Sepsis in Adults PDF

Overview and Recommendations
[+]Updated 2018 Oct 04 12:00 AM (ET)

[+]

Topic Editor Paritosh Prasad, MD
Recommendations Editor Allen Shaughnessy, PharmD, M Med Ed, FCCP
Deputy Editor Terence K. Trow, MD, FACP, FCCP
ACP Reviewer Philip A. Verhoef, MD, PhD, FAAP, FACP

Background
The Third International Consensus Definition of Sepsis is life-threatening organ dysfunction caused by
dysregulated host response to infection.
Without timely treatment, sepsis may advance to septic shock, which is defined as vasodilatory
hypotension below a mean arterial pressure of 65 mmHg and lactate level > 2 mmol/L (18 mg/dL)
despite adequate fluid resuscitation and is associated with increased mortality (> 40%).
Sepsis occurs when the host response to an infectious pathogen causes life-threatening organ
dysfunction, as manifested by
An increase in Sequential Organ Failure Assessment (SOFA) score of ≥ 2, which objectively measures
function in 6 different domains: pulmonary (oxygen requirements), renal (creatinine), neurologic
status (Glasgow Coma Score), coagulation (platelet counts), liver function (bilirubin) and
cardiovascular (systolic blood pressure).
Septic shock, which is a subset of sepsis specifically defined by vasodilatory hypotension below a mean
arterial pressure of 65 mm Hg and lactate level of > 2 mmol/L (18 mg/dL) despite adequate fluid
resuscitation.
Approximately 750,000 cases of sepsis occur annually in the United States.
Infection with gram-positive organisms appears to be the most common cause of sepsis in the United
States with sepsis due to fungal infections on the rise.
Evaluation
Because organ dysfunction can be measured by an acute change in the total Sequential Organ Failure
Assessment (SOFA) score of ≥ 2 points consequent to presumed infection, patients in whom sepsis is
suspected should have measurements to allow calculation of the SOFA score, including vital signs,
assessment of neurologic status, complete blood cell count, basic metabolic panel, and a hepatic
function panel.
The quick SOFA score (qSOFA), comprised of a respiratory rate of ≥ 22 per minute, altered mentation,
and systolic blood pressure of ≤ 100 mm Hg was developed to rapidly screen for sepsis without
requiring a wait for laboratory studies to be completed. qSOFA may be used at the bedside to identify
patients with suspected infection likely to have a prolonged intensive care unit (ICU) stay or to die in the
hospital.
Any patient in whom sepsis is suspected should be evaluated to identify the source of infection, which
may include cultures (of blood, urine, CSF, respiratory secretions), rapid viral antigen testing, or imaging
studies.
Management
See Sepsis treatment in adults for management recommendations.
Rapid delivery of care and frequent patient assessments (often requiring ICU admission) are critical to
improving outcomes in patients with sepsis.
Cornerstones of treatment are:
early fluid and vasopressors for resuscitation when needed in patients with an elevated lactic
acid, altered mental status, or poor urine output
early broad-spectrum antibiotics trageting likely pathogens
source control
Prompt management is key as hospital mortality increases with every 1 hour delay in providing
appropriate antibiotics.
Related Summaries
Sepsis treatment in adults
Sepsis in children
Sepsis treatment in children
Late-onset neonatal sepsis
Glucose control in critical care
Assessment of adequate fluid resuscitation

General Information
Description
severe organ dysfunction caused by dysregulated host response to documented or suspected
infection(3)
Definitions
General information on sepsis definitions
definitions of sepsis changed considerably in 2016 with publication of the Third Consensus Definitions
for Sepsis and Septic Shock (Sepsis-3)(3)
2016and
Overview definitions are based on predictions rule for organ dysfunction and mortality
Recommendations
prior definitions were based on fulfillment of systemic inflammatory response syndrome (SIRS)
criteria
2016 consensus definitions (Sepsis-3)

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)(3)
sepsis - life-threatening organ dysfunction caused by dysregulated host response to infection
oorgan dysfunction - acute change in total Sequential Organ Failure Assessment (SOFA) score ≥ 2
points consequent to infection
assume baseline SOFA score of 0 in patients without known preexisting organ dysfunction
SOFA score ≥ 2 points associated with overall mortality risk of about 10% in general hospital
population with suspected infection
septic shock
sepsis with underlying circulatory and cellular/metabolic abnormalities severe enough to
substantially increase mortality
clinically defined as persistent hypotension requiring vasopressors to maintain mean arterial
pressure (MAP) ≥ 65 mm Hg and serum lactate level ≥ 2 mmol/L (18 mg/dL) despite adequate
volume resuscitation
associated with hospital mortality ≥ 40%
quick SOFA (qSOFA) criteria(3)

may be used at bedside to identify patients with suspected infection likely to have prolonged ICU
stay or to die in hospital
incorporates respiratory rate ≥ 22 per minute, altered mentation, and systolic blood pressure ≤ 100
mm Hg
septic shock definition of hypotension requiring vasopressor therapy and serum lactate ≥ 2 mmol/L
after adequate fluid resuscitation may identify patients with sepsis at highest mortality risk
based on systematic review, Delphi consensus report, and cohort studies
systematic review identified 92 sepsis epidemiology studies
44 studies reported septic shock outcomes in 166,479 patients
septic shock associated crude mortality 46.5% (95% CI 42.7%-50.3%), results limited by
significant heterogeneity
Delphi process with 19 experts discussed systematic review, surveys, and cohort studies below to
reach consensus on variables related to mortality
patients divided into 6 groups based on 3 identified variables (hypotension [mean arterial pressure <
65 mm Hg] after fluids, need for vasopressor therapy, serum lactate level)
hypotension after fluids and vasopressor therapy with serum lactate levels > 2 mmol/L
hypotension after fluids and vasopressor therapy with serum lactate levels ≤ 2 mmol/L
hypotension after fluids and no vasopressors and serum lactate levels > 2 mmol/L
serum lactate levels > 2 mmol/L and no hypotension after fluids and no vasopressors
serum lactate levels between 2-4 mmol/L and no hypotension before fluids and no vasopressors
hypotension after fluids and no vasopressors and serum lactate levels ≤ 2 mmol/L
variables evaluated using patient data from Surviving Sepsis Campaign (SSC), University of
Pittsburgh Medical Center (UPMC) and Kaiser Permanente Northern California (KPNC)
Pittsburgh Medical Center (UPMC), and Kaiser Permanente Northern California (KPNC)
Overviewpatients
and Recommendations
with hypotension after fluids and vasopressor therapy with serum lactate levels > 2
mmol/L had significantly higher mortality (42.3%, 95% CI 41.2%-43.3%) compared to other groups
in risk-adjusted comparisons in analysis of 18,840 patients from the SSC database
similar results in analyses of UPMC and KPNS databases
Reference - JAMA 2016 Feb 23;315(8):775
2003 consensus definitions

DynaMed commentary --
2016 consensus definitions of sepsis and septic shock (Sepsis-3) have replaced the 2003
consensus definitions
updated 2016 definitions and clinical criteria clarify the prior 2003 descriptions and facilitate more
timely recognition and management of patients with sepsis and patients at risk of sepsis
Society of Critical Care Medicine (SCCM), European Society of Intensive Care Medicine (ESICM),
American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and Surgical Infection
Society (SIS) 2001 international Sepsis Definitions Conference
systemic inflammatory response syndrome (SIRS)
≥ 2 of
temperature > 38.3 degrees C (100.9 degrees F) or < 36 degrees C (96.8 degrees F)
heart rate > 90 beats/minute
respiratory rate > 20 breaths/minute or arterial partial pressure of carbon dioxide (PaCO2) < 32
mm Hg
white blood cell count (WBC) > 12,000/mm3 or WBC < 4,000/mm3 or > 10% immature
neutrophils (bands)
above abnormalities should represent change from baseline without other known cause (such as
leukopenia due to chemotherapy)
sepsis - SIRS due to documented or suspected infection

severe sepsis - sepsis plus evidence of acute organ dysfunction or tissue hypoperfusion (any of
below occurring due to infection)
sepsis-induced hypotension defined as 1 of
systolic blood pressure < 90 mm Hg
mean arterial pressure < 70 mm Hg
systolic blood pressure decrease > 40 mm Hg
systolic blood pressure > 2 standard deviations below normal for age in absence of other
causes of hypotension
elevated lactic acid (lactate) level
urine output < 0.5 mL/kg/hour for > 2 hours despite adequate fluid resuscitation
acute lung injury with partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) <
250 in absence of pneumonia
acute lung injury with PaO2/FiO2 < 200 in presence of pneumonia
creatinine > 2 mg/dL (176.8 mcmol/L)
bilirubin > 2 mg/dL (34.2 mcmol/L)

platelet count < 100,000/mcL
p ,
Overviewcoagulopathy (INR > 1.5)
and Recommendations
septic shock - sepsis-induced hypotension after adequate fluid resuscitation
Reference - Crit Care Med 2003 Apr;31(4):1250
strict adherence to SIRS criteria may exclude patients with infection, organ failure, and high mortality
rate
based on retrospective cohort study
109,663 patients with infection and ≥ 1 organ failure from the Australia and New Zealand Intensive
Care Society (ANZICS) Adult Patient Database (APD) from 2000 to 2013 were evaluated
patient data was gathered as part of routine quality-assurance benchmarking
infection-related diagnoses made according to APACHE III at admission
organ failure defined as Sequential Organ Failure Assessment (SOFA) score ≥ 3
87.9% of patients had ≥ 2 criteria for SIRS (defined as SIRS-positive sepsis), while 12.1% had < 2
criteria for SIRS (defined as SIRS-negative sepsis)
in-hospital mortality
24.5% in patients with SIRS-positive sepsis
16.1% in patients with SIRS-negative sepsis (p < 0.001 vs. SIRS-positive sepsis)
in adjusted analysis, mortality increased linearly with each additional SIRS criterion
odds ratio 1.13 (95% CI 1.11-1.15) for each additional criterion
no transitional increase in mortality risk at 2 SIRS criteria
Reference - N Engl J Med 2015 Apr 23;372(17):1629
Epidemiology
Incidence/Prevalence
reported incidence of sepsis(2)
about 2% of all hospitalizations in developed countries
6%-30% in intensive care unit patients
severe sepsis reported in 50-100 per 100,000 persons(2)
United States
6% incidence of sepsis in hospitalized adults in United States between 2009 and 2014
medical records for 2,901,019 adults 20 years or older (median age 62 years, 41% women)
admitted to 1 of 7 United States hospital networks in 2014 evaluated
sepsis diagnosed using Sepsis-3 criteria
6% had sepsis
Reference - JAMA 2017 Oct 3;318(13):1241 full-text, commentary can be found in JAMA 2017 Oct
3;318(13):1228
incidence of sepsis increased from 83 to 240 per 100,000 population in United States between
1979 and 2000

discharge data on about 750 million hospitalizations over 22 years evaluated
Overview10,319,418
and Recommendations
cases of sepsis reported
incidence of sepsis per 100,000 population increased from 82 in 1979 to 240 in 2000
in-hospital mortality decreased from 27.8% to 17.9%
Reference - N Engl J Med 2003 Apr 17;348(16):1546 full-text
sepsis may account for > 34% of in-hospital deaths in United States
based on nationwide cohort study
6,555,621 hospitalized adults in United States in 2010 included
4.3% had diagnosed sepsis and 10.9% had diagnosed or suspected sepsis (infection and acute
organ failure)
total in-hospital mortality 21.9%
proportion of total in-hospital mortality related to sepsis
34.7% for diagnosed sepsis
52% for diagnosed or suspected sepsis
consistent results in additional cohort with 482,828 adults hospitalized in California in 2010-2012
Reference - JAMA 2014 Jul 2;312(1):90
age-adjusted sepsis mortality in United States about 60 per 100,000 persons

based on cohort study
2003-2012 Compressed Mortality File data information on 3,108 contiguous counties in the
United States (excludes Hawaii and Alaska)
age-adjusted rate of death associated with infection 59.6 per 100,000 persons
sepsis mortality highest in Southern United States, particularly Mississippi Valley, Middle Georgia,
and Central Appalachia
Reference - Crit Care Med 2016 Jul;44(7):1380, commentary can be found in Ann Transl Med
2016 Aug;4(15):295
27% of admissions to intensive care units diagnosed with severe sepsis within 24 hours of admission
in England, Wales, and Northern Ireland
343,860 admissions to 172 adult critical care units in England, Wales, and Northern Ireland 1995-
2005 included
27% of admissions to intensive care units diagnosed with severe sepsis within 24 hours of
admission
Reference - Crit Care 2006;10(2):R42 full-text
Likely risk factors

immune system deficiency due to
functional or surgical asplenia
hematologic malignancy
infectious diseases, such as HIV
immunosuppressing drugs, such as high-dose corticosteroids and marrow suppressing

chemotherapy
Reference - BMJ 2007 Oct 27;335(7625):879
presence of malignancy associated with increased risk of sepsis
854 million acute care hospitalizations and 8.9 million patients with cancer from 1979 to 2001
evaluated
1,781,445 cases of sepsis occurred in patients with cancer (mean annual incidence rate 1,465 per
100,000 cancer patients)
cancer associated with increased risk of sepsis (relative risk [RR] 9.77, 95% CI 9.67-9.88)
factors associated with increased risk of sepsis among patients with cancer
African-American race (RR 1.28, 95% CI 1.16-1.4)
other nonwhite races (RR 1.47, 95% CI 1.22-1.72)
male gender (RR 1.17, 95% CI 1.1-1.23)
authors note racial and gender disparities likely related to socioeconomic status and access to care
as similar gaps exist for multiple other chronic medical conditions
Reference - Chest 2006 Jun;129(6):1432
Possible risk factors

genetic conditions conferring susceptibility may include
interleukin 1b-511 homozygosity
mannose binding lectin deficiency
terminal complement component deficiency
agammaglobulinemia
conditions associated with defects in phagocytosis or leukocyte trafficking
chronic granulomatous disease
myeloperoxidase deficiency
Chediak-Higashi syndrome
lazy leukocyte syndrome
leukocyte adhesion molecule deficiency
Job syndrome (hyper immunoglobulin E [IgE] syndrome)
Etiology and Pathogenesis

Causes
infection with bacteria, fungus, virus, or parasites(1, 2)
gram-positive and gram-negative bacteria responsible for majority of sepsis cases
184 adults (mean age 55 years, 63% men) presenting to emergency department with suspected
sepsis syndrome between 2010 and 2011 included
65% had cause of sepsis isolated, for which
51.6% had gram-positive bacteria

46 7% had gram negative bacteria
46.7% had gram-negative bacteria
Overview1.6%
andhad
Recommendations
fungi
Reference - J Intensive Care Med 2017 May;32(4):264
gram-positive bacteria responsible for majority of sepsis cases, and incidence of cases caused by
gram-positive bacteria and fungal organisms appears to be increasing
10,319,418 cases of sepsis reported
cases of sepsis in 2000
gram-positive bacteria in 52.1%
gram-negative bacteria in 37.6%
polymicrobial infection in 4.7%
anaerobes in 1%
fungi in 4.6%
between 1979 and 2000
incidence of gram-positive infection increased by 26.3% per year
number of cases caused by fungal organisms increased by 20.7%
Pathogenesis
pathogen stimulates host defense cells, resulting in systemic inflammation and activation of pro-
inflammatory mediators, ultimately leading to tissue damage
primary source of infection most commonly lung, abdomen, or urinary tract
exact pathogenesis unknown; factors involved may include
surge of pro-inflammatory cytokines
delayed apoptosis of neutrophils
decline in lymphocytes due to apoptosis
dysfunction of coagulation and inappropriate deposition of intravascular fibrin
Reference - Annu Rev Pathol 2011;6:19
pro-inflammatory mediators reported to be involved in sepsis include

tumor necrosis factor-alpha (TNF-alpha)
interleukins
macrophage migration inhibitory factor (MIF)
soluble triggering receptor expressed on myeloid cells (sTREM-1)
high mobility group box protein (HMGB-1)
platelet-activating factor (PAF)
prostaglandins
leukotrienes
thromboxane
tissue factor
; ( )
Overview
critical and Recommendations
illness associated with elevated cortisol and decreased corticotropin levels in adults
based on case-control study
47 critically ill adults were compared with 12 matched controls
daily morning blood samples were collected for 7 days
comparing cases vs. controls
mean cortisol level 16.8 mcg/dL (464 nmol/L) vs 11.9 mcg/dL (328 nmol/L) (p = 0.01)
mean corticotropin level 16.9 pg/mL (4 pmol/L) vs. 49.6 pg/mL (11 pmol/L) (p < 0.001)
History and Physical

Clinical presentation
clinical presentation highly variable and may include
fever(1)
hypothermia(1)
tachypnea(1)
altered mental status(1)
cold or clammy skin (Am Fam Physician 2013 Jul 1;88(1):44)
poor capillary refill time (Am Fam Physician 2013 Jul 1;88(1):44)
heart murmur (Am Fam Physician 2013 Jul 1;88(1):44)
signs of inflammation(1)
fever > 38.3 degrees C (100.9 degrees F) or hypothermia with core temperature < 36 degrees C (96.8
degrees F)
temperature abnormalities, including fever, may not be present in all patients
fever > 41.1 degrees C (106 degrees F) more likely result of noninfectious cause
Reference - Lancet Infect Dis 2002 Mar;2(3):137
tachycardia with heart rate > 90 beats/minute or > 2 standard deviations above normal value for age
significant edema or positive fluid balance (> 20 mL/kg over 24 hours)
signs of end-organ hypoperfusion(4)
hypotension
systolic blood pressure decrease > 40 mm Hg in adults
systolic blood pressure > 2 standard deviations below normal value for age
tachypnea
without hypoxia - consider compensatory respiratory alkalosis for metabolic acidosis (lactic
acidosis)
with hypoxia - consider pneumonia with acute lung injury/acute respiratory distress syndrome
(ALI/ARDS) or pulmonary edema or pulmonary embolism
tachyarrhythmias (such as atrial fibrillation with rapid ventricular response [RVR]) can contribute to
hypotension
decreased urine output (< 0.5 mL/kg/hour)
mottling of the skin or decreased capillary refill (> 2 seconds)
altered mental status
additional physical findings vary with source of infection and may include
meningismus or abnormal cranial nerve exam if bacterial meningitis
increased work of breathing, basilar crackles, or dullness to percussion if pneumonia
abdominal tenderness, guarding, rebound tenderness, or ascites if bacterial peritonitis
cardiac murmur, splinter hemorrhages, Osler nodes, Janeway lesions, or Roth spots if infective
endocarditis
assess and control possible sources of infection, such as indwelling catheter or other implanted
devices(4)
Diagnosis
Making the diagnosis
evaluate patients for symptoms or signs of sepsis or septic shock(1, 4)
documented or suspected infection
some of the following
general parameters
fever with core temperature > 38.3 degrees C (100.9 degrees F)
hypothermia with core temperature < 36 degrees C (96.8 degrees F)
heart rate > 90 beats/minute or > 2 standard deviations above normal value for age
tachypnea > 30 breaths/minute
significant edema or positive fluid balance (> 20 mL/kg over 24 hours)
hyperglycemia (plasma glucose > 110 mg/dL [7.7 mmol/L]) in absence of diabetes
inflammatory parameters
leukocytosis with white blood cell count > 12,000/mm3
leukopenia with white blood cell count < 4,000/mm3
normal white blood cell count with > 10% immature forms
plasma C-reactive protein > 2 standard deviations above normal value
plasma procalcitonin > 2 standard deviations above normal value
hemodynamic parameters
arterial hypotension
systolic blood pressure decrease > 40 mm Hg in adults or > 2 standard deviations below
normal value for age
mixed venous oxygen saturation > 70% once patient has been fluid repleted back to euvolemia
cardiac index > 3 5 L/minute/m2 (except in children for whom values are normally 3 5-5
cardiac index > 3.5 L/minute/m (except in children for whom values are normally 3.5 5
2
L/minute/m
Overview and )
Recommendations
organ dysfunction parameters
arterial hypoxemia (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FIO2] <
300)
acute oliguria (urine output < 0.5 mL/kg/hour or 45 mmol/L for at least 2 hours)
creatinine increase ≥ 0.5 mg/dL (44.2 mcmol/L)
coagulation abnormalities (INR > 1.5 or activated partial thromboplastin time [aPTT] > 60
seconds)
ileus (absent bowel sounds)
thrombocytopenia (platelet count < 100,000/mm3)
hyperbilirubinemia (total bilirubin > 4 mg/dL [70 mmol/L])
tissue perfusion parameters
lactate level > 1 mmol/L (1 mEq/L)
decreased capillary refill or mottling
2016 consensus definitions of sepsis use clinical criteria to make diagnosis(3)

sepsis - life-threatening organ dysfunction caused by dysregulated host response to infection
organ dysfunction - acute change in total Sequential Organ Failure Assessment (SOFA) score ≥ 2
points consequent to infection
assume baseline SOFA score of 0 in patients without known preexisting organ dysfunction
SOFA score ≥ 2 points associated with overall mortality risk of about 10% in general hospital
population with suspected infection
septic shock
sepsis with underlying circulatory and cellular/metabolic abnormalities severe enough to
substantially increase mortality
clinically defined as persistent hypotension requiring vasopressors to maintain mean arterial
pressure (MAP) ≥ 65 mm Hg and serum lactate level ≥ 2 mmol/L (18 mg/dL) despite adequate
volume resuscitation
associated with hospital mortality ≥ 40%
quick SOFA (qSOFA) criteria

may be used at beside to identify patients with suspected infection likely to have prolonged ICU
stay or die in hospital
incorporates respiratory rate ≥ 22 per minute, altered mentation, and systolic blood pressure ≤ 100
mm Hg
Differential diagnosis
over half of all febrile episodes in intensive care unit (ICU) may be due to noninfectious causes (Lancet
Infect Dis 2002 Mar;2(3):137)
differential diagnosis of systemic inflammatory response includes(2)
multiple trauma
full-thickness burn
acute pancreatitis
p
drugand
Overview reactions
Recommendations
other causes of hypotension
hypovolemic shock
cardiogenic shock including pericardial tamponade
neurogenic shock
noninfectious distributive shock
adrenocortical insufficiency
anaphylactic shock
propofol infusion syndrome reported to present as hypotension in 30% of 153 patients having
propofol infusion in systematic review of case series (Crit Care 2015 Nov 12;19:398)
Testing overview
routine blood tests such as
complete blood count with differential
comprehensive metabolic panel (electrolytes, glucose, liver function tests, albumin)
serum lactate
arterial blood gas (particularly in patients with hypoxia)
2 sets of blood cultures (if indwelling line (s) present and line infection suspected obtain peripheral
cultures as well as cultures from all lines)
coagulation studies
amylase and lipase
urinalysis and urine culture (once available)
sputum Gram stain and culture in those with productive cough
microbiologic cultures
Surviving Sepsis Campaign recommends performing routine cultures (including blood cultures)
obtained before starting antibiotics as long as sample collection does not substantially delay
antibiotics (SCCM Best practice statement ), including(4)
≥ 2 sets of blood cultures (both aerobic and anaerobic bottles)
≥ 1 blood culture should be percutaneously (or peripherally) drawn
1 blood culture from each vascular access device in place for > 48 hours
other sites as clinically indicated, such as urine, cerebrospinal fluid, wounds, respiratory
secretions, and other body fluids
paired quantitative blood culture may be most accurate test for diagnosis of intravascular device-
related bloodstream infection (level 2 [mid-level] evidence)
differential time to positive blood cultures > 2 hours between simultaneous catheter and peripheral
blood cultures may predict catheter-related sepsis (level 2 [mid-level] evidence)
quick sequential (sepsis-related) organ failure assessment (qSOFA) has lower sensitivity but higher
specificity than systemic inflammatory response syndrome (SIRS) criteria for predicting in-hospital
mortality in patients with suspected infection evaluated by rapid response team for acute deterioration
(level 1 [likely reliable] evidence)
Clinical prediction rules

i k ti l ( i l t d) f il t ( SOFA) h l iti it b t hi h
quick sequential (sepsis-related) organ failure assessment (qSOFA) has lower sensitivity but higher
Overview andthan
specificity Recommendations
systemic inflammatory response syndrome (SIRS) criteria for predicting in-hospital
mortality in patients with suspected infection evaluated by rapid response team for acute
deterioration (level 1 [likely reliable] evidence)
based on validation cohort study
1,708 hospitalized patients (mean age 68 years) with suspected infection and acute deterioration
were evaluated by rapid response teams
26.9% met qSOFA criteria for high risk, defined as ≥ 2 of
respiratory rate ≥ 22 per minute
altered mental status (Glasgow coma scale < 15)
systolic blood pressure ≤ 100 mm Hg
81.4% met SIRS criteria for sepsis
overall in-hospital mortality was 33.4%
for prediction of in-hospital mortality
high risk classification by qSOFA criteria had
sensitivity 64.9% (p < 0.05 vs. SIRS criteria)
specificity 92.2% (p < 0.05 vs. SIRS criteria)
positive predictive value 80.6%
negative predictive value 84%
sepsis by SIRS criteria had
sensitivity 91.6%
specificity 23.6%
positive predictive value 37.5%
negative predictive value 84.9%
Reference - Chest 2018 Aug;154(2):309

qSOFA has lower sensitivity but higher specificity for sepsis by 2016 definition compared to SIRS
criteria in patients presenting to emergency department with suspected infection (level 1 [likely
reliable] evidence)
8,871 adults presenting to emergency department with suspected infection were assessed for
sepsis by Sepsis-3 (2016 definition) and Sepsis-2 (2003 definition) using quick Sequential Organ
Failure Assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria
sepsis defined as
acute organ dysfunction (increase in SOFA score ≥ 2) caused by infection in Sepsis-3
≥ 2 SIRS criteria due to confirmed or suspected infection in Sepsis-2
acute organ dysfunction in

24.4% by Sepsis-3
17.3% by Sepsis-2 (SOFA score increase ≥ 2 in discrete organ system)
47.1% had ≥ 2 SIRS criteria
for prediction of Sepsis-3 defined organ dysfunction

qSOFA score ≥ 2 had sensitivity 29 9% and specificity 96 1%
qSOFA score ≥ 2 had sensitivity 29.9% and specificity 96.1%
Overview≥and Recommendations
2 SIRS criteria had sensitivity 72.3% and specificity 61.1%
SIRS and qSOFA both had moderate discrimination for predicting organ dysfunction by Sepsis-3
definition (c-statistic 0.72 vs. 0.73)
for prediction of 30-day mortality
qSOFA score ≥ 2 had sensitivity 50.2% and specificity 91.3%
≥ 2 SIRS criteria had sensitivity 77.4% and specificity 54.1%
patients meeting both Sepsis-2 and Sepsis-3 organ dysfunction criteria had slightly higher 30-day
mortality compared to patients meeting only Sepsis-3 criteria, but no significant differences in 1-year
mortality
Reference - Chest 2017 Mar;151(3):586
qSOFA appears to have lower sensitivity but higher specificity than SIRS criteria for predicting
mortality in adults with suspected infection (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 38 cohort studies evaluating quick Sequential Organ Failure Assessment
(qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria for predicting mortality
(in-hospital, 28-day, or 30-day) in 385,333 adults admitted to emergency departments, hospital
wards, or intensive care units for suspected infection
20 studies evaluated both qSOFA and SIRS criteria
studies varied in patient population and definition of suspected infection
pooled performance for predicting mortality
qSOFA in analysis of all studies had
sensitivity 60.8% (95% CI 51.4%-69.4%)
specificity 72% (95% CI 63.4%-79.2%)
positive likelihood ratio 2.17 (95% I 1.82-2.58)
negative likelihood ratio 0.55 (95% CI 0.47-0.63)
SIRS criteria in analysis of 20 studies with 352,571 patients had
sensitivity 88.1% (95% CI 82.3%-91.1%)
specificity 25.8% (95% CI 17.1%-36.9%)
positive likelihood ratio 1.19 (95% CI 1.09-1.29)
negative likelihood ratio 0.46 (95% CI 0.39-0.54)
for predicting mortality in patients in intensive care unit, qSOFA had pooled sensitivity 87.2% (95% CI
75.8%-93.7%) and pooled specificity 33.3% (95% CI 23.8%-44.4%) in analysis of 8 studies with
203,229 patients
Reference - Ann Intern Med 2018 Feb 20;168(4):266, editorial can be found in Ann Intern Med 2018
Feb 20;168(4):293
qSOFA and LODS scores appear to have higher predictive performance for in-hospital mortality in
patients outside of the ICU compared to SOFA and SIRS criteria, while SOFA and LODS scores appear
to have highest performance for patients in the ICU (level 2 [mid-level] evidence)
based on diagnostic cohort study
148,907 patients with suspected infection (89% in intensive care units [ICU]s) evaluated between
2010 and 2012 at 12 hospitals in United States
Overview74,453 patients included in derivation cohort
and Recommendations
74,454 patients included in validation cohort
overall hospital mortality 4.3% in derivation and validation cohorts
quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score derived using factors
significantly associated with mortality in derivation cohort (total score 0-3 points, with 1 point each
for systolic hypotension [≤ 100 mm Hg], tachypnea [≥ 22 per minute), or altered mentation)
qSOFA score compared to 3 other clinical criteria (Sequential Organ Failure Assessment [SOFA],
systemic inflammatory response syndrome [SIRS] criteria, and Logistic Organ Dysfunction System
[LODS]) using validation cohort
for predicting in-hospital mortality in patients in the ICU
qSOFA associated with lower predictive validity (c-statistic 0.66) compared to SOFA (c-statistic
0.74, p < 0.001) or LODS (c-statistic 0.75, p < 0.001)
qSOFA associated with higher predictive validity (c-statistic 0.66) compared to SIRS criteria (c-
statistic 0.64, p = 0.01)
SIRS associated with lower predictive validity compared to SOFA or LODS (p < 0.001 for both)
SOFA associated with similar predictive validity compared to LODS
for predicting in-hospital mortality in patients not in the ICU
qSOFA associated with similar predictive validity (c-statistic 0.81) compared to LODS (c-statistic
0.81, no significant difference)
qSOFA associated with higher predictive validity (c-statistic 0.81) compared to SOFA (c-statistic
0.79, p < 0.001) or SIRS (c-statistic 0.76, p < 0.001)
SOFA associated with higher predictive validity than SIRS (p < 0.001)
qSOFA associated with similar performance in 4 outside data sets with 706,399 patients evaluated in
and out of hospitals
Reference - JAMA 2016 Feb 23;315(8):762, correction can be found in JAMA 2016 May
24;315(20):2237
predicting mortality in patients admitted to intensive care unit

SOFA score had higher discrimination for in-hospital mortality than qSOFA score or SIRS criteria in
patients admitted to intensive care with infection-related diagnoses (level 1 [likely reliable]
evidence)
184,875 adults (mean age 63 years, 55% male) admitted to ICU with infection-related diagnosis
from Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database were
assessed
most common diagnosis was bacterial pneumonia (17.7%)
18.7% died in hospital and 55.7% died in hospital or had ICU stay ≥ 3 days
baseline SOFA score of 0 was assumed for all patients
patients were assessed using different sepsis definitions
90.1% had increase in SOFA score ≥ 2
54.4% had qSOFA score ≥ 2
86.7% had ≥ 2 SIRS criteria
20.2% with SOFA score ≥ 2 vs. 4.4% with SOFA score < 2 (p < 0.001)
22 8% with qSOFA score ≥ 2 vs 13 6% with qSOFA score < 2 (p < 0 001)
22.8% with qSOFA score ≥ 2 vs. 13.6% with qSOFA score < 2 (p < 0.001)
19.9% with ≥ 2 SIRS criteria vs. 9.8% with < 2 SIRS criteria (p < 0.001)
performance of sepsis definitions for prediction of in-hospital mortality

SOFA had moderate discrimination (c-statistic 0.75) (p < 0.001 vs. qSOFA or SIRS)
qSOFA had modest discrimination (c-statistic 0.61)
SIRS criteria had modest discrimination (c-statistic 0.59)
consistent results for prediction of in-hospital mortality or ICU stay ≥ 3 days

Reference - JAMA 2017 Jan 17;317(3):290, editorial can be found in JAMA 2017 Jan
17;317(3):267
predicting mortality in patients presenting to emergency department

qSOFA may have lower sensitivity but higher specificity for predicting in-hospital mortality
compared to SIRS criteria in patients with confirmed or suspected infection outside ICU (level 2
[mid-level] evidence)
based on systematic review limited by heterogeneity
systematic review of 23 prognostic cohort studies evaluating SIRS criteria and/or qSOFA for
predicting unfavorable outcomes in 146,551 patients with suspected or confirmed infection
outside ICU
most studies enrolled patients in emergency department or general hospital ward
positive score according to qSOFA and SIRS criteria defined as ≥ 2 points
acute organ dysfunction defined as acute increase in SOFA score > 2 according to Sepsis-3
definitions, or severe sepsis in studies using Sepsis-2
pooled performance for predicting in-hospital mortality, acute organ dysfunction, and ICU
admission
Outcome Predictor Sensitivity Specificity Number of

Studies
(Patients)
In-hospital qSOFA 51% (95% CI 83% (95% CI 20 studies

mortality 39%-62%)* 74%-89%)* (29,709
patients)
Abbreviations: ICU, intensive care unit; qSOFA, quick Sequential Organ Failure
Assessment; SIRS, systemic inflammatory response syndrome.
* Indicates statistically significant heterogeneity.

Overview andOutcome
Recommendations
Predictor Sensitivity Specificity Number of
Studies
(Patients)
SIRS criteria 86% (95% CI 29% (95% CI 11 studies
79%-92%)* 17%-45%)* (67,225
patients
Acute organ qSOFA 47% (95% CI 93% (95% CI 9 studies

dysfunction 28%-66%)* 88%-97%)* (2,936
patients)

71%-91%)* 29%-69%)* (5,047
patients)
ICU qSOFA 53% (95% CI 75% (95% CI 10 studies

admission 52%-54%)* 75%-76%)* (14,384
patients)

90%-92%) 13%-14%)* (27,759
patients)
Assessment; SIRS, systemic inflammatory response syndrome.
* Indicates statistically significant heterogeneity.
Reference - Crit Care 2018 Feb 6;22(1):28 full-text

qSOFA has similar performance as SOFA and better performance than SIRS and severe sepsis
criteria for predicting in-hospital mortality in patients with suspected infection in emergency
department (level 1 [likely reliable] evidence)
879 adults (median age 67 years, 53% male) presenting to 30 emergency departments with
clinically suspected infection were followed until hospital discharge or death
43% had respiratory tract infection
patients were assessed using different sepsis definitions
25% had qSOFA score ≥ 2
34% had SOFA score ≥ 2
74% had ≥ 2 SIRS criteria
20% fulfilled previous criteria for severe sepsis (≥ 2 SIRS elements plus blood lactate > 2
mmol/L)
Overviewin-hospital
and Recommendations
mortality
8% overall
3% in patients with qSOFA score < 2
24% in patients with qSOFA score ≥ 2 (p < 0.05 vs. qSOFA score < 2)
performance of sepsis definitions for prediction of in-hospital death
Predictor Sensitivity Specificity PPV NPV c-

statistic
qSOFA 70% 79% 24% 97% 0.8
SOFA 73% 70% 18% 97% 0.77
SIRS criteria 93% 27% 11% 98% 0.65
Previous 47% 82% 20% 94% 0.65

severe
sepsis
criteria
Abbreviations: NPV, negative predictive value; PPV, positive predictive value;

qSOFA, quick Sequential Organ Failure Assessment; SIRS, systemic
inflammatory response syndrome; SOFA, Sequential Organ Failure
Assessment.
qSOFA > 2 associated with increased risk of in-hospital mortality compared to score < 2 (adjusted
hazard ratio 6.2, 95% CI 3.8-10.3)
previous criteria for severe sepsis associated lower risk of in-hospital mortality (adjusted HR 3.5,
95% CI 2.2-5.5), showing poorer risk stratification
Reference - JAMA 2017 Jan 17;317(3):301, editorial can be found in JAMA 2017 Jan
17;317(3):267
qSOFA score may stratify risk of inpatient death and ICU admission in adults presenting to
emergency department (level 2 [mid-level] evidence)
based on retrospective validation cohort study with potential selection bias
22,530 adults (mean age 54 years) presenting to emergency department with simultaneous
reporting of vital signs and Modified Early Warning System score and not triaged to dentistry,
psychiatry, or labor and delivery were assessed by qSOFA score
patients were excluded due to lack of Modified Early Warning System score or independent
documentation of vital signs (44,945 otherwise eligible patients) and these excluded patients
were younger, had lower rates of hospital and ICU admission, and had lower in-hospital mortality
compared to included patients
45% were admitted to hospital and 7% were admitted to ICU

in-hospital mortality 1.6%
p y
Overview18%
andreceived IV antibiotics and were classified as having suspected infection
Recommendations
rates of death, ICU admission, and hospital admission in all patients stratified by qSOFA score
qSOFA Score Number of Inpatient ICU Hospital

Patients Death Rate Admission Admission
Rate Rate
0 16,507 0.6% 5.1% 38%
1 5,290 2.8% 10.5% 59%
2 649 12.8% 20.8% 84%
3 84 25% 27.4% 93%
Assessment.
qSOFA had moderate discrimination for prediction of in-hospital death in patients with suspected
infection (c-statistic 0.75) and in patients without suspected infection (c-statistic 0.7)
performance of qSOFA to predict mortality at cutoff ≥ 1 had sensitivity 71%, specificity 74%, and
Reference - Ann Emerg Med 2017 Apr;69(4):475
Blood tests
Overview of tests and general findings
blood tests routinely performed include(1)
complete blood count with differential
comprehensive metabolic panel (electrolytes, glucose, liver function tests, albumin)
serum lactate
arterial blood gas (particularly in patients with hypoxia)
2 sets of blood cultures (if indwelling line (s) present and line infection suspected obtain peripheral
cultures as well as cultures from all lines
coagulation studies
amylase and lipase
urinalysis and urine culture (once available)
sputum Gram stain and culture in those with productive cough
procalcitonin and plasma C-reactive protein (CRP) may also be considered(4)
general findings may include(1)
evidence of inflammation
3
l k h h bl d ll /
leukocytosis with white blood cell count > 12,000/mm3
Overviewleukopenia
and Recommendations
with white blood cell count < 4,000/mm3
normal white blood cell count with > 10% immature forms
plasma CRP > 2 standard deviations above normal value
plasma procalcitonin > 2 standard deviations above normal value (use of this assay is
investigational)
hyperglycemia (plasma glucose > 110 mg/dL or 7.7 mmol/L) in the absence of diabetes
serum lactate > 1 mmol/L (9 mg/dL)
beta-blocker use associated with lower initial blood lactate levels in patients with severe sepsis
or septic shock, despite similar disease severity and mortality in these patients
260 adults with severe sepsis or septic shock were evaluated
25% had previous beta-blocker therapy
comparing patients with history of beta-blocker therapy vs. patients without history of beta-
blockers
initial blood lactate levels 3.9 mmol/L vs. 5.6 mmol/L in patients (p = 0.0006, significance
remained after adjusting for mortality, Predisposition Insult Response of Organ failure
score, and source of infection)
mean Sequential Organ Failure Assessment (SOFA) score 5 vs. 5.3 (not significant)
28-day mortality 35% vs. 49% (p = 0.08)
Reference - Crit Care Med 2015 Dec;43(12):2616
organ dysfunction parameters

arterial hypoxemia (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FIO2] <
300)
creatinine increase ≥ 0.5 mg/dL (44.2 mcmol/L)
coagulation abnormalities (INR > 1.5 or activated partial thromboplastin time [aPTT] > 60
seconds)
thrombocytopenia (platelet count < 100,000/mm3)
hyperbilirubinemia (total bilirubin > 4 mg/dL [70 mmol/L])
Blood cultures
paired quantitative blood cultures may be most accurate method of diagnosing intravascular device-
related bloodstream infection (level 2 [mid-level] evidence)
based on systematic review limited by heterogeneity
systematic review of 51 studies assessing 8 methods for diagnosing intravascular device-related
bloodstream infection
reference standard was catheter segment culture or blood culture
overall sensitivity and specificity for 8 methods of diagnosis (significant heterogeneity present in all
analyses of sensitivity)
paired quantitative blood culture had sensitivity 87% (95% CI 83%-91%), specificity 98% (95% CI
97%-99%) in analysis of 10 studies
intravascular device-drawn quantitative blood culture had sensitivity 77% (95% CI 69%-85%),
specificity 90% (95% CI 88%-92%) in analysis of 7 studies
quantitative catheter segment culture had sensitivity 83% (95% CI 78%-88%), specificity 87% (95%
CI 85%-89%) in analysis of 14 studies
acridine orange leukocyte cytospin had sensitivity 72% (95% CI 60%-84%), specificity 91% (95% CI
intravascular device-drawn qualitative blood culture had sensitivity 87% (95% CI 80%-94%),
specificity 83% (95% CI 78%-88%) in analysis of 7 studies
semiquantitative catheter segment culture had sensitivity 85% (95% CI 81%-89%), specificity 82%
(95% CI 80%-84%) in analysis of 19 studies
differential time to positivity had sensitivity 85% (95% CI 78%-92%), specificity 81% (95% CI
qualitative catheter segment culture had sensitivity 72% (95% CI 66%-78%), specificity 90% (95%
CI 83%-97%) in analysis of 6 studies
Reference - Ann Intern Med 2005 Mar 15;142(6):451, correction can be found in Ann Intern Med 2005
May 3;142(9):803, commentary can be found in ACP J Club 2005 Nov-Dec;143(3):77
differential time to positive blood cultures > 2 hours between simultaneous catheter and peripheral
blood cultures may predict catheter-related sepsis (level 2 [mid-level] evidence)
64 cancer patients with same microorganisms cultured from simultaneous central and peripheral
blood samples were evaluated
catheter-related sepsis considered established in 28, ruled out in 14, and indeterminate in 22
central sample time to positivity > 2 hours earlier than peripheral sample positivity had sensitivity
96.4% and specificity 100% for diagnosis of catheter-related sepsis
Reference - J Clin Microbiol 1998 Jan;36(1):105 full-text
systematic review of 16 diagnostic studies evaluating rapid molecular and phenotypic techniques using
positive blood cultures can be found in Clin Microbiol Rev 2016 Jan;29(1):59 full-text
PhenoTest BC Kit FDA approved to rapidly identify organisms that cause bloodstream infections and to
provide antibiotic sensitivity information on 18 selected antibiotics for subset of identified organisms
FDA Press Release 2017 Feb 23
Biomarkers
biomarkers (1,3 beta-D-glucan, galactomannan, procalcitonin) may be used to support and supplement
clinical assessment(4)
1,3 beta-D-glucan assay
administration of > 30 g albumin within 2 days of 1,3-beta-D-glucan assay may increase rate of
false-positives (level 2 [mid-level] evidence)
based on retrospective cohort study without validation
267 patients (mean age 61.5 years) in intensive care unit at risk for developing invasive
candidiasis were assessed using serum 1,3-beta-D-glucan levels and blood cultures (reference
standard)
receiver operating characteristic curves identified optimal cutoff value of 1,3-beta-D-glucan 95.9
pg/mL, which had
sensitivity 82.9%
specificity 56.7%
administration of > 30 g of albumin within 2 days of 1,3-beta-D-glucan assay associated with

increased false-positive results (p < 0.05)
azole use, IV immunoglobulin, and red blood cell infusion had no significant effect on 1,3-beta-D-
glucan assay results
Reference - Eur J Clin Microbiol Infect Dis 2015 Feb;34(2):357
DynaMed commentary -- authors state that false-positives may occur due to use of cellulose filters
during albumin production; IV immunoglobulin may undergo same type of production but rate of
false-positive not shown to be statistically significant (p = 0.083)
procalcitonin
procalcitonin may aid in diagnosis of sepsis, but diagnostic accuracy of the assay varies widely
between studies (level 2 [mid-level] evidence)
based on systematic review with heterogeneity
systematic review of 30 studies evaluating diagnostic accuracy of procalcitonin for sepsis in
3,244 patients with systemic inflammatory response syndrome (SIRS)
overall prevalence of sepsis 57%
20% had severe sepsis
38% had septic shock
in analysis of all 30 studies
pooled sensitivity 77% (95% CI 72%-81%)
pooled specificity 79% (95% CI 74%-84%)
results limited by heterogeneity
subgroup analyses evaluating patients according to population, admission category, disease
severity, procalcitonin assay, or reference standard could not account for heterogeneity
Reference - Lancet Infect Dis 2013 May;13(5):426
procalcitonin may not differentiate sepsis from noninfectious causes of systemic inflammatory
response syndrome in critically ill adults (level 2 [mid-level] evidence)
based on systematic review with publication bias
systematic review of 18 studies of diagnostic accuracy of procalcitonin for sepsis with well-
defined reference standards and microbiologic culture confirmation including 2,097 patients
only 8 studies had diagnosis of sepsis/SIRS independent of result of procalcitonin test
prevalence of sepsis ranged from 31% to 88%
sensitivity of procalcitonin ranged from 55% to 97%
specificity of procalcitonin ranged from 48% to 93%
meta-analysis of 14 phase 2 studies with 1,602 patients
pooled positive likelihood ratio 3.03 (95% CI 2.51-3.65)
pooled negative likelihood ratio 0.43 (95% CI 0.37-0.48)
pooled diagnostic odds ratio 7.79 (95% CI 5.86-10.35)
1 study accounted for most of heterogeneity
meta-analysis of 4 phase 3 studies with 495 patients not possible due to high degree of
heterogeneity
Reference - Lancet Infect Dis 2007 Mar;7(3):210, commentary can be found in Lancet Infect Dis
2007 Aug;7(8):498
procalcitonin may be better than C-reactive protein as diagnostic test for sepsis (level 3 [lacking
direct] evidence)
Overviewbased on indirect comparisons in systematic review
and Recommendations
systematic review of 33 studies evaluating procalcitonin or CRP levels for diagnosis of infection
complicated by systemic inflammation in adults in critical care or after surgery or trauma
procalcitonin had global odds ratio 15.7 (95% CI 9.1-27.1) in meta-analysis of 25 studies with
2,966 patients
CRP had global odds ratio 5.4 (95% CI 3.2-9.2) in meta-analysis of 15 studies with 1,322 patients
Reference - Crit Care Med 2006 Jul;34(7):1996, commentary can be found in Crit Care Med 2007
Feb;35(2):679
Treatment
Treatment overview
approach to sepsis treatment in adults
rapid delivery of care and frequent patient assessment are critical to improving outcomes in patients
with sepsis
immediate management (first 10-15 minutes)
assess for septic shock in patients with systemic inflammatory response syndrome (SIRS)
systolic blood pressure < 90 mm Hg, mean arterial pressure (MAP) < 65 mm Hg
end-organ hypoperfusion
tachypnea
without hypoxia - consider compensatory respiratory alkalosis for metabolic acidosis
(lactic acidosis)
with hypoxia - consider pneumonia with acute lung injury/acute respiratory distress
syndrome (ALI/ARDS) or pulmonary edema or pulmonary embolism
tachycardia
decreased urine output (UOP) (< 0.5 mL/kg/hour)
slow capillary refill (> 2 seconds)
obtain diagnostic testing to identify organ hypoperfusion and potential source of infection at time
of exam
blood tests
complete blood count with differential, comprehensive metabolic panel, amylase and lipase,
lactate, coagulation studies, and arterial blood gas (ABG) if developing hypoxia
blood cultures (≥ 2 sets) before antibiotics providing this does not delay start substantially
(SCCM Best practice statement)
urinalysis and urine culture
sputum Gram stain and culture if concern for pneumonia
see Sepsis in adults for details

early management (initiate within 1 hour of presentation)
initiate resuscitation and treatment immediately (SCCM Best practice statement)

f l f d dh f ll d /k h
for initial resuscitation of sepsis-induced hypoperfusion, give IV crystalloid ≥ 30 mL/kg within
Overview and
firstRecommendations
3 hours (1 L is about 15 mL/kg for 70-kg [154.3 lbs] patient) (SCCM Strong
recommendation, Low-quality evidence)
consider tailoring crystalloid choice to aid in correction of electrolyte imbalances once known
consider trial of albumin in cirrhotic patients with hypoalbuminemia (World J Hepatol 2016
Mar 8;8(7):345)
assess fluid responsiveness at bedside based on serial
physical findings
static variables, such as blood pressure and heart rate
dynamic variables, such as
central venous pressure (CVP)
arterial wave form
inferior vena cava (IVC) diameter variation
pulse pressure variation
stroke volume variation
response to passive leg raising
in volume responsive patients, repeat IV fluid boluses if hypotension recurs or lactate is

elevated
see also Assessment of adequate fluid resuscitation
initiate broad-spectrum antibiotics as soon as possible (SCCM Strong recommendation,

Moderate-quality evidence)
ensure antibiotics are given within 1 hour of development of hypotension
starting antibiotics within 1 hour associated with lower mortality in patients with severe
sepsis or septic shock (level 2 [mid-level] evidence)
each hour of delay of antimicrobial therapy after onset of hypotension in septic shock
associated with increased mortality (level 2 [mid-level] evidence)
antibiotic selection should be based on presumed source, patient's prior microbiology data,
and local resistance patterns
designate order in which antibiotics should be given (typically agents with activity against
gram-negative organisms given first); if strong suspicion of fungemia, start appropriate
antifungal therapy
plan for source control (for example, if intravascular catheter/access device is a potential
source, remove promptly)
consider prompt imaging confirm a potential source of infection
resuscitation phase (first 6 hours)

continue volume resuscitation if hypotension or tissue hypoperfusion persists despite initial
resuscitation efforts
continued fluid resuscitation should be guided by frequent reassessment of hemodynamic
status (SCCM Best practice statement) including
clinical examination
physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate,
temperature, urine output)
other invasive and noninvasive monitoring as available (such as changes in serum lactate
over time in response to fluid resuscitation)
dynamic variables suggested over static variables for prediction of fluid responsiveness
(SCCM Weak recommendation, Low-quality evidence)
further hemodynamic assessment (such as cardiac function monitoring) recommended to
determine type of shock if diagnosis is not clear after clinical assessment (SCCM Best
practice statement)
target mean arterial pressure of 65 mm Hg in patients with septic shock requiring
vasopressors (SCCM Strong recommendation, Moderate-quality evidence)
initiate vasopressor therapy via central access if hypotension or tissue hypoperfusion persists
despite adequate volume resuscitation
norepinephrine is standard first-line pressor for central administration (SCCM Strong
recommendation, Moderate-quality evidence)
consider addition of vasopressin (up to 0.03 units/minute) if norepinephrine requirement is
rising (SCCM Weak recommendation, Moderate-quality evidence)
epinephrine may also be added to vasopressin to raise mean arterial pressure (SCCM Weak
consider dobutamine for ongoing hypoperfusion despite adequate intravascular volume
repletion and vasopressor use (SCCM Weak recommendation, Low-quality evidence), but
reduce or discontinue in case of worsening hypotension or arrhythmia
corticosteroids
corticosteroids suggested if septic shock unresponsive to fluid resuscitation and moderate-to-
high dose vasopressors (SCCM/ESICM Conditional recommendation, Low quality of evidence)
low dose (such as hydrocortisone 400 mg/day IV) and long course(> 3 days) suggested over
high dose and short course(< 3 days) (SCCM/ESICM Conditional recommendation, Low quality
of evidence)
adjunctive care
transfusion if hemoglobin (Hgb) < 7 g/dL (assuming absence of myocardial ischemia, severe
hypoxemia, acute hemorrhage, or ischemic heart disease) (SCCM Strong recommendation, High-
quality evidence)
glucose control with insulin drip to keep serum glucose ≤ 180 mg/dL (10 mmol/L) and ≥ 110
mg/dL (6.1 mmol/L) (SCCM Strong recommendation, High-quality evidence)
for intubated patients, minimize sedation (SCCM Best practice statement) and use weaning
protocol (SCCM Strong recommendation, Moderate-quality evidence)
renal replacement therapy with intermittent hemodialysis or continuous venovenous
hemofiltration (latter may be easier to manage in hemodynamically unstable patients) may be
needed in patients with acute kidney injury (SCCM Weak recommendation, Moderate-quality
evidence)
deep vein thrombosis (DVT) prophylaxis is recommended (SCCM Strong recommendation,
Moderate-quality evidence)
stress ulcer prophylaxis with histamine-2 receptor antagonist or proton pump inhibitor
recommended for patients with risk factors for gastrointestinal bleeding (SCCM Strong
nutrition - initiate enteral nutrition early in patients who can be fed enterally (SCCM Strong
recommendation, Moderate-quality evidence)
Overview andtreatment
see Sepsis Recommendations
in adults for details
Complications and Prognosis

Complications
disseminated intravascular coagulation (DIC) (Annu Rev Pathol 2011;6:19)
acute respiratory distress syndrome (ARDS) (4)
acute renal failure (4)
cardiomyopathy (Curr Cardiol Rev 2011 Aug;7(3):163)
hypoxic hepatitis (ischemic hepatitis or "shock liver") (Liver Int 2012 Aug;32(7):1039)
multiple organ dysfunction/failure(3, 4)
critical illness myopathy and polyneuropathy (Lancet Neurol 2011 Oct;10(10):931)
sepsis-associated encephalopathy (Nat Rev Neurol 2012 Oct;8(10):557)
psychological complications, such as anxiety, depression, or posttraumatic stress disorder (PTSD)
(Minerva Anestesiol 2013 Nov;79(11):1306)
about 15% of sepsis patients admitted to ICU may acquire new infection, most commonly catheter-
related bloodstream infection and pneumonia
based on prospective cohort study
1,504 patients (median age 62 years) with 1,719 intensive care unit (ICU) admissions lasting > 48
hours were evaluated
patients with infection onset from 24 to 48 hours after admission were excluded
334 ICU-acquired infections occurred during 232 admissions (13.5%), with most common infections
catheter-related bloodstream infection (26.3% of infections)
pneumonia (25.4% of infections)
abdominal infection (15.3% of infections)
factors associated with increased risk of ICU-acquired infection in multivariate analysis included
initiation of mechanical ventilation during admission (hazard ratio [HR] 6.22, 95% CI 1.54-25.17)
central venous catheter placement during admission (HR 2.63, 95% CI 1.53-4.53)
Acute Physiology and Chronic Health Evaluation (APACHE) IV score 100-205 (HR 1.86, 95% CI
1.18-2.92)
chronic respiratory insufficiency (HR 1.44, 95% CI 1.05-2.99)
male sex (HR 1.31, 95% CI 1-1.73)
ICU mortality
20.9% overall
35.8% in patients with ICU-acquired infection
15.5% in patients without ICU-acquired infection (p < 0.001 vs. patients who acquired infection)
Reference - JAMA 2016 Apr 12;315(14):1469, editorial can be found in JAMA 2016 Apr
12;315(14):1457
sepsis associated with increased risk of subsequent stroke or myocardial infarction
based on retrospective population-based cohort study

42 316 patients with sepsis from National Health Insurance Research Database in Taiwan included
42,316 patients with sepsis from National Health Insurance Research Database in Taiwan included
Overview and
stroke Recommendations
developed in 831 patients and myocardial infarction developed in 184 patients within 180
days of hospital discharge
compared with matched population controls, sepsis associated with increased risk of stroke or
myocardial infarction in the first week after discharge (hazard ratio [HR] 4.78, 95% CI 3.19-7.17)
Reference - CMAJ 2018 Sep 10;190(36):E1062
adrenal failure common in septic shock
102 patients > 18 years old with septic shock and no previous steroid use were evaluated
23 patients (22.5%) had adrenal failure defined as baseline serum cortisol ≤ 10 mcg/dL (275.9
nmol/L) or increase in serum cortisol of ≤ 9 mcg/dL (248.3 nmol/L) 1 hour after being given
corticotropin 249 mcg
Reference - Crit Care 2006;10(5):R149 full-text
multiple organ failure associated with increased muscle loss in critically ill adults
63 patients (mean age 55 years) in intensive care unit with critical illness (49.2% with sepsis and
25.4% with trauma) were followed up to 10 days
multiple organ failure in 75%
muscle loss assessed by ultrasound of rectus femoris
mean muscle loss at 7 days after intensive care admission 15.7% in patients with multiple organ
failure vs. 3% in patients with single organ failure (p < 0.001)
Reference - JAMA 2013 Oct 16;310(15):1591, correction can be found in JAMA 2014 Jan
12;311(6):625, editorial can be found in JAMA 2013 Oct 16;310(15):1569
Prognosis
Mortality
19% inpatient mortality in adults presenting to emergency department with suspected sepsis
syndrome
184 adults (mean age 55 years, 63% men) presenting to emergency department with suspected
sepsis syndrome between 2010 and 2011 included
19% overall inpatient mortality
Reference - J Intensive Care Med 2017 May;32(4):264
in-hospital mortality 11.7%-19.5% in patients with healthcare-associated sepsis in United States

69 million hospital discharges in United States from 1998 to 2006 evaluated
19.5% in analysis of 108,610 patients with healthcare-associated sepsis following invasive
surgery
11.7%-16% in analysis of 384,640 patients with sepsis classified as healthcare-associated who

did not have invasive surgery
OverviewReference
and Recommendations
- Arch Intern Med 2010 Feb 22;170(4):347, editorial can be found in Arch Intern Med
2010 Feb 22;170(4):353
in-hospital mortality 18.4% in patients with severe sepsis in 2012 in Australia and New Zealand,
down from 35% in 2000
101,064 patients with severe sepsis in intensive care units in Australia and New Zealand from
2000-2012 were analyzed
in-hospital mortality in 12,512 patients with severe sepsis in 2012
18.4% overall
14.2% in patients without septic shock
22% in patients with septic shock
14% in patients without comorbidities (as defined by Acute Physiology and Chronic Health
Evaluation)
26.4% in patients with comorbidities
in 2000, in-hospital mortality was 35% overall in patients with severe sepsis
Reference - JAMA 2014 Apr 2;311(13):1308, editorial can be found in JAMA 2014 Apr
2;311(13):1295
hospital mortality increases with increasing stage of sepsis
3,608 intensive care unit patients in European Sepsis Study categorized as having infection with
or without systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock on
first day of infection
crude overall hospital mortality 40%
mortality by sepsis stage
25.5% in 584 patients with infection without SIRS
25.5% in 1,063 patients with sepsis (infection with SIRS)
40.9% in 827 patients with severe sepsis
60.5% in 1,134 patients with septic shock
Reference - Am J Respir Crit Care Med 2003 Jul 1;168(1):77

DynaMed commentary -- mortality has declined since the time of this study; the 90 day mortality
was estimated at about 45% among hospitalized patients with severe sepsis or septic shock
between 2008 and 2013 (Crit Care Med 2017 Feb;45(2):241)
sepsis associated with increased late mortality

3,029 adults ≥ 65 years old in the United States Health and Retirement Study between 1998 and 2008
were evaluated for late mortality (mortality between 31 days and 2 years)
960 patients hospitalized with sepsis
777 adults not currently hospitalized
788 patients hospitalized with nonsepsis infection
504 patients hospitalized with acute sterile inflammatory condition
patients with sepsis were matched on baseline characteristics to adults in other cohorts
in patients with sepsis
in patients with sepsis
Overview30-day
and Recommendations
mortality 25.4% (95% CI 22.7%-28.1%)
90-day mortality 35.3% (95% CI 32.3%-38.2%)
180-day mortality 41.3% (95% CI 38.3%-44.3%)
1-year mortality 48.5% (95% CI 45.4%-51.6%)
2-year mortality 56.5% (95% CI 53.5%-59.6%)
patients with sepsis associated with increased late mortality compared to
adults not in hospital (absolute increase 22.1%, 95% CI 17.5%-26.7%)
patients hospitalized for nonsepsis infection (absolute increase 10.4%, 95% CI 5.4%-15.4%)
patients hospitalized for sterile inflammatory conditions (absolute increase 16.2%, 95% CI
10.2%-22.2%)
Reference - BMJ 2016 May 17;353:i2375 full-text
6-month mortality about 33% in patients with severe sepsis who lived independently prior to
hospitalization
based on cohort analysis of data from 2 randomized trials
2,130 patients with severe sepsis from ACCESS and PROWESS-SHOCK trials were evaluated 6-12
months after sepsis hospitalization
all patients were living at home independently prior to sepsis hospitalization
outcomes at 6 months
mortality 32.8%
inability to live independently in about 40%
quality of life measured at 6 months in 1,060 patients
mobility problems in 37%
problems performing usual activities in 42.7%
problems performing self-care activities in 20.5%
outcomes at 1 year in patients from ACCESS trial

1-year mortality 37.2%
inability to live independently in 31%
quality of life measured at 1 year in 448 patients in ACCESS study
mobility problems in 31.7%
problems performing usual activities in 32.3%
problems performing self-care activities in 14.7%
factors associated with increased risk of mobility and self-care problems at 6 months in multivariate
analyses included older age, ventilator support for > 14 days, and dialysis for > 14 days
Reference - Crit Care Med 2016 Aug;44(8):1461
acute neurologic dysfunction associated with increased mortality in adults with sepsis
30,163 patients with sepsis (mean age 69 years) presenting to emergency department during 2010
and 2013 were assessed
acute organ dysfunction was assessed by modified Sequential Organ Failure Assessment (SOFA)
scores calculated at 6-hour intervals
median follow-up time after discharge from hospital 797 days
9.4% died in hospital, 31.7% at 1 year, and 59.7% at 3 years
propensity score for likelihood of having organ dysfunction was calculated for each patient using
international classification of diseases diagnostic and procedure codes prior to sepsis
hospitalization
propensity matched analyses included 13,787 patients for nervous system, 14,985 for coagulation,
and 7,205 for liver
increased mortality associated with every 1-point increase in modified SOFA score for dysfunction of
nervous system (adjusted hazard ratio [HR] 1.18, 95% CI 1.15-1.22)
coagulation (adjusted HR 1.11, 95% CI 1.08-1.15)
liver (adjusted HR 1.07, 95% CI 1.01-1.14)
Reference - Crit Care Med 2018 Jun;46(6):843
Time to appropriate therapy

longer time to antimicrobial therapy associated with increased mortality (level 2 [mid-level] evidence)
each hour of delay of antimicrobial therapy associated with increased in-hospital mortality in
patients with severe sepsis and septic shock (level 2 [mid-level] evidence)
28,150 patients with severe sepsis and septic shock from January 2005 to February 2010 in 165
intensive care units (ICUs) in Europe, the United States, and South America evaluated
17,990 patients who received antibiotics and had data available on timing of administration were
included in analysis
overall in-hospital mortality 29.7%
time to first antibiotic defined as difference between time of presentation and first antibiotic
administration
Association Between Time to First Antibiotic and Mortality:
Time to First Antibiotic Hospital Mortality Adjusted Odds Ratio
0-1 hours 32% 1 (reference)
1-2 hours 28.1% 1.07 (95% CI 0.97-1.18)
2-3 hours 28.6% 1.14 (95% CI 1.02-1.26)
3-4 hours 29.8% 1.19 (95% CI 1.04-1.35)

Time to First Antibiotic Hospital Mortality Adjusted Odds Ratio
4-5 hours 32.5% 1.24 (95% CI 1.06-1.45)
5-6 hours 36.6% 1.47 (95% CI 1.22-1.76)
> 6 hours 39.6% 1.52 (95% CI 1.36-1.7)
in logistic regression analysis adjusted for sepsis-severity score, ICU admission source, and
geographic region, hospital mortality risk steadily increased from 24.6% in patients receiving
antibiotics within first hour to 33.1% in patients with > 6-hour delay
Reference - Crit Care Med 2014 Aug;42(8):1749, editorial can be found in Crit Care Med 2014
Aug;42(8):1931, commentary can be found in Crit Care Med 2014 Dec;42(12):e802, Crit Care Med
2015 Mar;43(3):e102
starting appropriate antibiotics within 1 hour associated with lower mortality in patients with
severe sepsis or septic shock (level 2 [mid-level] evidence)
261 patients with severe sepsis or septic shock at academic tertiary care center had early goal-
directed therapy started in emergency department
in-hospital mortality 31%
median time from triage to antibiotics 119 minutes, median time from qualification for early goal-
directed therapy to antibiotics 42 minutes
time from triage to appropriate antibiotics ≤ 1 hour associated with lower mortality (19.5% vs.
33.2%, p = 0.02)
time from qualification to appropriate antibiotics ≤ 1 hour associated with lower mortality (25%
vs. 38.5%, p = 0.03)
Reference - Crit Care Med 2010 Apr;38(4):1045, editorial can be found in Crit Care Med 2010
Apr;38(4):1211, commentary can be found in Crit Care Med 2011 Apr;39(4):923
each hour of delay of antimicrobial therapy after onset of hypotension in septic shock associated
with increased mortality (level 2 [mid-level] evidence)
2,154 adults with septic shock in 14 intensive care units and 10 hospitals in United States and
Canada evaluated
survival rate 79.9% if effective treatment administered within 1 hour of documented hypotension
delay of effective therapy associated with increased risk of in-hospital mortality
adjusted odds ratio 1.119 per hour delay (95% CI 1.103-1.136)
survival decreased 7.6% with each hour effective treatment was delayed
Reference - Crit Care Med 2006 Jun;34(6):1589, editorial can be found in Crit Care Med 2006
Jun;34(6):1819, commentary can be found in Can J Anaesth 2006 Nov;53(11):1157
delaying antibiotic administration until shock recognition associated with increased mortality (level
2 [mid-level] evidence)
based on secondary analysis of randomized trial without blinding
291 patients from EMShockNet trial with severe sepsis and evidence of hypoperfusion or septic
shock who received first dose of antibiotics after presentation to hospital were analyzed
in-hospital mortality 19%
59% received antibiotics after shock recognition
mortality 23.8% in patients who received antibiotics after shock recognition vs. 11.8% in patients
who received antibiotics before shock recognition (p < 0.05, NNH 8)
no significant increase in mortality with hourly delays in antibiotic administration up to 6 hours
after triage
Reference - Crit Care Med 2011 Sep;39(9):2066 full-text, editorial can be found in Crit Care Med
2011 Sep;39(9):2184, commentary can be found in Crit Care Med 2012 Mar;40(3):1035
similar trend in mortality found in systematic review of 11 studies (including 4 above) evaluating
timing of antibiotic administration in 16,178 adults with severe sepsis or septic shock, although
statistical significance not met; this may be related to exclusion of a large number of patients who
did have explicit enough records on timing (Crit Care Med 2015 Sep;43(9):1907)
no randomized trials identified comparing early (< 1 hour after presentation to emergency
department) vs. late administration of broad-spectrum antibiotics in adults with severe sepsis
based on Cochrane review
Reference - Cochrane Database Syst Rev 2010 Oct 6;(10):CD007081
delayed initiation of effective antimicrobial therapy associated with increased risk of hospital
mortality (level 2 [mid-level] evidence)
based on retrospective cohort
5,715 adults (mean age 63 years) with septic shock had appropriateness of initial therapy evaluated
appropriate antimicrobial therapy initiated in 80.1%
overall survival 43.7%
survival rate 52% with prompt starting of appropriate therapy vs. 10.3% with delayed initiation of
effective antimicrobial therapy (adjusted odds ratio 8.99, p < 0.0001)
Reference - Chest 2009 Nov;136(5):1237
Factors associated with mortality

meeting Sepsis-3 septic shock criteria but not SIRS criteria associated with increased in-hospital
mortality in patients evaluated by rapid response team for acute deterioration
based on prognostic cohort study
1,708 hospitalized patients (mean age 68 years) with suspected infection who were acutely
deteriorating were evaluated by rapid response teams
24.5% had sepsis (SOFA score > 2) and met sepsis-3 septic shock criteria
31.9% met SIRS-based septic shock criteria (SIRS score > 2 plus systolic blood pressure < 90 mm
Hg)
overall in-hospital mortality was 33.4%

in-hospital mortality by septic shock criteria
40.9% of patients meeting sepsis-3 septic shock criteria (p < 0.001 vs. SIRS criteria)
33.5% of patients meeting SIRS criteria
compared to not meeting septic shock criteria
meeting sepsis-3 septic shock criteria associated with increased in-hospital mortality (odds ratio
1 55 95% CI 1 23-1 94)
1.55, 95% CI 1.23 1.94)
Overviewno
and Recommendations
significant difference in in-hospital mortality for meeting SIRS criteria (odds ratio 1.01, 95% CI
0.82-1.22)
low central venous oxygen saturation for 6 hours associated with increased 90-day mortality in
patients with severe sepsis or septic shock
based on cohort analysis of data from randomized trial
1,475 patients with severe sepsis or septic shock who were randomized to 20% albumin plus
crystalloid solution vs. crystalloid solution alone in the ALBIOS trial were assessed
all patients had early goal-directed therapy targeting central venous oxygen saturation (ScvO2) ≥
70% at 6 hours
34.8% had ScvO2 < 70% at baseline
compared to ScvO2 > 70% at 6 hours in patients with ScvO2 < 70% at baseline, ScvO2 < 70% at 6 hours
associated with
increased 90-day mortality (adjusted odds ratio 1.84, 95% CI 1.19-2.85)
significantly higher levels of markers of cardiac dysfunction (NT-proBNP, hs-cTnT)
no significant association between ScvO2 at 6 hours and 90-day mortality in patients with ScvO2 ≥
70% at baseline
Reference - Chest 2018 May 19 early online
new-onset atrial fibrillation in patients with severe sepsis associated with increased risk of in-hospital
stroke and mortality
3,144,787 hospitalized adults evaluated for severe sepsis and new-onset atrial fibrillation (AF)
severe sepsis defined by validated ICD-9 Clinical Modification (ICD-9-CM) code 995.92 and new-
onset AF defined as AF that occurred during hospital stay
49,082 patients had severe sepsis
severe sepsis associated with increased risk of developing AF compared to patients without severe
sepsis (5.9% vs. 0.65%, p < 0.001)
comparing severe sepsis with vs. without new-onset AF
in-hospital stroke 2.6% vs. 0.6% (p < 0.001)
in-hospital mortality 56% vs. 39% (p < 0.001)
Reference - JAMA 2011 Nov 23;306(20):2248 full-text, editorial can be found in JAMA 2011 Nov
23;306(20):2264
some heart rate variability parameters may be associated with increased mortality in patients with
sepsis
based on systematic review of observational studies
systematic review of 9 observational studies evaluating heart rate variability as risk factor for
mortality in 536 patients with sepsis
mortality rate ranged from 8% to 61% across studies
heart rate variability analysis was on short-term (≤ 1 hour) recordings in 7 studies and long-term (≥
24 hour) recordings in 3 studies
lower Standard deviation of the Normal to Normal interval) (SDNN) significantly associated with
increased mortality in 2 studies with short-term recordings
higher log high frequency (HF) power significantly associated with increased mortality in 1 study
with long-term recordings
Reference - PLoS One 2018;13(9):e0203487
black race associated with increased risk of sepsis severity and mortality
2,261,857 infection-related hospital discharges evaluated
16.8% had severe sepsis
comparing age- and sex-standardized rates in black patients vs. white patients
severe sepsis 9.4 per 1,000 population vs. 5.6 per 1,000 population (p < 0.001)
mortality 1.8 per 1,000 population vs. 1 per 1,000 population (p < 0.001)
authors state that multiple factors, such as access to medical care, smoking status, alcohol
consumption, and nutritional status may contribute to differences among races
Reference - JAMA 2010 Jun 23;303(24):2495
commentary indicates that differences in HIV infection between races may also have contributed to
increased risk of sepsis (JAMA 2010 Oct 13;304(14):1556)
cardiovascular failure, preexisting terminal illness, respiratory compromise, tachycardia, and

decreased platelet count associated with increased mortality in elderly patients admitted into
emergency department for infection
based on secondary analysis of derivation and validation study
3,940 patients > 65 years old presenting to emergency department who were admitted to hospital
with suspected infection included in derivation cohort, 2,015 similar patients included in validation
cohort
mortality 6% in derivation cohort, 7% in validation cohort
mortality risk factors identified in derivation cohort
cardiovascular failure (systolic blood pressure [SBP] < 90 mm Hg despite fluid challenge or
lactate ≥ 4 mmol/L [36 mg/dL]) (odds ratio [OR] 9, 95% CI 4.7-17)
preexisting terminal illness (OR 5.7, 95% CI 2.2-15)
respiratory compromise (breathing rate > 20 breaths/minute or hypoxemia) (OR 4, 95% CI 1.7-9.4)
tachycardia (heart rate ≥ 120 beats/minute) (OR 3.2, 95% CI 1.6-6.3)
platelet count < 150,000/mm3 (OR 2.7, 95% CI 1.3-5.6)
Mortality by Number of Risk Factors:
Number of Risk Factors Derivation Cohort Validation Cohort
0 0.51% 2%
1 3.1% 6.8%
2 14% 13.9%
Number of Risk Factors Derivation Cohort Validation Cohort
≥3 47% 27.4%
Reference - J Am Geriatr Soc 2009 Jul;57(7):1184, commentary can be found in J Am Geriatr Soc
2010 Jan;58(1):194
risk of in-hospital mortality may differ by infection source in adults with septic shock
7,974 adults (mean age 63 years) with septic shock were evaluated
overall in-hospital mortality 52%
in analyses adjusted for predisposing and downstream factors
increased risk of in-hospital mortality significantly associated with ischemic bowel and central
nervous system infections, disseminated infections, and other intra-abdominal infections
decreased risk of in-hospital mortality significantly associated with obstructive uropathy-
associated urinary tract infection, enterocolitis/diverticulitis, pyelonephritis,
cholecystitis/cholangitis, and intravascular catheter infections
Reference - Am J Respir Crit Care Med 2014 May 15;189(10):1204, editorial can be found in Am J
Respir Crit Care Med 2014 May 15;189(10):1156
thrombocytopenia at onset of sepsis in Staphylococcus aureus bacteremia associated with increased

risk of 30-day mortality
1,052 adults with S. aureus bacteremia evaluated
thrombocytopenia (platelet count < 150 x 109/L) at onset of sepsis in 22.3%
30-day all-cause mortality in 56.2% with thrombocytopenia vs. 34.4% without thrombocytopenia (p <
0.001)
increased risk of mortality proportional to degree of thrombocytopenia
Reference - Mayo Clin Proc 2011 May;86(5):389 full-text
higher lactate clearance associated with reduced mortality in patients with severe sepsis or septic
shock
based on systematic review limited by clinical heterogeneity
systematic review of 3 randomized trials and 12 observational studies evaluating lactate clearance
in critically ill patients
definition of lactate clearance varied between studies
overall mortality 23%-54.3% in 5 studies with patients with severe sepsis or septic shock
higher lactate clearance associated with reduced mortality in analysis of 5 studies with 627 patients
with sepsis or septic shock
risk ratio 0.41, 95% CI 0.28-0.6
result limited by significant heterogeneity
Reference - Crit Care Med 2014 Sep;42(9):2118, editorial can be found in Crit Care Med 2014
Sep;42(9):2149
severe hyperglycemia at admission associated with increased 30-day mortality in patients with sepsis
Overview
987 and Recommendations
patients hospitalized with sepsis who had admission glucose levels > 70 mg/dL evaluated
519 (52.6%) had normal glucose level (glucose level 71-140 mg/dL)
267 (27.1%) had mild hyperglycemia (glucose level 144-199 mg/dL)
201 (20.4%) had severe hyperglycemia (glucose level ≥ 200 mg/dL)
severe hyperglycemia associated with increased 30-day mortality

overall (adjusted hazard ratio [HR] 1.66, 95% CI 1.24-2.23)
in patients without diabetes (adjusted HR 1.65, 95% CI 1.12-2.42)
in patients with diabetes (adjusted HR 1.91, 95% CI 1.01-3.62)
mild hyperglycemia not associated with increased 30-day mortality

Reference - Crit Care Med 2016 Jul;44(7):1338, commentary can be found in J Thorac Dis 2016
Jul;8(7):E575, J Thorac Dis 2016 Jul;8(7):E621, J Thorac Dis 2016 Jul;8(7):E567, J Thorac Dis 2016
Jul;8(7):E581
solid organ transplant associated with reduced mortality in patients with bacteremic sepsis
123 solid organ transplant recipients with culture-proven sepsis were compared to 246
nontransplant patients with sepsis
in multivariate analysis adjusting for clinical presentation, illness severity, and infection type, solid
organ transplant associated with decreased mortality
at 28 days (hazard ratio [HR] 0.22, 95% CI 0.09-0.54)
at 90 days (HR 0.43, 95% CI 0.2-0.89)
Reference - Clin Infect Dis 2015 Jan 15;60(2):216
Prediction models
prediction models based on predisposition, insult/infection, response, and organ dysfunction (PIRO)
while both models detailed below go by the PIRO acronym, scoring methods differ
PIRO risk model predicts hospital mortality in patients with severe sepsis (level 1 [likely reliable]
evidence)
based on prognostic cohort study with independent derivation and validation cohorts
PIRO risk model derived from 840 patients in placebo arm of PROWESS trial
PIRO risk model validated in 10,610 patients > 18 years old with severe sepsis in PROGRESS
global registry, excluding patients treated with drotrecogin alfa (activated protein C)
PIRO score determined by 4 factors
Predisposition ranges 0-4 points
0 points if age < 46 years
1 point if age 46-64 years with no chronic liver disease
2 points if age 64-85 years with no chronic liver disease and no congestive cardiomyopathy
3 points if age 46-64 years with chronic liver disease or age 64-85 years with congestive
cardiomyopathy
4 points if age > 85 years or age 64-85 years with chronic liver disease
Insult/Infection ranges 0-4 points

0 points if gram-negative community-acquired urinary tract infection
0 points if gram negative community acquired urinary tract infection
Overview and 1Recommendations
point if non-gram-negative community-acquired urinary tract infection
2 points if community-acquired infection other than urinary tract infection, or nosocomial
gram-positive infection
3 points if non-gram-positive nosocomial infection or nonabdominal nosocomial fungal
infection
4 points if abdominal nosocomial fungal infection
Response ranges 0-1 points

0 points if no tachycardia and/or no tachypnea
1 point if tachycardia plus tachypnea
Organ dysfunction ranges 0-4 points

0 points if 2 organ failures
1 point if hepatic failure plus 2 other organ failures
2 points if 3 organ failures (other than hepatic failure)
hospital mortality by PIRO score
PIRO Score Hospital Mortality in Validation Cohort
0-3 points 20.6%
4 points 31%
5 points 40.1%
6 points 48.5%
7 points 56.8%
8 points 63.9%
9 points 72.2%
Abbreviations: PIRO, Predisposition, Insult/infection, Response, and Organ

dysfunction.
PIRO Score Hospital Mortality in Validation Cohort
10-13 points 79.9%

dysfunction.
Reference - Crit Care Med 2009 Apr;37(4):1329
PIRO staging score predicts hospital mortality in emergency department patients with suspected
infection (level 1 [likely reliable] evidence)
based on prognostic cohort study with independent derivation and validation cohorts
derivation cohort included 2,132 patients > 18 years old who were admitted to emergency
department with suspected infection
validation cohort 1 included 4,618 similar patients and validation cohort 2 included 1,004 similar
patients
PIRO staging score developed based on 4 factors in derivation cohort
predisposition
0 points if age ≤ 65 years
1 point if age 65-80 years
2 points if age > 80 years
1 point if chronic obstructive pulmonary disease (COPD)
2 points if liver disease
2 points if nursing home resident
1 point if malignancy without metastases
2 points if malignancy with metastases
infection
4 points if pneumonia
0 points if skin/soft tissue infection (SSTI)
2 points if any other infection
response
3 points if respiratory rate > 20 breaths/minute
1 point if bands > 5%
2 points if heart rate > 120 beats/minute
organ failure
2 points if blood urea nitrogen (BUN) > 20 mg/dL
3 points if respiratory failure/hypoxemia
3 points if lactate > 4 mmol/L (36 mg/dL)
4 points if SBP < 70 mm Hg
2 points if SBP 70-90 mm Hg
0 points if SBP > 90 mm Hg
2 points if platelet count < 150,000/mm3

predictive performance for hospital mortality in validation cohorts
PIRO Score Mortality in Validation Mortality in Validation
Cohort 1 Cohort 2
< 5 points 0.3% 0.3%
5-9 points 3% 3.7%
10-14 points 10.4% 8.4%
15-19 points 20.1% 32%
≥ 20 points 38.9% 40%

dysfunction.
Reference - Crit Care Med 2011 Feb;39(2):322, editorial can be found in Crit Care Med 2011
Feb;39(2):408
Mortality in Emergency Department Sepsis (MEDS) score predicts 28-day mortality in patients with
systemic inflammatory response syndrome (level 1 [likely reliable] evidence)
385 patients aged 18-100 years who presented to emergency department, met criteria for SIRS, and
were admitted to hospital, evaluated
score based on
terminal illness (6 points)
tachypnea or hypoxemia (3 points)
septic shock (3 points)
platelet count < 150,000 cells/mm3 (3 points)
band count as percentage of total white blood cell count > 5% (3 points)
age > 65 years (3 points)
lower respiratory infection (2 points)
nursing home residence (2 points)
altered mental status (2 points)
mortality by MEDS score
MEDS Score Mortality Rate
Abbreviations: MEDS, Mortality in Emergency Department Sepsis.

MEDS Score Mortality Rate
0-4 points 0.6% (95% CI 0%-3%)
5-7 points 5% (95% CI 1%-13%)
8-12 points 19% (95% CI 11%-29%)
13-15 points 32% (95% CI 15%-54%)
> 15 points 40% (95% CI 12%-74%)
Abbreviations: MEDS, Mortality in Emergency Department Sepsis.
Reference - Crit Care Med 2008 Feb;36(2):421, editorial can be found in Crit Care Med 2008
Feb;36(2):625, commentary can be found in Crit Care Med 2008 Sep;36(9):2715
PIRO score may have better performance than MEDS score for prediction of 30-day mortality in
emergency department patients with sepsis, septic shock, or infection without organ failure (level 2
based on validation cohort study with borderline statistical significance
240 patients in emergency department with sepsis, septic shock, or infection without organ
dysfunction were evaluated by PIRO, MEDS, and Sequential Organ Failure Assessment (SOFA) scores
30-day mortality 20%
for prediction of 30-day mortality
PIRO score had nonsignificantly better predictive performance compared to MEDS score (p =
0.064)
PIRO score had better predictive performance compared to SOFA score (p = 0.01)
no significant difference in predictive performance comparing MEDS score to SOFA score
Reference - Acad Emerg Med 2014 Nov;21(11):1257
risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classes may predict hospital mortality
in patients with sepsis (level 2 [mid-level] evidence)
182 patients with sepsis admitted to infectious disease intensive care unit evaluated
68 patients (37.4%) had acute renal failure
RIFLE classification may be based on glomerular filtration rate (GFR) or urine output criteria
risk of renal dysfunction
GFR criteria - increased serum creatinine 1.5-fold or GFR decrease > 25%
urine output criteria - urine output < 0.5 mL/kg/hour for 6 hours
injury to kidney
GFR criteria - increased serum creatinine 2-fold or GFR decrease > 50%
urine output criteria - urine output < 0 5 mL/kg/hour for 12 hours
urine output criteria urine output < 0.5 mL/kg/hour for 12 hours
Overviewfailure
and Recommendations
of kidney function
GFR criteria - increased serum creatinine 3-fold or GFR decrease > 75% or serum creatinine > 4
mg/dL (350 mcmol/L) in setting of acute increase of at least 0.5 mg/dL (44 mcmol/L)
urine output criteria - urine output < 0.3 mL/kg/hour for 24 hours (oliguria) or anuria for 12
hours
RIFLE Class and Hospital Mortality:
RIFLE Class Number of Patients Hospital Mortality
No renal failure 114 9.6%
Risk 11 27.3%
Injury 21 28.6%
Failure 36 55%
Abbreviation: RIFLE, Risk, Injury, Failure, Loss, and End-stage kidney

disease.
Reference - Crit Care 2007 Apr 5;11(2):408 full-text
Adherence to Surviving Sepsis Campaign guidelines

Surviving Sepsis Campaign guidelines associated with reduced mortality (level 2 [mid-level] evidence)
based on 3 observational studies
compliance with Surviving Sepsis Campaign guidelines associated with decreased mortality (level
2 [mid-level] evidence)
29,470 patients treated for severe sepsis or septic shock evaluated for compliance with
resuscitation and management bundles from Surviving Sepsis Campaign guidelines from 2005 to
2012
for resuscitation bundle
high compliance in 61%
hospital mortality 29% in high compliant group vs. 38.6% in low compliant group (p < 0.001)
for management bundle
high compliance in 53%
hospital mortality 32.3% in high compliant group vs. 33.4% in low compliant group (p = 0.04)
Reference - Crit Care Med 2015 Jan;43(1):3
Surviving Sepsis Campaign guidelines-based education associated with reduced mortality (level 2
Overviewbased
and Recommendations
on before-and-after study of patients in intensive care units in Spain
854 patients evaluated preintervention and 1,465 patients evaluated postintervention
intervention was national educational program based on Surviving Sepsis Campaign guidelines
hospital mortality reduced from 44% preintervention to 39.7% postintervention (p = 0.04)
Reference - JAMA 2008 May 21;299(19):2294, editorial can be found in JAMA 2008 May
21;299(19):2322, commentary can be found in JAMA 2008 Oct 15;300(15):1762
noncompliance with Surviving Sepsis Campaign guidelines associated with increased mortality
(level 2 [mid-level] evidence)
based on prospective cohort study without assessment of patient characteristics between groups
101 consecutive adults treated for severe sepsis or septic shock evaluated for compliance with 6-
hour and 24-hour sepsis care bundles from Surviving Sepsis Campaign guidelines
for 6-hour bundle
rate of compliance 52%
hospital mortality 23% in compliant group vs. 49% in noncompliant group (p = 0.01)
for 24-hour bundle
rate of compliance 30%
hospital mortality 29% in compliant group vs. 50% in noncompliant group (not significant)
Reference - Crit Care 2005;9(6):R764 full-text, editorial can be found in Crit Care 2005;9(6):653
Biomarkers
increasing blood lactate associated with increased 28-day mortality in patients with septic shock
665 patients with septic shock who had arterial lactate measured within mean 18 hours after onset
were analyzed
septic shock defined by ≥ 2 diagnostic criteria for SIRS, proven or suspected infection, ≥ 1 new organ
dysfunction by Brussels criteria, and hypotension despite adequate fluid resuscitation
28-day mortality by quartile of blood lactate concentration
Quartile Median Lactate 28-day Mortality* Hazard Ratio (vs.

Concentration Quartile 1)
1 1.1 mmol/L 27% Not applicable

(9.91 mg/dL)
2 1.8 mmol/L 41% 1.78

(16.22 mg/dL)
* Estimated from figure.

Overview andQuartile
RecommendationsMedian Lactate 28-day Mortality* Hazard Ratio (vs.
Concentration Quartile 1)
3 3 mmol/L (27 38% 1.65
mg/dL)
4 6.7 mmol/L 59% 3.5

(60.37 mg/dL)
* Estimated from figure.
similar trend for mortality was observed in second cohort of 469 patients who had arterial lactate
measured within 4 hours of onset
Reference - Shock 2012 Jul;38(1):4
other biomarkers may aid in prognosis but are experimental and still considered to be in preclinical
phases of development
decision tree using multiple biomarkers has moderate predictive performance for 28-day mortality
in adults with septic shock (level 1 [likely reliable] evidence)
based on prognostic cohort study with independent derivation and validation
derivation cohort included 672 adults presenting to intensive care unit with septic shock and
validation cohort included 209 similar adults
28-day mortality 31% in derivation cohort and 42% in validation cohort
decision tree derived using panel of serum biomarkers and other risk factors significantly
associated with 28-day mortality in derivation cohort (refer to full text for details)
C-C chemokine ligand 3
C-C chemokine ligand 4
heat shock protein 70 kDa 1B
interleukin 1-alpha
interleukin 8
granzyme B
lactate
age
presence of chronic disease
for prediction of 28-day mortality in validation cohort, decision tree had
sensitivity 85%
specificity 60%
positive predictive value 61%
Reference - Crit Care Med 2014 Apr;42(4):781, editorial can be found in Crit Care Med 2014
Apr;42(4):974
elevated cardiac troponin levels associated with increased risk of mortality in adults with sepsis
based on systematic review of observational studies
systematic review of 17 studies reporting troponin levels (troponin I and/or troponin T) in 1,857
y p g p ( p p ) ,
adults with sepsis, severe sepsis, or septic shock
60.5% of patients had elevated (positive) troponin
elevated troponin associated with increased risk of mortality in analysis of all trials (risk ratio
1.91, 95% CI 1.65-2.22)
similar results in analysis of studies that included only patients with septic shock or only patients
with sepsis, studies using only troponin T levels, and studies using only troponin I levels
Reference - Heart Lung 2015 Jan-Feb;44(1):75
review of sepsis biomarkers can be found in Crit Care 2010;14(1):R15 full-text
Morbidity
readmission within 30 days in about 30% after hospitalization for sepsis
based on cross-sectional study
633,407 patients ≥ 65 years old who were hospitalized with sepsis in 3,315 acute care hospitals
between 2008 and 2011 were evaluated
exclusion criteria included index hospitalizations involving transfer to another facility, discharge
against medical advice, and ineligibility for Medicare benefits
30-day risk-standardized readmission rates for sepsis survivors were generated over the 3-year
period at individual hospital level based on observed and expected readmission rates
30-day risk-standardized readmission rates ranged from 22.2% to 37.8% across hospitals (mean
29.2%)
hospitals with higher measures of quality of care and lower mortality had highest risk-standardized
readmission rates
Reference - Crit Care Med 2017 Jul;45(7):1130
readmission within 90 days in about 43% after hospitalization for severe sepsis
based on retrospective cohort study with 2,617 patients ≥ 50 years old (mean age 79 years) in United
States discharged from hospital following episode of severe sepsis
readmission within 90 days in 42.6%
most common causes of readmission
sepsis in 6.4%
congestive heart failure in 5.5%
pneumonia in 3.5%
acute renal failure in 3.3%
rehabilitation in 2.8%
respiratory failure in 2.5%
Reference - JAMA 2015 Mar 10;313(10):1055
severe sepsis in elderly persons associated with increased risk of cognitive impairment and functional
disability (level 2 [mid-level] evidence)
9,223 persons ≥ 50 years old from Medicare database had baseline cognitive and functional
assessment and were followed for 8 years
5.7% survived episodes of severe sepsis and had ≥ 1 follow-up assessment
prevalence of moderate-to-severe cognitive impairment increased 10.6% after severe sepsis (odds
ratio 3.34, 95% CI 1.53-7.25)
severe sepsis associated with increased functional disability
mean 1.57 disabilities (95% CI 0.99-2.15) for persons with no limitations before sepsis
mean 1.5 new disabilities (95% CI 0.87-2.12) for persons with mild-to-moderate limitations before
sepsis
Reference - JAMA 2010 Oct 27;304(16):1787 full-text, editorial can be found in JAMA 2010 Oct
27;304(16):1833
prior bacteremia or sepsis associated with increased 5-year risk of cardiovascular events
47,009 patients hospitalized ≥ 2 times between 2008 and 2012 evaluated (156,380 total
hospitalizations)
bacteremia occurred in 4,923 hospitalizations (3.1%) among 3,932 patients
sepsis occurred in 5,544 hospitalizations (3.5%) among 4,474 patients
first cardiovascular event (stroke, transient ischemic attack, or myocardial infarction) occurred in
3,501 hospitalizations (2.2%)
factors associated with increased risk of first cardiovascular event in multivariate analysis
prior bacteremia (odds ratio [OR] 1.52, 95% CI 1.21-1.9)
prior sepsis of any severity (OR 2.39, 95% CI 1.88-3.03)
prior sepsis (OR 1.99, 95% CI 1.5-2.63)
prior severe sepsis (OR 3.6, 95% CI 2.59-5)
prior septic shock (OR 4.55, 95% CI 3.58-5.78)
Reference - Clin Infect Dis 2016 Aug 15;63(4):495
review of enhancing recovery from sepsis can be found in JAMA 2018 Jan 2;319(1):62
Prevention and Screening

Prevention
selective decontamination of digestive tract and selective oropharyngeal decontamination
selective decontamination of digestive tract associated with decrease in multiple organ
dysfunction syndrome but not mortality (level 2 [mid-level] evidence)
based on systematic review of mostly moderate quality trials
systematic review of 7 randomized trials evaluating effect of selective decontamination of
digestive tract with parenteral and enteral antibiotics (vs. placebo or standard therapy) on multiple
organ dysfunction syndrome in 1,270 critically ill patients
selective decontamination group associated with decreased rate of multiple organ dysfunction
syndrome in analysis of 7 studies (odds ratio 0.5, 95% CI 0.34-0.74)
no significant difference between groups in
total mortality in analysis of 7 studies
multiple organ dysfunction syndrome-related mortality in analysis of 5 studies
Reference - Crit Care Med 2010 May;38(5):1370, editorial can be found in Crit Care Med 2010
May;38(5):1386
selective digestive decontamination as pneumonia prophylaxis reduces risk of ICU mortality in
critically ill patients (level 1 [likely reliable] evidence)
based on systematic review
systematic review of 145 randomized trials assessing pneumonia prophylaxis in 37,156 critically
ill adult patients hospitalized in intensive care units (ICUs)
any pneumonia prophylactic intervention associated with reduced risk of ICU mortality (risk ratio
0.95, 95% CI 0.92-0.99)
digestive decontamination associated with reduced risk of mortality in subgroup analysis of
10,227 patients (risk ratio 0.84, 95% CI 0.76-0.92)
other digestive or circuit strategies to prevent hospital-acquired pneumonia not associated with
reduced risk of mortality in subgroup analyses
Reference - Clin Infect Dis 2015 Jan 1;60(1):64
selective digestive tract decontamination or selective oropharyngeal decontamination may reduce

risk of bacteremia and might reduce mortality in ICU patients with or without mechanical
ventilation (level 2 [mid-level] evidence)
based on cluster-randomized trial without blinding and with baseline differences
13 surgical and nonsurgical ICUs were randomized to provide 1 of 3 treatments for 5,939 patients
with expected duration of mechanical ventilation > 48 hours or expected ICU stay > 72 hours
selective oropharyngeal decontamination including tobramycin, colistin, and amphotericin B in
oropharynx
selective digestive tract decontamination including selective oropharyngeal decontamination
antibiotics in oropharynx and stomach plus cefotaxime IV for 4 days
standard care
at baseline, patients in selective decontamination groups were more severely ill than controls with
higher rates of mechanical ventilation and admission to nonsurgical ICUs
92% stayed in ICU > 72 hours
Outcomes:
Standard Care Selective Selective

Oropharyngeal Digestive Tract
Decontamination Decontamination
Bacteremia 13% 9% (NNT 25)* 7% (NNT 17)*
28-day mortality 27.5% 26.6% 26.9%
Abbreviation: ICU, intensive care unit.
* p < 0.05 vs. standard care.

Standard Care Selective Selective
Oropharyngeal Digestive Tract
Decontamination Decontamination
Endotracheal 15% 10% (NNT 20)* 8% (NNT 15)*
aspirate
cultures with
highly resistant
microorganisms
(in subgroup
with > 3-day ICU
stay)
Abbreviation: ICU, intensive care unit.
* p < 0.05 vs. standard care.
no significant differences in crude 28-day mortality

selective oropharyngeal decontamination and selective digestive decontamination each
associated with significant reduction in 28-day mortality compared to standard care after
adjustment for age, sex, acute physiology, and chronic health evaluation (APACHE II) score,
intubation status, medical specialty, study site, and study period
References
N Engl J Med 2009 Jan 1;360(1):20
Lancet Infect Dis 2011 May;11(5):372, editorial can be found in Lancet Infect Dis 2011
May;11(5):337, commentary can be found in Lancet Infect Dis 2012 Mar;12(3):179
bathing with chlorhexidine-impregnated washcloth may decrease risk of hospital-acquired

bloodstream infection (level 2 [mid-level] evidence)
based on cluster-randomized crossover trial without intention-to-treat analysis
12 intensive care and bone marrow transplantation units were randomized to bathing with no-rinse
chlorhexidine 2%-impregnated washcloth vs. nonantimicrobial washcloth daily for 6 months followed
by crossover to other intervention for additional 6 months
washcloths were used on all body surfaces excluding face
3 units withdrew from trial or had low compliance and were excluded from analyses
7,727 patients who signed trial consent were included in analyses
primary bloodstream infection defined as hospital-acquired bloodstream infection detected > 48
hours after admission without attributable secondary source of infection
comparing chlorhexidine-impregnated washcloth vs. nonantimicrobial washcloth
hospital-acquired bloodstream infections (at > 48 hours from admission) 4.78 per 1,000 patient-
days vs. 6.6 per 1,000 patient-days (p = 0.007)
primary bloodstream infections 3.61 per 1,000 patient-days vs. 5.24 per 1,000 patient-days (p =
0.006)
central catheter-associated bloodstream infections 1.55 per 1,000 catheter-days vs. 3.3 per 1,000
catheter-days (p = 0.004)
multidrug-resistant organism colonizations (with methicillin-resistant Staphylococcus aureus or
vancomycin-resistant Enterococcus) 5.1 per 1,000 patient-days vs. 6.6 per 1,000 patient-days (p =
0.03)
skin reactions in 2% vs. 3.4% (no p value reported)
Reference - N Engl J Med 2013 Feb 7;368(6):533, correction can be found in N Engl J Med 2013 Jun
13;368(24):2341
tunneling internal jugular catheterization (separating cutaneous puncture site from venous puncture
site by > 8 cm) decreases risk of sepsis (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
241 intensive care unit patients requiring jugular venous catheter for > 48 hours randomized to
tunneled vs. nontunneled catheters
tunneling associated with
decreased catheter-related sepsis (odds ratio [OR] 0.33, 95% CI 0.13-0.83)
decreased catheter-related septicemia (OR 0.23, 95% CI 0.07-0.81)
Reference - JAMA 1996 Nov 6;276(17):1416
antimicrobial coatings that appear to reduce risk of central venous catheter-related bloodstream
infection include minocycline-rifampicin (level 1 [likely reliable] evidence), chlorhexidine silver
sulfadiazine, silver, and heparin (level 2 [mid-level] evidence), but antimicrobial coatings do not appear
to reduce risk of sepsis or mortality (level 2 [mid-level] evidence)
based on Cochrane review of trials with methodologic limitations (for catheter-related bloodstream
infection [CRBSI] with coatings other than minocycline-rifampicin and for sepsis outcome)
systematic review of 57 randomized trials comparing antimicrobial-coated central venous catheters
(CVC) vs. non-antimicrobial-coated catheters or alternative antimicrobial coatings in adults requiring
CVC in hospital setting
review included 2 high-quality trials evaluating effect of minocycline-rifampicin coatings on CRBSI
(neither trial evaluated effect on sepsis or mortality)
remaining trials had ≥ 1 limitation including
unclear or no allocation concealment
unclear or no blinding
comparing antimicrobial-coated CVC to standard CVC

for outcome of CRBSI
significant reduction with
minocycline-rifampicin catheters (risk ratio [RR] 0.26, 95% CI 0.13-0.49) in analysis of 4
trials with 1,335 catheters
chlorhexidine silver sulfadiazine impregnated catheters (RR 0.73, 95% CI 0.57-0.94) in
analysis of 19 trials with 4,886 catheters
silver impregnated catheters (RR 0.56, 95% CI 0.38-0.82) in analysis of 6 trials with 1,587
catheters
heparin-coated catheters (RR 0.27, 95% CI 0.08-0.95) in 1 trial with 240 catheters
no significant difference with silver-platinum-carbon impregnated catheters in analysis of 4

trials with 1,320 catheters
no significant differences in
sepsis in analysis of 12 trials with 3 686 catheters
sepsis in analysis of 12 trials with 3,686 catheters
mortality in analysis of 10 trials with 2,643 adults
minocycline-rifampicin-impregnated catheters associated with decreased risk of CRBSI compared to

chlorhexidine silver sulfadiazine impregnated catheters (RR 0.11, 95% CI 0.02-0.58) in analysis of 2
trials with 812 catheters
Reference - Cochrane Database Syst Rev 2016 Mar 16;(3):CD007878
intensive glucose control in critical care

intensive glucose control associated with reduced risk for sepsis (level 2 [mid-level] evidence)
effect of intensive glucose control on mortality has been inconsistent (increased, decreased, or no
significant effect) across randomized trials and systematic reviews
see Glucose control in critical care for details
Société Française d'Anesthésie et de Réanimation/Société de Réanimation de Langue Française
guideline on prevention of hospital-acquired sepsis in intensive care unit can be found in Ann Fr Anesth
Reanim 2009 Oct;28(10):912 [French]
Screening
hospitals and hospital systems should have performance improvement program for sepsis that
includes screening for sepsis in acutely ill, high-risk patients (SCCM Best practice statement)(4)
Quality Improvement
Medicare/Joint Commission National Hospital Inpatient Quality Measures
SEP-1 Early Management Bundle, Severe Sepsis/Septic Shock
measured as proportion of patients with diagnosis of sepsis, severe sepsis or septic shock who
received all of the following
initial lactate measured
blood cultures obtained prior to starting antibiotics and received within 6 hours of presentation of
severe sepsis
broad spectrum or other antibiotics administered
repeat lactate levels performed only if initial lactate level is elevated
if septic shock present received resuscitation with 30 mL/kg crystalloid fluids within 3 hours of
presentation
if hypotension persists after fluid administration, received vasopressors within 6 hours of
presentation
if hypotension persists after fluid administration or initial lactate ≥ 4 mmol/L, reassessment of
volume status and tissue perfusion received within 6 hours of presentation of septic shock
Study Summaries On Quality Improvement

delay in initial lactate measurement as recommended in Early Management Bundle may increase time
to treatment in patients with severe sepsis, and increasing delay associated with increasing in-
hospital mortality in patients with initial lactate > 2 mmol/L (level 2 [mid-level] evidence)
5,762 patients hospitalized with severe sepsis were assessed
severe sepsis defined by presence of all of 3 factors within 6-hour time frame (modified Severe
se e e seps s de ed by p ese ce o a o 3 acto s t 6 ou t e a e ( od ed Se e e
Sepsis and Septic Shock
Overview and Recommendations [SEP-1] Early Management Bundle criteria)
suspicion of infection (assessed by time of blood culture)
≥ 1 organ dysfunction
≥ 2 of 4 systemic inflammatory response syndrome (SIRS) criteria (excluding urine output and
systolic blood pressure drop > 40 mm Hg from baseline)
60% had initial serum lactate draw within SEP-1 Early Management Bundle-mandated time frame (6
hours before to 3 hours after severe sepsis onset)
14% had delayed lactate draw (drawn 3-24 hours after suspicion of infection)
26% did not have lactate draw within 24 hours
comparing delayed lactate draw vs. no delay
median time to antibiotics 3.9 hours vs. 2 hours (p < 0.001)
median time to IV fluid bolus 4.8 hours vs. 1.3 hours (p < 0.001)
compared to no delay in initial lactate draw, increasing delay associated with increased in-hospital
mortality (adjusted odds ratio 1.02 per hour of delay, 95% CI 1.0003-1.05)
no significant difference in mortality with initial lactate ≤ 2 mmol/L comparing delayed draw to no
delay
increasing time to starting antibiotics and completing 3-hour sepsis care protocol associated with
increased risk of in-hospital death in adults presenting to emergency department with sepsis and
septic shock (level 2 [mid-level] evidence)
49,331 adults (median age 73 years) with sepsis and septic shock who had standardized sepsis
protocol initiated within 6 hours of presentation to emergency department in New York State (149
hospitals) from 2014-2016 were evaluated
protocols required 3-hour bundle of testing and treatment including blood culture prior to
antibiotics, serum lactate measurement, and broad-spectrum antibiotics and 6-hour bundle
including IV fluid bolus in patients with hypotension or serum lactate ≥ 4 mmol/L, plus
vasopressors for refractory hypotension
all patients had 3-hour bundle completed within 12 hours of presentation
82.5% had 3-hour bundle completed within 3 hours (median time to completion overall was 1.3
hours)
median time to broad-spectrum antibiotics was 0.95 hours and to completion of IV fluid bolus was
2.56 hours
increased risk of in-hospital death associated with
increasing time start of antibiotics (adjusted OR 1.04 per hour increase, 95% CI 1.03-1.06)
increasing time to completion of 3-hour bundle (adjusted odds ratio 1.04 per hour increase, 95%
CI 1.02-1.05)
no significant association between time to completion of IV fluid bolus and in-hospital mortality
Reference - N Engl J Med 2017 Jun 8;376(23):2235, commentaries can be found in J Thorac Dis
2017 Sep;9(9):2808 and J Thorac Dis 2017 Oct;9(10):3453
Surviving Sepsis Campaign-based performance improvement program may reduce mortality in severe
sepsis (level 2 [mid-level] evidence)
based on before-and-after study

15 022 patients with severe sepsis or septic shock at 165 institutions in Europe South America and
15,022 patients with severe sepsis or septic shock at 165 institutions in Europe, South America, and
Overview and
United Recommendations
States were analyzed over 39-month period during program implementation
improvement program based on Society of Critical Care Medicine (SCCM) Surviving Sepsis
Campaign guidelines and included
initial care bundle (first 6 hours after presentation)
serum lactate measured
blood cultures obtained prior to antibiotic administration
broad-spectrum antibiotics administered within 3 hours for emergency department
admissions and 1 hour for intensive care unit admissions
if hypotension develops and/or lactate > 4 mmol/L (36 mg/dL)
deliver initial minimum of 20 mL/kg of crystalloid (or colloid equivalent)
apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain
mean arterial pressure > 65 mm Hg
if persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L
(36 mg/dL)
achieve central venous pressure > 8 mm Hg
achieve central venous oxygen saturation > 70%
management bundle (first 24 hours after presentation)

low-dose steroids administered for septic shock
drotrecogin alfa (activated protein C) administered for sepsis-induced organ dysfunction
glucose control maintained > lower limit of normal < 150 mg/L (8.3 mmol/L)
inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated patients
comparing first quarter of implementation vs. 2 years of implementation

compliance with initial care bundle 10.9% vs. 31.3% (p < 0.0001)
compliance with management bundle 18.4% vs. 36.1% (p = 0.008)
mortality 37% vs. 30.8% (p = 0.001, NNT 17)
in adjusted analysis, improvement program associated with absolute 5.4% (95% CI 2.5%-8.4%)
decrease in mortality over first 2 years of implementation
specific targets associated with reduced hospital mortality after adjustment for baseline
characteristics
administration of broad-spectrum antibiotics
obtaining blood cultures before antibiotics
maintaining blood glucose control
drotrecogin alfa (activated protein C) in first 24 hours among patients with shock
achieving plateau pressure control (< 30 cm H2O) among patients needing mechanical ventilation
Reference - Intensive Care Med 2010 Feb;36(2):222 full-text, editorial can be found in Intensive Care
Med 2010 Feb;36(2):187
DynaMed commentary -- drotrecogin alfa (activated protein C) (Xigris) has been WITHDRAWN from
all markets due to failure to show survival benefit for patients with severe sepsis and septic shock
(FDA MedWatch 2011 Oct 25)
hospital volume not associated with in-hospital mortality or severity of illness in adults with severe
sepsis admitted to critical care units in United Kingdom (level 2 [mid-level] evidence)
based
Overview onRecommendations
and retrospective cohort study
30,727 adults with severe sepsis admitted to 170 critical care units in United Kingdom during 2008-
2009 analyzed
no association found between hospital volume and in-hospital mortality, acute severity of illness, or
receipt of mechanical ventilation
Reference - BMJ 2012 May 29;344:e3394 full-text, editorial can be found in BMJ 2012 May
29;344:e3494
Guidelines and Resources

Guidelines
International guidelines
Surviving Sepsis Campaign 2016 international guideline on management of sepsis and septic shock in
adults can be found in Intensive Care Med 2017 Mar;43(3):304, commentary can be found in JAMA
2017 Feb 28;317(8):807
Society of Critical Care Medicine/European Society of Intensive Care Medicine (SCCM/ESICM) third
international consensus definitions for sepsis and septic shock (Sepsis-3) can be found in JAMA 2016
Feb 23;315(8):801 full-text, commentary can be found in JAMA 2016 Jul 26;316(4):456
Department of Health of Ireland (An Roinn Sláinte) national clinical guideline on sepsis management
can be found at An Roinn Sláinte 2015 May PDF, accredited by United Kingdom National Institute for
Health and Care Excellence
Society of Critical Care Medicine/European Society of Intensive Care Medicine (SCCM/ESICM) guideline
on diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically
ill patients (Part I) can be found in Crit Care Med 2017 Dec;45(12):2078, also published in Intensive Care
Med 2017 Dec;43(12):1751, correction can be found in Intensive Care Med 2018 Mar;44(3):401,
commentary can be found in Crit Care 2017 Dec 28;21(1):327
United States guidelines

Infectious Diseases Society of America (IDSA) position statement on why IDSA did not endorse
Surviving Sepsis Campaign guidelines can be found in Clin Infect Dis 2018 May 2;66(10):1631 full-text
American Society for Microbiology/Centers for Disease Control and Prevention Laboratory Medicine
Best Practices (ASM/CDC LMBP) guideline on effectiveness of practices to increase timeliness of
providing targeted therapy for inpatients with bloodstream infections can be found in Clin Microbiol Rev
2016 Jan;29(1):59 full-text
Society of Critical Care Medicine (SCCM) practice parameter on hemodynamic support of sepsis in
adult patients can be found in Crit Care Med 2004 Sep;32(9):1928
American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guideline on
management of adults with hospital-acquired and ventilator-associated pneumonia can be found in Clin
Infect Dis 2016 Sep 1;63(5):e61 full-text, commentary can be found in Can J Hosp Pharm 2017 May-
Jun;70(3):251
Eastern Association for Surgery of Trauma/Society of Critical Care Medicine (EAST/SCCM) clinical
practice guideline on red blood cell transfusion in adult trauma and critical care can be found in Crit
Care Med 2009 Dec;37(12):3124, correction can be found in Crit Care Med 2010 Jul;38(7):1621,
commentary can be found in Crit Care Med 2010 Aug;38(8):1755
American College of Endocrinology/American Diabetes Association (ACE/ADA) consensus statement

on inpatient diabetes and glycemic control can be found in Diabetes Care 2009 Jun;32(6):1119 full text
on inpatient diabetes and glycemic control can be found in Diabetes Care 2009 Jun;32(6):1119 full-text
or in Endocr
Overview Pract 2009 May-Jun;15(4):353 PDF, commentary can be found in Endocr Pract 2009 Nov-
and Recommendations
Dec;15(7):763
United Kingdom guidelines

National Institute for Health Care Excellence (NICE) guideline on recognition, diagnosis and early
management of sepsis can be found at NICE 2016 Jul:NG51 PDF
Royal College of Gynecologists (RCOG) guidelines on
bacterial sepsis in pregnancy can be found at RCOG 2012 Apr PDF
bacterial sepsis following pregnancy can be found at RCOG 2012 Apr PDF
United Kingdom joint specialist societies guideline on diagnosis and management of acute meningitis
and meningococcal sepsis in immunocompetent adults can be found in J Infect 2016
Apr;72(4):405 full-text, correction can be found in J Infect 2016 Jun;72(6):768, commentary can be
found in J Infect 2016 Aug;73(2):173
European guidelines
European Society of Intensive Care Medicine (ESICM) recommendations on ventilatory support of
patients with sepsis or septic shock in resource-limited settings can be found in Intensive Care Med
2016 Jan;42(1):100 full-text
Dutch Working Party on Antibiotic Policy (Stichting Werkgroep Antibioticabeleid [SWAB]) guideline on
antibacterial therapy of adult patients with sepsis can be found at SWAB 2010 PDF
Netherlands Society of Intensive Care (Nederlandse Vereniging voor Intensive Care [NVIC]) guidelines
on
hemodynamic effects of severe sepsis can be found at NVIC 2002 PDF [Dutch]
corticosteroid therapy for severe sepsis and septic shock can be found at NVIC 2010 Jan PDF
[Dutch, English]
German Sepsis Society/German Interdisciplinary Association for Intensive and Emergency Care
Medicine (DSG/DIVI) guideline on prevention, diagnosis, treatment, and follow-up care of sepsis can be
found in Anaesthesist 2010 Apr;59(4):347, Ger Med Sci 2010 Jun 28;8:Doc14 full-text, or in Internist
(Berl) 2010 Jul;51(7):925 [German]
Asian guidelines
Japanese Society of Intensive Care Medicine/Japanese Association for Acute Medicine Japanese
Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016) can be
found in Acute Med Surg 2018 Jan;5(1):3 full-text
Japanese Society of Chemotherapy Committee/Japanese Association for Anaerobic Infection Research

guideline on anaerobic infections (individual fields): blood stream infections with anaerobic bacteria
can be found in J Infect Chemother 2011 Jul;17 Suppl 1:47
Mexican guidelines
Grupos de Desarrollo de las Instituciones Públicas del Sistema Nacional de Salud de México (Secretaría
de Salud, Instituto Mexicano de Seguro Socia/Instituto de Seguridad y Servicios Sociales para los
Trabajadores del Estado/Secretaria de la Defensa Nacional/Secretaria de Marina/Sistema Nacional
para el Desarrollo Integral de la Familia/Petroleos Mexicano)
(IMSS/ISSSTE/SEDENA/SEMAR/DIF/PEMEX) guías de práctica clínica en diagnóstico y tratamiento de
sepsis grave y choque séptico en el adulto se pueden encontrar en Secretaría de Salud-México 2015
PDF [Spanish]
Overview and South
Central and Recommendations
American guidelines
Brazilian Association of Critical Care Medicine/Brazilian Society of Infectious Diseases (Associação de
Medicina Intensiva Brasileira/Sociedade Brasileira de Infectologia [AMIB/SBI]) guideline on sepsis:
hemodynamic resuscitation can be found in Rev Assoc Med Bras 2010 Sep-Oct;56(5):497 full-text
[Portuguese]
Australian and New Zealand guidelines

Clinical Excellence Commission (CEC) adult antibiotic guideline for severe sepsis and septic shock can
be found at CEC 2016 PDF
Government of South Australia Department for Health and Ageing (SA Health) clinical guideline on
sepsis in pregnancy can be found at SA Health 2017 Mar PDF
Review articles
review can be found in BMJ 2007 Oct 27;335(7625):879 full-text
review can be found in N Engl J Med 2006 Oct 19;355(16):1699, correction can be found in N Engl J
Med 2006 Nov 23;355(21):2267, commentary can be found in N Engl J Med 2007 Mar 15;356(11):1179
review of sepsis: pathophysiology and clinical management can be found in BMJ 2016 May
23;353:i1585
review of identifying patients with sepsis in hospital wards can be found in Chest 2017 Apr;151(4):898
review of advances in diagnosis and treatment of septic shock can be found in JAMA 2015 Aug
18;314(7):708, correction can be found in JAMA 2015 Oct 6;314(13):1404
review of effect of HIV infection on host response to bacterial sepsis can be found in Lancet Infect Dis
2015 Jan;15(1):95
review of septic shock can be found in N Engl J Med 2013 Oct 31;369(18):1726
review of severe sepsis and septic shock can be found in N Engl J Med 2013 Aug 29;369(9):840,
correction can be found in N Engl J Med 2013 Nov 21;369(20):2069
review of changes in incidence, pathogens, and outcomes in sepsis, severe sepsis, and septic shock
can be found in Expert Rev Anti Infect Ther 2012 Jun;10(6):701 full-text
review of management of refractory vasodilatory shock can be found in Chest 2018 Aug;154(2):416
review of care of asplenic patient can be found in N Engl J Med 2014 Jul 24;371(4):349
review of pathogenesis of sepsis can be found in Annu Rev Pathol 2011;6:19
review of blood culture-based diagnosis of bacteremia can be found in Clin Microbiol Infect 2015
Apr;21(4):313
review of early recognition and management of sepsis in adults: the first six hours can be found in Am
Fam Physician 2013 Jul 1;88(1):44
review of current understanding of molecular mechanisms and clinical implications for septic
cardiomyopathy can be found in Chest 2018 Aug 29 early online
review of severe sepsis and septic shock in pregnancy can be found in Obstet Gynecol 2012
Sep;120(3):689
review of hospital-acquired infections due to gram-negative bacteria can be found in N Engl J Med 2010
May 13;362(19):1804
review of normal maternal physiologic parameters in relationship to systemic inflammatory response
syndrome (SIRS) criteria can be found in Obstet Gynecol 2014 Sep;124(3):535
MEDLINE search
t h MEDLINE f (S i i d lt ) ith t t d h (Cli i lQ i ) li k th
to search MEDLINE for (Sepsis in adults) with targeted search (Clinical Queries), click therapy,
Overview andorRecommendations
diagnosis, prognosis
Patient Information
handouts from EBSCO Health Library on
blood poisoning or in Spanish
septic shock or in Spanish
handout from National Institute of General Medical Sciences PDF
handout from National Health Service
handout from Patient UK PDF
handout on protecting yourself from sepsis from Centers for Disease Control and Prevention PDF or in
Spanish PDF
ICD-9/ICD-10 Codes
ICD-9 codes
003.1 salmonella septicemia
022.3 anthrax septicemia
038 septicemia
038.0 streptococcal septicemia
038.1 staphylococcal septicemia
038.10 staphylococcal septicemia, unspecified
038.11 methicillin susceptible Staphylococcus aureus septicemia
038.12 methicillin resistant Staphylococcus aureus septicemia
038.19 other staphylococcal septicemia
038.2 pneumococcal septicemia

038.3 septicemia due to anaerobes
038.4 septicemia due to other gram-negative organisms
038.40 septicemia due to gram-negative organism, unspecified
038.41 septicemia due to Haemophilus influenzae (H. influenzae)
038.42 septicemia due to Escherichia coli (E. coli)
038.43 septicemia due to Pseudomonas
038.44 septicemia due to Serratia
038.49 other septicemia due to gram-negative organisms
038.8 other specified septicemias

038.9 unspecified septicemia
054.5 herpetic septicemia
670.2 puerperal sepsis
670.20 puerperal sepsis, unspecified as to episode of care or not applicable
670.22 puerperal sepsis, delivered, with mention of postpartum complication
670.24 puerperal sepsis, postpartum condition or complication
785 52 septic shock

785.52 septic shock
790.7 bacteremia
908.6 late effect of certain complications of trauma
958 certain early complications of trauma
958.3 posttraumatic wound infection not elsewhere classified
995.9 systemic inflammatory response syndrome (SIRS)

995.90 systemic inflammatory response syndrome (SIRS), unspecified
995.91 systemic inflammatory response syndrome due to infectious process without acute organ
dysfunction (sepsis)
995.92 systemic inflammatory response syndrome due to infectious process with acute organ
dysfunction (severe sepsis)
995.93 systemic inflammatory response syndrome (SIRS), due to non-infectious process without
acute organ dysfunction
995.94 systemic inflammatory response syndrome (SIRS), due to non-infectious process with acute
organ dysfunction
998.02 postoperative shock, septic

999.3 infection as complication of medical care
999.31 other and unspecified infection due to central venous catheter
999.32 bloodstream infection due to central venous catheter
999.33 local infection due to central venous catheter
ICD-10 codes
A02.1 salmonella sepsis
A22.7 anthrax sepsis
A24.1 acute and fulminating melioidosis [melioidosis sepsis]
A26.7 erysipelothrix septicaemia
A32.7 listerial septicaemia
A39.2 acute meningococcemia
A39.3 chronic meningococcemia
A39.4 meningococcemia, unspecified
A40 streptococcal sepsis
A40.0 sepsis due to streptococcus, group A
A40.1 sepsis due to streptococcus, group B
A40.2 sepsis due to streptococcus, group D
A40.3 sepsis due to Streptococcus pneumoniae
A40.8 other streptococcal sepsis
A40.9 streptococcal sepsis, unspecified
A41 other sepsis

A41.0 sepsis due to Staphylococcus aureus
A41.1 sepsis due to other specified staphylococcus
A41.2 sepsis due to unspecified staphylococcus
A41.3 sepsis due to Haemophilus influenzae
A41.4 sepsis due to anaerobes
p
A41.5
Overview sepsis
and due to other gram-negative organisms
Recommendations
ICD-10-CA modification in Canada: A41.5 subdivided to identify
A41.50 septicaemia due to Escherichia coli [E. Coli]
A41.51 septicaemia due to Pseudomonas
A41.52 septicaemia due to Serratia
A41.58 septicaemia due to other gram-negative organisms
A41.59 septicaemia due to gram-negative septicaemia, unspecified
A41.8 other specified sepsis

ICD-10-CA modification in Canada: A41.8 subdivided to identify
A41.80 septicaemia due to enterococcus
A41.88 other specified septicaemia
A41.9 sepsis, unspecified

A42.7 actinomycotic sepsis
A49.9 bacterial infection, unspecified
A54.8 other gonococcal infections [gonococcal sepsis]
B00.7 disseminated herpes viral disease [herpes viral sepsis]
B37.7 candidal sepsis
O07.0 failed medical abortion, complicated by genital tract and pelvic infection
O07.5 other and unspecified failed attempted abortion, complicated by genital tract and pelvic infection
O08.0 genital tract and pelvic infection following abortion and ectopic and molar pregnancy
O75.3 other infection during labor [sepsis during labor]
O85 puerperal sepsis
use additional code (B95-B97), if desired, to identify infectious agent
T79 certain early complications of trauma, not elsewhere classified

T79.3 post-traumatic wound infection, not elsewhere classified
use additional code (B95-B97), if desired, to identify infectious agent
T79.4 traumatic shock
T79.8 other early complications of trauma
T79.9 unspecified early complication of trauma
T80.2 infections following infusion, transfusion and therapeutic injection

T81.4 infection following a procedure, not elsewhere classified
T88.0 infection following immunization
T98.2 sequelae of certain early complications of trauma
References
General references used
1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee, Pediatric
Subgroup. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and
Septic Shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637, also published in Intensive Care Med 2013
Feb;39(2):165
2. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes.
Expert Rev Anti Infect Ther. 2012 Jun;10(6):701-6 full-text
3. Singer M, Deutschman CS, Seymour CW, et al; The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10 full-text, commentary can be
found in JAMA 2016 Jul 26;316(4):456
4. Rhodes A, Evans LE, Alhazzani W, et al; Surviving Sepsis Campaign: International Guidelines for
Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017 Mar;43(3):304
Recommendation grading systems used

Society of Critical Care Medicine (SCCM) uses Grading of Recommendations, Assessment,
Development, and Evaluation (GRADE)
strength of recommendation
Strong - benefits clearly outweigh risks and burdens (or vice versa) for most, if not all, patients
Weak - benefits and risks closely balanced and/or uncertain
Best practice statement - recommendation not conducive to GRADE process
quality of evidence
High - randomized trials without factors that reduce quality of evidence, or well-done
observational studies with very large magnitude of effect
Moderate - downgraded randomized trials or upgraded observational studies
Low - well-done observational studies, or randomized trials with many limitations
Very low - case series or expert opinion
Reference - SCCM Surviving Sepsis Campaign 2016 international guideline on management of

severe sepsis and septic shock (Intensive Care Med 2017 Mar;43(3):304)
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Special acknowledgements
Paritosh Prasad, MD (Assistant Professor of Pulmonary Diseases and Critical Care, University of
Rochester School of Medicine; New York, United States)
Dr. Prasad declares no relevant financial conflicts of interest.
Allen Shaughnessy, PharmD, M Med Ed, FCCP (Professor of Family Medicine and Director of Master
Teacher Fellowship, Tufts University Family Medicine Residency; Cambridge Health Alliance;
Massachusetts, United States)
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Terence K. Trow, MD, FACP, FCCP (Deputy Editor of Pulmonary, Critical Care, and Sleep Medicine; Ex-
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Yale University School of Medicine; Connecticut, United States)
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On behalf of the American College of Physicians

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DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 115805,
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Overview and Recommendations

[+]Updated 2018 Oct 04 12:00 AM (ET)

Topic Editor Paritosh Prasad, MD

Recommendations Editor Allen Shaughnessy, PharmD, M Med Ed, FCCP

Deputy Editor Terence K. Trow, MD, FACP, FCCP

ACP Reviewer Philip A. Verhoef, MD, PhD, FAAP, FACP

Overview and Recommendations

2016 consensus deﬁnitions (Sepsis-3)

quick SOFA (qSOFA) criteria(3)

2003 consensus deﬁnitions

sepsis - SIRS due to documented or suspected infection

bilirubin > 2 mg/dL (34.2 mcmol/L)

based on retrospective cohort study

age-adjusted sepsis mortality in United States about 60 per 100,000 persons

Likely risk factors

immunosuppressing drugs, such as high-dose corticosteroids and marrow suppressing

Possible risk factors

Etiology and Pathogenesis

51.6% had gram-positive bacteria

pro-inﬂammatory mediators reported to be involved in sepsis include

History and Physical

2016 consensus deﬁnitions of sepsis use clinical criteria to make diagnosis(3)

quick SOFA (qSOFA) criteria

Clinical prediction rules

Reference - Chest 2018 Aug;154(2):309

acute organ dysfunction in

for prediction of Sepsis-3 deﬁned organ dysfunction

predicting mortality in patients admitted to intensive care unit

performance of sepsis deﬁnitions for prediction of in-hospital mortality

consistent results for prediction of in-hospital mortality or ICU stay ≥ 3 days

predicting mortality in patients presenting to emergency department

Outcome Predictor Sensitivity Speciﬁcity Number of

In-hospital qSOFA 51% (95% CI 83% (95% CI 20 studies

* Indicates statistically signiﬁcant heterogeneity.

Acute organ qSOFA 47% (95% CI 93% (95% CI 9 studies

SIRS criteria 83% (95% CI 49% (95% CI 4 studies

ICU qSOFA 53% (95% CI 75% (95% CI 10 studies

SIRS criteria 91% (95% CI 14% (95% CI 3 studies

* Indicates statistically signiﬁcant heterogeneity.

Reference - Crit Care 2018 Feb 6;22(1):28 full-text

Predictor Sensitivity Speciﬁcity PPV NPV c-

qSOFA 70% 79% 24% 97% 0.8

SOFA 73% 70% 18% 97% 0.77

SIRS criteria 93% 27% 11% 98% 0.65

Previous 47% 82% 20% 94% 0.65

Abbreviations: NPV, negative predictive value; PPV, positive predictive value;

45% were admitted to hospital and 7% were admitted to ICU

qSOFA Score Number of Inpatient ICU Hospital

0 16,507 0.6% 5.1% 38%

1 5,290 2.8% 10.5% 59%

2 649 12.8% 20.8% 84%

3 84 25% 27.4% 93%

Reference - Crit Care Med 2015 Dec;43(12):2616

organ dysfunction parameters

administration of > 30 g of albumin within 2 days of 1,3-beta-D-glucan assay associated with

see Sepsis in adults for details

initiate resuscitation and treatment immediately (SCCM Best practice statement)

in volume responsive patients, repeat IV ﬂuid boluses if hypotension recurs or lactate is

initiate broad-spectrum antibiotics as soon as possible (SCCM Strong recommendation,

resuscitation phase (ﬁrst 6 hours)

Complications and Prognosis

sepsis associated with increased risk of subsequent stroke or myocardial infarction

based on retrospective population-based cohort study