pulse pressure) are preferred, static measures
of determining adequacy of fluid administration (eg, central venous pressure 8 to 12
mmHg or central venous oxygen saturation ≥70 percent) may be more readily
available. (See 'Monitoring catheters' above and 'Hemodynamic' above.)

• Laboratory – Serum lactate should be followed (eg, every six hours) until there is a
definitive clinical response. It is prudent that other measures of the overall response to
infection also be followed (eg, routine laboratory studies, arterial blood gases,
microbiology studies). (See 'Laboratory' above.)

• Source control – Following initial investigations and empiric antimicrobial therapy,

further efforts aimed at identifying and controlling the source(s) of infection (ideally
within 6 to 12 hours) should be performed in all patients with sepsis ( table 2 and
table 1). In addition, for those who fail despite therapy or those who fail having
initially responded to therapy, further investigations aimed at removal of devices
suspected to be infected, adequacy of the antimicrobial regimen, or nosocomial super

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infection should be considered. (See 'Septic focus identification and source control'
above.)

● Patients who fail initial therapy – For patients with sepsis who remain hypotensive
despite adequate fluid resuscitation (eg, 3 L in first three hours), we recommend
vasopressors (Grade 1B); the preferred initial agent is norepinephrine ( table 4). For
patients who are refractory to intravenous fluid and vasopressor therapy, additional
therapies, such as glucocorticoids, inotropic therapy, and blood transfusions, can be
administered on an individual basis. We typically reserve red blood cell transfusion for
patients with a hemoglobin level <7 g/dL. (See 'Additional therapies' above and "Use of
vasopressors and inotropes", section on 'Choice of agent in septic shock'.)

● Patients who respond to therapy – For patients with sepsis who have demonstrated a
response to therapy, we suggest that the rate of fluid administration should be reduced or
stopped, vasopressor support weaned, and, if necessary, diuretics administered. We also
recommend that antimicrobial therapy be narrowed once pathogen identification and
susceptibility data return. Antimicrobial therapy should be pathogen and susceptibility
directed for a total duration of 7 to 10 days, although shorter or longer courses are
appropriate for select patients. (See 'Patients who respond to therapy' above.)

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Topic 1613 Version 143.0

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GRAPHICS

Initial evaluation of common sources of sepsis

Initial microbiologic
Suspected site Symptoms/signs*
evaluation ¶

Upper respiratory tract Pharyngeal inflammation plus Throat swab for aerobic culture
exudate ± swelling and
lymphadenopathy

Lower respiratory tract Productive cough, pleuritic Sputum of good quality, rapid
chest pain, consolidative influenza testing, urinary
auscultatory findings antigen testing (eg,
pneumococcus, legionella; not
recommended in children),
quantitative culture of
protected brush or
bronchoalveolar lavage

Urinary tract Urgency, dysuria, loin, or back Urine culture and microscopy
pain showing pyuria

Vascular catheters: arterial, Redness or drainage at Culture of blood (from the

central venous insertion site Δ catheter and a peripheral site),
culture catheter tip (if removed)

Indwelling pleural catheter Redness or drainage at Culture of pleural fluid (through

insertion site Δ catheter)

Wound or burn Inflammation, edema, Gram stain and culture of

erythema, discharge of pus draining pus, wound culture not
reliable

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

pus; role of tissue aspirates not
proven

Central nervous system Signs of meningeal irritation CSF cell count, protein, glucose,
Gram stain, and culture ◊

Gastrointestinal Abdominal pain, distension, Stool culture for Salmonella,

diarrhea, and vomiting Shigella, or Campylobacter;
detection of Clostridium difficile
toxin

Intra-abdominal Specific abdominal Aerobic and anaerobic culture

symptoms/signs of percutaneously or surgically
drained abdominal fluid
collections

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PD catheter Cloudy PD fluid, abdominal pain Cell count and culture of PD

fluid

Genital tract Female: Low abdominal pain, Female: Endocervical and high
vaginal discharge vaginal swabs onto selective
media
Male: Dysuria, frequency,
urgency, urge incontinence, Male: Urine Gram stain and
cloudy urine, prostatic culture
tenderness

Bone Pain, warmth, swelling, Blood cultures, MRI, bone

decreased use cultures at surgery or by
interventional radiology

Joint Pain, warmth, swelling, Arthrocentesis with cell counts,

decreased range of motion Gram stain, and culture

CSF: cerebrospinal fluid; PD: peritoneal dialysis; MRI: magnetic resonance imaging.

* Fever is frequently seen with all conditions.

¶ Suggested initial tests are not considered to be comprehensive. Additional testing and infectious
disease consultation may be warranted.

Δ This is not always present.

◊ Bacterial antigen and/or molecular testing may also be appropriate in selected patients. Refer to
UpToDate topics on diagnostic testing for meningitis.

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

Graphic 59769 Version 14.0

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Source control methods for common ICU infections

Source Interventions

Pneumonia Chest physiotherapy, suctioning

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

infected catheters

Catheter-related bacteremia Removal of catheter

Peritonitis Resection, repair, or diversion of ongoing sources of contamination,

drainage of abscesses, debridement of necrotic tissue

Pancreatic infection Drainage or debridement

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

Septic arthritis Joint drainage and debridement

Endocarditis Valve replacement

Prosthetic device infection Device removal

Empyema Drainage, decortication

Sinusitis Surgical decompression of the sinuses

Cholangitis Bile duct decompression

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

Graphic 58257 Version 2.0

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Vasoactive agents in septic shock

Effect on heart Effect on Arterial constriction

Drug
rate contractility effects

Dobutamine + +++ - (dilates)

Dopamine ++ ++ ++

Epinephrine +++ +++ ++

Norepinephrine ++ ++ +++

Phenylephrine 0 0 +++

Graphic 74872 Version 2.0

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Vasopressors and inotropes in treatment of acute hypotensive states and

shock: Adult dose and selected characteristics

Range of
United
Usual maximum
States
Agent Initial dose maintenance doses used in
trade
dose range refractory
name
shock

Vasopressors (alpha-1 adrenergic)

Norepinephrine Levophed 5 to 15 mcg/minute 2 to 80 mcg/minute 80 to

(noradrenaline) (0.05 to (0.025 to 250 mcg/minute (1
0.15 mcg/kg/minute) 1 mcg/kg/minute) to
3.3 mcg/kg/minute)
Cardiogenic shock: Cardiogenic shock:
0.05 mcg/kg/minute 0.05 to
0.4 mcg/kg/minute

Epinephrine Adrenalin 1 to 15 mcg/minute 1 to 40 mcg/minute 40 to

(adrenaline) (0.01 to (0.01 to 160 mcg/minute
0.2 mcg/kg/minute) 0.5 mcg/kg/minute) (0.5 to
2 mcg/kg/minute)

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Phenylephrine Neo- 40 to 20 to 80 to
Synephrine, 160 mcg/minute 400 mcg/minute 730 mcg/minute
Vazculep until stabilized (0.25 to (1.1 to
(alternatively, 0.5 to 5 mcg/kg/minute) 9.1 mcg/kg/minute)
2 mcg/kg/minute)

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Dopamine Inotropin 2 to 2 to 20 mcg/kg/minute

5 mcg/kg/minute 20 mcg/kg/minute

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Antidiuretic hormone

Vasopressin Pitressin, 0.03 units/minute 0.01 to Doses

(arginine- Vasostrict 0.04 units/minute >0.04 units/minute
vasopressin) (not titrated) can cause cardiac
ischemia and
should be reserved
for salvage therapy

Inotrope (beta1 adrenergic)

Dobutamine Dobutrex Usual: 2 to 2 to 20 mcg/kg/minute

5 mcg/kg/minute 10 mcg/kg/minute
(range: 0.5 to
5 mcg/kg/minute;
lower doses for less

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severe cardiac
decompensation)

Inotrope (nonadrenergic, PDE3 inhibitor)

Milrinone Primacor 0.125 to 0.125 to 0.75 mcg/kg/minute

0.25 mcg/kg/minute 0.75 mcg/kg/minute

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All doses shown are for intravenous (IV) administration in adult patients. The initial doses shown
in this table may differ from those recommended in immediate post-cardiac arrest management
(ie, advanced cardiac life support). For details, refer to the UpToDate topic review of post-cardiac
arrest management in adults, section on hemodynamic considerations.
Vasopressors can cause life-threatening hypotension and hypertension, dysrhythmias, and
myocardial ischemia. They should be administered by use of an infusion pump adjusted by
clinicians trained and experienced in dose titration of intravenous vasopressors using continuous
noninvasive electronic monitoring of blood pressure, heart rate, rhythm, and function.
Hypovolemia should be corrected prior to the institution of vasopressor therapy. Reduce infusion
rate gradually; avoid sudden discontinuation.
Vasopressors can cause severe local tissue ischemia; central line administration is preferred.
When a patient does not have a central venous catheter, vasopressors can be temporarily
administered in a low concentration through an appropriately positioned peripheral venous
catheter (ie, in a large vein) for less than 24 hours. The examples of concentrations shown in this
table are useful for peripheral (short-term) or central line administration. Closely monitor
catheter site throughout infusion to avoid extravasation injury. In event of extravasation, prompt
local infiltration of an antidote (eg, phentolamine) may be useful for limiting tissue ischemia.
Stop infusion and refer to extravasation management protocol.
Vasopressor infusions are high-risk medications requiring caution to prevent a medication error
and patient harm. To reduce the risk of making a medication error, we suggest that centers have
available protocols that include steps on how to prepare and administer vasopressor infusions
using a limited number of standardized concentrations. Examples of concentrations and other
detail are based on recommendations used at experienced centers; protocols can vary by
institution.

D5W: 5% dextrose water; MAP: mean arterial pressure; NS: 0.9% saline.

Prepared with data from:

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of sepsis
and septic shock: 2016. Crit Care Med 2017; 45:486.

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2. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011; 183:847.
3. Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.

Graphic 99963 Version 21.0

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Contributor Disclosures
Gregory A Schmidt, MD No relevant financial relationship(s) with ineligible companies to disclose. Jess
Mandel, MD, MACP, ATSF, FRCP No relevant financial relationship(s) with ineligible companies to
disclose. Polly E Parsons, MD No relevant financial relationship(s) with ineligible companies to
disclose. Daniel J Sexton, MD Equity Ownership/Stock Options: Magnolia Medical Technologies [Medical
diagnostics – Ended August 2022]. Consultant/Advisory Boards: Magnolia Medical Technologies [Medical
diagnostics – Ended August 2022]. All of the relevant financial relationships listed have been
mitigated. Korilyn S Zachrison, MD, MSc Grant/Research/Clinical Trial Support: American College of
Emergency Physicians [Stroke quality improvement]; CRICO [Headache management]; National Institutes
of Health/National Institute of Neurological Disorders and Stroke [Telestroke, telehealth, prehospital
stroke care, COVID and thromboembolic risk]. Speaker's Bureau: Efficient CME [Honorarium ]. Other
Financial Interest: Journal of the American Heart Association [Associate Editor]. All of the relevant financial
relationships listed have been mitigated. Geraldine Finlay, MD No relevant financial relationship(s) with
ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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