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Evaluation and management of suspected sepsis and

septic shock in adults
AUTHORS: Gregory A Schmidt, MD, Jess Mandel, MD, MACP, ATSF, FRCP
SECTION EDITORS: Daniel J Sexton, MD, Korilyn S Zachrison, MD, MSc, Michelle Ng Gong, MD, MS
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: Nov 2023.

This topic last updated: Nov 09, 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 for the most-part 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
pharmacologic therapies for sepsis" and "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]. The following table summarizes emergency
management of the patient with severe sepsis during the first hour ( table 1).

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 in adults
for emergency medicine and critical care" 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 or intraosseous 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 "Central venous
catheters: Overview of complications and 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 the suspected source and complications of sepsis, and therefore,
helps guide empiric therapy and additional testing ( table 2). (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, rapid antigen or polymerase
chain reaction tests) 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.

● 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. The following table summarizes emergency management of
the patient with severe sepsis during the first hour ( table 1).

● 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
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.

● 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].

● A post-hoc analysis of the ANROMEDA-SHOCK trial [23] suggested that peripheral

perfusion-targeted resuscitation (using capillary refill time [CRT]) may be associated
with a lower mortality and faster resolution of organ dysfunction than lactate-targeted
 resuscitation [24]. Additional studies suggest a poor correlation between MAP and CRT
[25]. Further study is required before clinicians should use CRT routinely as a marker of
resuscitation.

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) [26]. 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
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 [27]. 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, Ringer's
lactate, normal saline) in the treatment of sepsis or septic shock, but they have identified
potential harm from using pentastarch or hydroxyethyl starch [28-37]. There is no role for
hypertonic saline [38].

In our practice, we generally use a balanced crystalloid solution, and less commonly, normal
saline, instead of an albumin solution because of the lack of clear benefit and higher cost of
albumin. Balanced crystalloid rather than normal saline is 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 [29,36,37]. 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 [28]. Among the 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) [30]. 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 [31]. 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 2) (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 [39].
Institutional protocols should address timeliness as a quality improvement measure [40].
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 [5,41]. 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 [42-52].

● 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
[50]. Similar results were reported in an emergency department cohort of 35,000
patients [52].

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

selection was surprisingly common (32 percent) [46]. 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 [53-57]. 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 occasionally viruses (eg, influenza, coronavirus disease 2019 [COVID-
19]). Broad spectrum is defined as therapeutic agent(s) 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 [58].

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 [59,60]. 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
"Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia"
and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults",
section on 'Risk factors for MRSA'.)

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"):

• 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)

Choosing among the preceding options should be individualized. Cefepime and

piperacillin-tazobactam are probably the most commonly prescribed antipseudomonal
agents. Piperacillin-tazobactam has been hypothesized to cause acute kidney injury,
and cefepime has been hypothesized to cause neurologic dysfunction. Use of these two
agents were directly compared in a randomized trial of 2511 patients with suspected
infection who needed empiric treatment with an antipseudomonal agent [61]. Rates of
acute kidney injury or death by day 14 were similar between the two groups. In
contrast, patients in the cefepime group experienced fewer days alive and free of
delirium and coma (11.9 versus 12.2 days; odds ratio 0.79, 95% CI 0.65-0.95), although
the difference, while significant, was small. Interpretation is limited since the study was
an open-label trial with significant crossover between the groups and longer-term
outcomes beyond 14 days are not known. In addition, the dosing regimen was lower
than typical for piperacillin-tazobactam and cefepime was administered as an
intravenous push, which may have increased the risk of neurotoxicity. Lastly, the role of
other antibiotics, such as anaerobic coverage with metronidazole, was not examined in
this study. Further details regarding the adverse effects of beta-lactam antibiotics are
provided elsewhere. (See "Beta-lactam antibiotics: Mechanisms of action and resistance
and adverse effects", section on 'Adverse effects'.)

● 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 [46,62-66].
Furthermore, one meta-analysis found double coverage that included an
aminoglycoside was associated with an increased incidence of adverse events
(nephrotoxicity) [65,66]. 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 [64]. (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 [67].

• 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 [68].

• 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 [69].

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 [70-72] and that higher clinical success rates have been
reported in patients with higher peak concentrations of antimicrobials [73-75].

Continuous infusions of antibiotics as compared with intermittent dosing regimens remains

investigational at this time [76]. Continuous infusions of beta lactam antimicrobials have
been shown to provide higher and sustained drug levels above the minimum inhibitory
concentration compared with the peaks and trough of intermittent dosing [77-79]. In a
double-blind randomized trial of 607 patients prescribed meropenem for sepsis, outcomes
were compared when meropenem was administered as a continuous infusion or
intermittent infusion [80]. The mode of administration did not affect the composite outcome
of 28-day mortality and the emergence of pandrug-resistant bacteria (47 versus 49 percent).
In addition, there also was no difference in the length of ICU or hospital stay, days alive and
free from the ICU, or 90-day mortality. However, therapeutic monitoring was not performed
and the prescription of other microbials was common, both of which may limit the ability to
detect a difference between the groups. We believe that further study is needed before
continuous infusions can be recommended, although some experts favor continuous
infusions given study biases, lack of harm, and possibility of benefit. Further details on
prolonged infusions of antimicrobials are provided separately. (See "Prolonged infusions of
beta-lactam antibiotics".)

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) [81]. 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
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 [82].

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 [83-85]. 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 [86,87]. (See "Pulmonary artery catheterization: Indications,
contraindications, and complications in adults".)

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 [88]. 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) [89]. 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") [90]. 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 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 [90] reported increased
mortality in patients in whom a higher MAP was targeted with vasopressor use for
greater than six hours [91] and a greater risk of supraventricular cardiac arrhythmias
[92]. Another meta-analysis found no difference in mortality or the need for renal
replacement therapy when higher versus lower MAP targets were used [93].

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 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 [14,94-99]. 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 [97,98]. 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 [100]. 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 [101-103].

● 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'.)

● 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 3). As examples, potentially infected vascular access devices
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 [104-106], 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 4 and table 5). 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 should not delay their administration via a peripheral catheter.

● 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 [107-113]. These trials studied norepinephrine versus phenylephrine [114],
norepinephrine versus vasopressin [115-118], norepinephrine versus terlipressin [119-
121], norepinephrine versus epinephrine [122], and vasopressin versus terlipressin
[123]. 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
[118,124], two meta-analyses reported increased mortality among patients who
received dopamine during septic shock compared with those who received
norepinephrine (53 to 54 versus 48 to 49 percent) [110,125]. 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) [126]. 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 0.77, 95% CI 0.67-0.88) [127]. 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 [128-132].

• 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) [133]. (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 [134].

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 5) [8,135-137]. Inotropic therapy should not be used to increase the
cardiac index to supranormal levels [138]. 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
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) [139]. 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 [140-142], 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 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 [143-145]. 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 [146-148].

● Another trial has shown no difference in mortality when fluid restriction was compared
with a more liberal approach [148]. 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 [149,150]. 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 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 [151-155]. 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 [156-159]. 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 [160-165]. 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) [166-169].

● 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 [170], several randomized trials and meta-analyses
found that using procalcitonin-guided algorithms to guide antimicrobial de-escalation
did not result in any mortality benefit [171-177]. 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 clinically meaningful outcomes were measured in this study [178]. Other
 studies suggest that procalcitonin may distinguish infectious from noninfectious
conditions and may therefore facilitate the decision to de-escalate empiric therapy
[171,179-181]. 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 "Acute respiratory distress syndrome:

Ventilator management strategies for adults" and "Sedative-analgesia in ventilated
adults: Management strategies, agent selection, monitoring, 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 C) (see "Investigational and ineffective pharmacologic 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 [182]. Further
details regarding the management of critically ill pregnant patients are provided separately.
(See "Critical illness during pregnancy and the peripartum period".)

POSTSEPSIS 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) in
adults: Clinical features and diagnostic evaluation" 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.

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 ( table 1).
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's 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.)

• 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 3 and
table 2). 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 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 5). 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 148.0
GRAPHICS

Severe sepsis in adults: Rapid overview of emergency management during

first hour

Clinical presentation

Findings of severe sepsis and septic shock can include elevated respiratory rate, decreased SpO2,
hypotension, elevated HR, positive shock index (HR/SBP>1), elevated or low temperature, altered
mentation, signs of compromised end-organ perfusion (eg, cool or mottled skin, decreased
capillary refill, decreased urine output, ileus), and other signs or laboratory results showing orga
system dysfunction.

Diagnostic evaluation and monitoring

Measure vital signs and pulse oximetry. Perform continual cardiac and SpO2 monitoring. Monitor
urine output. Reassess vital signs frequently.
Search closely for symptoms and signs of infectious source (eg, productive cough, urinary
symptoms, abdominal tenderness or guarding, purulent exudate from surgical wound or
catheter site, meningeal irritation, skin lesions). Reassess after urgent interventions initiated.
Perform bedside ultrasound assessment if available, including assessment of fluid status (eg, IVC
diameter) and organ systems as clinically indicated (eg, hydronephrosis, cholecystitis, pulmonary
fluid/consolidation).
Obtain the following tests (if feasible): serum lactate, complete blood count with differential,
basic electrolytes, kidney function, liver function, lipase, coagulation studies including venous (or
arterial) blood gas, and electrocardiogram. Some centers measure procalcitonin when CAP
suspected.
Obtain aerobic and anaerobic blood cultures from two distinct sites; obtain other cultures as
clinically indicated (eg, urine, wound, sputum, CSF, indwelling vascular access devices).
Perform imaging studies of suspected sources of infection as clinically indicated (eg, chest
radiograph, CT of chest and/or abdomen and pelvis, biliary ultrasound).
Evaluate for source control (eg, abscess/empyema drainage, infected/necrotic tissue
debridement, potentially infected indwelling hardware/catheter removal, ongoing microbial
contamination control).

Initial respiratory and hemodynamic interventions

Provide supplemental oxygen as needed to maintain SpO2 ≥92%.

Possible interventions include low-flow oxygen via nasal cannula, noninvasive ventilation (if
no contraindication), high-flow oxygen via nasal cannula, nonrebreather mask, or bag-mask
apparatus.
Perform tracheal intubation and mechanical ventilation as necessary (eg, increased work of
breathing, depressed consciousness).
Use hemodynamically neutral induction agents for RSI (eg, ketamine, etomidate).
If MAP <65 mmHg, premedicate with phenylephrine 50 to 200 micrograms IV.
LPPV is preferred strategy for mechanical ventilation. *
Settings vary by patient, but standard initial settings for LPPV include: volume-limited assist
control; tidal volume 6 mL/kg; rate 16 to 36 bpm ¶ ; PEEP 5 to 10 cm H2O; FiO2 1.0 with rapid
 wean to target O2 saturation; inspiratory flow 60 L/min; and trigger sensitivity –1 to –2 cm
H2O.
Obtain IV access; do not delay urgent interventions to place central venous catheter. Place
intraosseous catheter if difficult to obtain IV access.
Administer rapid IV boluses (typically 500 to 1000 mL) of isotonic crystalloid (eg, Lactated Ringer)
Boluses are repeated based on clinical response.
Volume totals of 30 mL/kg in first hours after presentation are reasonable, but clinical
circumstances may warrant larger (eg, severe diarrhea) or smaller (eg, heart failure) volumes
Treatment goals include MAP ≥65 mmHg and urine output ≥0.5 mL/kg per hour.
If hemodynamic response to IV fluids is inadequate or constrained by fluid overload (eg, heart
failure), administer vasopressor. Norepinephrine (5 to 15 mcg/minute) is preferred. Peripheral IV
may be used temporarily for administration pending placement of central venous catheter.

Antimicrobial medication

Initiate empiric, broad-spectrum IV antibiotic therapy, ideally within 1 hour of presentation,

targeted at suspected source(s) of infection. Maximal dosing should be used. Examples include: Δ
Vancomycin plus one of these:
Third- or fourth-generation cephalosporin (eg, ceftriaxone, cefepime [antipseudomonal])
or
Carbapenem (eg, meropenem, imipenem) or
Piperacillin-tazobactam.
When selecting targeted antimicrobial therapy, consider the following factors: history (eg, recent
antibiotics received, previous organisms), comorbidities (eg, diabetes, organ failures, immune
deficiencies), context (eg, community- versus hospital-acquired infection), suspected infection
site, presence of invasive devices, Gram stain data, prior culture data from patient (if available),
and local prevalence and resistance patterns (eg, MRSA, Pseudomonas).

Additional interventions and therapies

Obtain consultation as indicated to address infection source (eg, surgery for peritonitis or
necrotizing soft tissue infection, interventional radiology for drainage of cholecystitis/cholangitis
or obstructing kidney stone).
If anemic, transfuse red blood cells to goal hemoglobin concentration >7 g/dL.
If adrenal insufficiency suspected or refractory shock present (eg, multiple vasopressors at high
doses required), administer a stress-dose glucocorticoid (eg, hydrocortisone 100 mg IV).
If hypotension persists despite adequate IV fluid resuscitation and vasopressor therapy, a second
vasopressor (eg, vasopressin) and possibly inotropic medication (eg, dobutamine) may be
needed.
Provide appropriate analgesia and sedation.

bpm: beats per minute; CAP: community-acquired pneumonia; CSF: cerebrospinal fluid; CT: computed
tomography; FiO2: fraction of inspired oxygen; HR: heart rate; H2O: water; IV: intravenous; IVC: inferior
vena cava; LPPV: lung-protective positive-pressure ventilation; MAP: mean arterial pressure; MRSA:
Methicillin-resistant Staphylococcus aureus; O2: oxygen; PEEP: positive end-expiratory pressure; RSI:
rapid sequence intubation; SBP: systolic blood pressure; SpO2: oxygen saturation.

* Refer to UpToDate table describing initial ventilator settings for common modes of invasive
mechanical ventilation and to topics discussing initiation of mechanical ventilation.
¶ Patients may breathe above the set rate; thus, compare the set minute ventilation and the actual
minute ventilation when interpreting respiratory status and adjusting ventilator settings.

Δ Refer to UpToDate table and topic discussing initial management of severe sepsis in adults for
details of antimicrobial selection.

Graphic 143200 Version 4.0

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 chest Sputum of good quality, rapid
pain, consolidative auscultatory influenza testing, urinary
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 insertion Culture of blood (from the
central venous site Δ catheter and a peripheral site),
culture catheter tip (if removed)

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

symptoms/signs percutaneously or surgically
drained abdominal fluid
collections

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, Male: Urine Gram stain and
urgency, urge incontinence, culture
cloudy urine, prostatic
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

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

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

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)
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)
Dopamine Inotropin 2 to 2 to 20 mcg/kg/minute
5 mcg/kg/minute 20 mcg/kg/minute
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
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
 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.
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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