Sepsis Screen Treatment Algorithm
Sepsis Screen Treatment Algorithm
Sepsis Screen Treatment Algorithm
Category:
A: Arrival
B: Bed Placement
C: Clinician Initial Evaluation &
Throughput
E: Exit from the ED
Key Words:
Sepsis
Triage
Hospital Metrics:
Annual ED Volume: 117,571
Hospital Beds: 1,065
Ownership: Baylor Healthcare System,
Not-For-Profit
Trauma Level: 1
Teaching Status: Yes
Tools Provided:
BHCS Adult Sepsis Screen & Treatment Algorithm
Tools Provided:
Hahnemann University Hospital
Clinical Areas Affected:
Triage Plan
Emergency Department
Staff Involved:
ED Staff
Nurses
Pharmacists
Physicians
Technicians
Innovation
Severe sepsis and septic shock are major drivers of in-hospital mortality, with rates that are over 8 times higher than
those associated with other inpatient admissions. When coupled with an apparent rise in incidence: hospital admission
rates for severe sepsis and septic shock doubled between 2000 and 2008, sepsis is projected to be a growing source of
mortality, morbidity, and healthcare cost within the United States. This data is especially pertinent to Emergency
Departments (ED): effective treatments for patients with severe sepsis and septic shock are time-sensitive whereby early
recognition and treatment significantly impacts mortality.
Based upon growing evidence that rapid recognition and aggressive treatment significantly improves outcomes, the
Surviving Sepsis Campaign (SSC) recently released updated guidelines detailing a standard operating procedure for early
risk stratification and management of patients with severe sepsis and septic shock. These guidelines have been
endorsed by the National Quality Forum (NQF). More specifically, these guidelines describe a 3 hour and 6 hour bundles
of care to be completed in patients with severe sepsis and septic shock. In patients admitted to the ED with evidence of
sepsis, the 3 hour bundle includes four aspects of patient care that occur within the first 3 hours following triage in the
ED. These include the institution of aggressive screening for occult severe sepsis with serum lactates, obtaining blood
cultures prior to antibiotic administration, the administration of broad spectrum antibiotics, and completion of a
30ml/kg crystalloid bolus. Those patients who fail to respond to the 3 hour bundle or have serum lactate of greater than
4 mg/gL are eligible for the 6 hour bundle. Importantly, multiple studies have demonstrated that a delay in the
administration of effective antibiotics is associated with increased mortality in patients with severe sepsis and septic
shock. More telling perhaps is a reported 7.6% increase in mortality for every hour delay in antibiotic administration
following initial hypotension in patients with septic shock. Based upon this literature, the SSC suggests that broadspectrum antibiotic administration should occur as soon as possible following the diagnosis of severe sepsis. Rapid
identification of these patients in a busy ED is very difficult. Additionally, several events must occur, often in serial order,
prior to the administration of antibiotics.
Sepsis has long been noted to be a major driver of inpatient mortality within our institution. As such, it has been the
focus of a continual quality improvement (CQI) project for the past 3 years at Baylor University Medical Center (BUMC).
These CQI projects led to several improvements. One of these was the development of a hospital wide sepsis
notification aimed at expediting the septic patients from the ED to the Intensive Care Unit. Additionally, this pulled
Intensive Care nursing resources to the ED to help with patient care. These interventions dramatically improved ED
disposition to ICU times, reducing this timeframe by almost 60% (374 minutes to 151 minutes). Additionally a sepsis
screen based upon SIRS criteria was added to the initial triage forms completed by the triage nurse. A positive screen
prompted the triage nurse to contact an EM physician for further instructions.
Our Emergency Department set out to develop a nursing driven sepsis screening protocol and treatment algorithm
whereby patients at risk for severe sepsis and septic shock would be rapidly identified in triage. A positive screen then
triggers a multidisciplinary response involving ED nursing and technicians, radiology technicians, respiratory therapy,
pharmacists, and Emergency Medicine physicians. The goal of this response was to perform the necessary tasks to:
Initiate broad spectrum antibiotics within 2 hours of triage
Complete the remainder of the 3 hour bundle of care as described by the NQF and SSC.
Triage was defined at the time that first vital are entered into the chart. In the Baylor University Medical Center ED this
occurs within 2-3 minutes of patient arrival as pulse rate and oxygen saturation are measured and recorded at the time
chief complaint is collected.
Despite these improvements, no impact was made on improving processes that would impact patient morbidity and
mortality. Timeframes associated with triage to lactate result, triage to administration of antibiotics, and triage to
completion of initial crystalloid bolus were essentially unchanged between July of 2009 and February of 2013.We
recognized several major impediments in reaching our goal of triage to antibiotics within 2 hours and successful
completion of the 3 hour bundle. In 2012, the ED at BUMC had an annual census of 117,571 patients. BUMC is a level 1
trauma center and flagship hospital for the Baylor Healthcare System. It also serves as a training center for multiple
levels of Emergency Medicine (EM) practitioners: we host a 1 month rotation for a local EM residency, are the training
campus for a midlevel practitioner EM internship, and have rotating non-EM interns from other service lines within the
hospital. As such protocol education and protocol mastery in our group or transient residents and mid-level providers is
difficult. Additionally the average door to bed placement time at BUMC is 46 minutes. On average this left 74 minutes
for provider evaluation, order entry, IV start, blood culture collection from two sites, lactate processing and resulting,
antibiotic preparation, and antibiotic administration. Oftentimes these steps occurred in the setting of ongoing patient
resuscitation.
Innovation Implementation
The team responsible for the development and implementation of the sepsis screen and treatment algorithm was a
multidisciplinary group of ED nurses, EM physicians, and ED staff. With support of ED leadership, the primary team
consisted of two ED nurse champions (Scott Garvin RN & Lisa Ball RN), ED nursing informatics (Millie Early RN), and EM
physician champions (John Garrett MD & Matthew Muller MD). Each team member was instrumental and cooperatively
involved in each aspect of the design, implementation, and ongoing education required for successful deployment of the
algorithm.
Given the limitations of our ED size and patient volume, we recognized that the delays associated with waiting for a
provider to trigger a sepsis screening labs prevented rapid recognition and treatment of patients with occult severe
sepsis and septic shock. As such a team comprised of representatives from ED nursing, Emergency Medicine, and the
BUMC pharmacy met to develop a nursing based triage sepsis screen and protocol (Appendix 1: BHCS Adult Sepsis
Screen & Treatment Algorithm). It was quickly realized that the triage nurse played a critical role in the early
recognition and screening of septic patients. We had seen marked success in rapid mobilization of resources when the
triage nurse is empowered to start workups and initiate treatment. This had become standard care at BUMC when
identifying patients with STEMI, acute stroke, and trauma. We hoped that by coupling the existing sepsis screen with a
nursing protocol that facilitated rapid treatment, we would remove the delays inherent in waiting for the provider's
evaluation. Throughout this process the sepsis screen itself remained essentially unchanged. A positive screen was
considered when two SIRS criteria existed in the setting of suspected infection, which the triage nurse would identify
through a list of potential sources. The definition of SIRS was expanded to include high risk patients such as hypotension
upon arrival. (Appendix 1) After linking the positive screen to a sepsis screening protocol the nurse triggered a process
to:
Page an ED technician to draw labs and a blood culture, and then transport the sample to the lab;
Order a sepsis screening bundle containing a serum lactate, complete metabolic panel, and complete blood
count with differential; and
Expedited processing within the ED laboratory. In the event that a bed was immediately available, this process
was completed at the bedside prior to provider evaluation.
In the event that no ED bed was available, this occurred in the triage area of the ED. Results from the screen were then
called to the triage nurse. As noted in the Sepsis Algorithm (Appendix 1), if the serum lactate was abnormal (>2 mg/dL)
or the patient needed immediate resuscitation, the triage nurse was to immediately bed the patient, start fluid
resuscitation, and trigger a multidisciplinary team comprised of the ED supervisor, an ED nurse, ED technician,
Respiratory therapy, and ED pharmacist. The EM physician would be notified of the patient while each team member
was assigned a specific task during the resuscitation. ED pharmacist was asked to pull, prepare, and bring a normal saline
bolus and broad-spectrum antibiotics for an unknown source of infection to the patient's bedside. The ED technician was
asked to pull blood cultures, label samples, and obtain EKGs. ED nurses were asked to start IV and hang medications
provided by the ED pharmacist while the ED supervisor was responsible for charting interventions. To improve
compliance and standardization, order sets were built into our electronic health record (HER) to allow single-click, easy
to use, standardized order entry for sepsis screening. After implementation of the protocol and algorithm a robust
education program was initiated. In order to provide real-time feedback and impact nurse and provider practice
patterns, a nurse and physician sepsis champion reviewed each sepsis case within 48-72 hours. Utilizing a standardized
form, they provided real time feedback on metrics and delays. Additionally, providers and nurses were asked to provide
feedback to further improve the process.
Timeline
January 2013: Development of our sepsis screening protocol and treatment algorithm occurred during the month of
January 2013. As noted previously, a sepsis screen was in place at the time this new process was being developed;
however this screen required physician oversight. As ED nursing would be triggering the screen staff education was
required. ED staff education occurred continuously during February of 2013. February 22nd 2013: Phase I: The new
sepsis screening process and EHR support was launched. After the launch of our nursing driven sepsis screen, continual
staff education and feedback was provided to ED nursing staff and physicians. April 28th of 2013: Phase II: The EHR was
further augmented to include "one-click" ordering for sepsis resuscitation and antibiotics. At this time education efforts
were re-initiated to include EHR education and provide case specific and provider specific feedback.
Results
Upon initiation of the nursing driven sepsis screening protocol and treatment algorithm, we saw an immediate
improvement in our metrics. With augmentation of the EHR we again saw a rapid improvement in these metrics. In
those patients who were discharged from the hospital with discharge diagnosis codes of 995.92 or 785.52 and had either
a lactate of >4 or systolic BP of < 90 mmHg documented in the ED we saw the following:
Median triage to antibiotic administration time dropped 48% (Figure 1)
Baseline: 153 minutes
Phase I: 125 minutes
Phase II: 80 minutes
The percent of patients who received antibiotics within 2 hours of triage increased 211% (Figure 1)
Baseline of 35%
Phase I: 61%
Phase II: 74%
The percent of patients who received antibiotics within 3 hours of triage increased 39% (Figure 1)
Baseline: 66%
Phase I: 79%
Phase II: 92%
The percent of patients who completed the 30ml/kg fluid bolus within 3 hours of triage increased 35% (Figure 2)
Baseline: 63%
Phase I: 68%
Phase II: 85
The percent of patients who completed the 30ml/kg fluid bolus within 3 hours of triage increased 35% (Figure 2)
Baseline: 53%
Phase I: 67%
Phase II: 81%)
Cost/Benefit Analysis
Though specific cost savings associated with this innovation are not available, the anticipated significant improvement in
patient morbidity and mortality is projected to lead to reductions in health care resource consumption. As described by
Rivers et al, rapid recognition and treatment of patients with severe sepsis and septic shock has been shown to reduce
absolute and relative mortality by 16 and 30% respectively. In light of the projected increase in annual sepsis related
hospital stays due to our aging population and the significant cost associated short and long term care, sepsis is
projected to represent a significant burden on Medicare and Medicaid resources. As cited in the NQF 0500 document,
interventions that lead to improved sepsis care "lead to significant reduction in morbidity, mortality, and health care
resource consumption. Given the impact of the intervention, the costs associated with the development and
implementation of the sepsis screening protocol and treatment algorithm was minimal. These primarily focused around
personnel time required to design the protocol and then again to review individual cases and provide feedback to
providers. At BUMC our annual census provides an average of 10 cases of severe sepsis or septic shock per week. Chart
review, abstraction, and provider feedback represents a total workload of approximately 4-5 hours per week or 20-30
minutes per case.
Advice and Lessons Learned
Following the initial success of the BUMC sepsis screening algorithm, the same process was implemented at 9 EDs of
other hospitals in the Baylor Healthcare system. The size and inpatient resources available to each facility varied
significantly. Despite these limitations, we have seen similar improvement in all sites. The most important lesson we
have learned during this process is the importance of the multidisciplinary team. Successful development and
implementation of the sepsis screening and treatment algorithm was dependent upon participation of ED nursing,
technician, and EM providers. Second, we noticed that the implementation of the sepsis screening and treatment
algorithm results in a marked increase in the number of serum lactates that were ordered, drawn, and sent in our ED.
Special handling was required to compensate and expedite these specific tests within our ED. Finally, it seemed that EM
provider and ED nursing education and feedback was an essential component of our intervention. This alone represents
the single greatest labor intensive aspect of our implementation.
Sustainability
The sepsis screening and treatment algorithm has been in place at BUMC for approximately 5 months, we are continuing
to see improvement in all of our metrics. In order to sustain these levels we will continue to provide feedback to our
nurses and providers of individual case data. We have also started to share the aggregate data from the preceding week
during nursing shift huddles. This has helped to distribution the knowledge and experience gained to the staff as a
whole.
Tools to Download
BHCS Adult Sepsis Screen & Treatment Algorithm
Related Resources
Triage to Antibiotic Compliance by Hour (Figure 1)
Triage to Fluid Complete Compliance & Bundle Complete (Figure 2)
Surviving Sepsis Campaign Guidelines
100%
91%
90%
63%
67%
50%
40%
40%
31%
35%
68%
68%
37%
34%
32%
4%
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7%
Nov-12
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9%
13%
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10%
72%
78%
55%
30%
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72%
93%
61%
59%
60%
77%
19%
22%
24%
Jun-13
70%
73%
83%
May-13
80%
78%
91%
16%
3%
Jul-13
Apr-13
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Feb-13
Jan-13
Sep-12
0%
60%
50%
60%
73%
63%
58%
54%
47%
40%
63%
56%
51%
70%
69%
62%
80%
82%
Jun-13
70%
69%
86%
May-13
80%
83%
69%
62%
46%
30%
20%
10%
Jul-13
Apr-13
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0%
Special Articles
Objective: To provide an update to the Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic
Shock, last published in 2008.
Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal
groups were assembled at key international meetings (for those
committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process
and enforced throughout. The entire guidelines process was
conducted independent of any industry funding. A stand-alone
meeting was held for all subgroup heads, co- and vice-chairs,
and selected individuals. Teleconferences and electronic-based
discussion among subgroups and among the entire committee
served as an integral part of the development.
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before antibiotic therapy (1C); imaging studies performed
promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of
recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B);
infection source control with attention to the balance of risks and
benefits of the chosen method within 12 hrs of diagnosis (1C);
initial fluid resuscitation with crystalloid (1B) and consideration
of the addition of albumin in patients who continue to require
substantial amounts of crystalloid to maintain adequate mean
arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced
tissue hypoperfusion and suspicion of hypovolemia to achieve a
minimum of 30mL/kg of crystalloids (more rapid administration
and greater amounts of fluid may be needed in some patients)
(1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to
maintain mean arterial pressure 65mm Hg (1B); epinephrine
when an additional agent is needed to maintain adequate blood
pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or
to decrease norepinephrine dose but should not be used as
the initial vasopressor (UG); dopamine is not recommended
except in highly selected circumstances (2C); dobutamine
infusion administered or added to vasopressor in the presence
of a) myocardial dysfunction as suggested by elevated cardiac
filling pressures and low cardiac output, or b) ongoing signs
of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use
of intravenous hydrocortisone in adult septic shock patients if
adequate fluid resuscitation and vasopressor therapy are able
to restore hemodynamic stability (2C); hemoglobin target of
79g/dL in the absence of tissue hypoperfusion, ischemic
coronary artery disease, or acute hemorrhage (1B); low tidal
volume (1A) and limitation of inspiratory plateau pressure (1B)
for acute respiratory distress syndrome (ARDS); application of
at least a minimal amount of positive end-expiratory pressure
(PEEP) in ARDS (1B); higher rather than lower level of PEEP
for patients with sepsis-induced moderate or severe ARDS
(2C); recruitment maneuvers in sepsis patients with severe
refractory hypoxemia due to ARDS (2C); prone positioning in
sepsis-induced ARDS patients with a Pao2/Fio2 ratio of 100
mm Hg in facilities that have experience with such practices
(2C); head-of-bed elevation in mechanically ventilated patients
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Dellinger et al
Dr. Dellinger consulted for Biotest (immunoglobulin concentrate available in
Europe for potential use in sepsis) and AstraZeneca (anti-TNF compound
unsuccessful in recently completed sepsis clinical trial); his institution received
consulting income from IKARIA for new product development (IKARIA has
inhaled nitric oxide available for off-label use in ARDS) and grant support from
Spectral Diagnostics Inc (current endotoxin removal clinical trial), Ferring (vasopressin analog clinical trial-ongoing); as well as serving on speakers bureau for
Eisai (anti-endotoxin compound that failed to show benefit in clinical trial).
Dr. Levy received grant support from Eisai (Ocean State Clinical Coordinating Center to fund clinical trial [$500K]), he received honoraria from Eli
Lilly (lectures in India $8,000), and he has been involved with the Surviving
Sepsis Campaign guideline from its beginning.
Dr. Rhodes consulted for Eli Lilly with monetary compensation paid to himself as well as his institution (Steering Committee for the PROWESS Shock
trial) and LiDCO; travel/accommodation reimbursement was received from
Eli Lilly and LiDCO; he received income for participation in review activities
such as data monitoring boards, statistical analysis from Orion, and for Eli
Lilly; he is an author on manuscripts describing early goal-directed therapy,
and believes in the concept of minimally invasive hemodynamic monitoring.
Dr. Annane participated on the Fresenius Kabi International Advisory Board
(honorarium 2000). His nonfinancial disclosures include being the principal investigator of a completed investigator-led multicenter randomized controlled trial assessing the early guided benefit to risk of NIRS tissue oxygen
saturation; he was the principal investigator of an investigator-led randomized
controlled trial of epinephrine vs norepinephrine (CATS study)Lancet 2007;
he also is the principle investigator of an ongoing investigator-led multinational randomized controlled trial of crystalloids vs colloids (Crystal Study).
Dr. Gerlach has disclosed that he has no potential conflicts of interest;
he is an author of a review on the use of activated protein C in surgical
patients (published in the New England Journal of Medicine, 2009).
Dr. Opal consulted for Genzyme Transgenics (consultant on transgenic antithrombin $1,000), Pfizer (consultant on TLR4 inhibitor project
$3,000), British Therapeutics (consultant on polyclonal antibody project
$1,000), and Biotest A (consultant on immunoglobul project $2,000).
His institution received grant support from Novartis (Clinical Coordinating Center to assist in patient enrollment in a phase III trial with the use
of Tissue Factor Pathway Inhibitor [TFPI] in severe community acquired
pneumonia [SCAP] $30,000 for 2 years), Eisai ($30,000 for 3 years),
Astra Zeneca ($30,000 for 1 year), Aggenix ($30,000 for 1 year), Inimex
($10,000), Eisai ($10,000), Atoxbio ($10,000), Wyeth ($20,000), Sirtris
(preclinical research $50,000), and Cellular Bioengineering Inc. ($500).
He received honoraria from Novartis (clinical evaluation committee TFPI
study for SCAP $20,000) and Eisai ($25,000). He received travel/accommodations reimbursed from Sangart (data and safety monitoring $2,000),
Spectral Diagnostics (data and safety monitoring $2,000), Takeda (data
and safety monitoring $2,000) and Canadian trials group ROS II oseltamivir study (data and safety monitoring board (no money). He is also on the
Data Safety Monitoring Board for Tetraphase (received US $600 in 2012).
Dr. Sevransky received grant support to his institution from Sirius Genomics Inc; he consulted for Idaho Technology ($1,500); he is the co-principal
investigator of a multicenter study evaluating the association between
intensive care unit organizational and structural factors, including protocols and in-patient mortality. He maintains that protocols serve as useful
reminders to busy clinicians to consider certain therapies in patients with
sepsis or other life-threatening illness.
Dr. Sprung received grants paid to his institution from Artisan Pharma
($25,000$50,000), Eisai, Corp ($1,000$5,000 ACCESS), Ferring
Pharmaceuticals A/S ($5,000$10,000), Hutchinson Technology Incorporated ($1,000$5,000), Novartis Corp (less than $1,000). His institution
receives grant support for patients enrolled in clinical studies from Eisai Corporation (PI. Patients enrolled in the ACCESS study $50,000$100,000),
Takeda (PI. Study terminated before patients enrolled). He received grants
paid to his institution and consulting income from Artisan Pharma/Asahi
Kasei Pharma America Corp ($25,000$50,000). He consulted for Eli
Lilly (Sabbatical Consulting fee $10,000$25,000) and received honoraria
from Eli Lilly (lecture $1,000$5,000). He is a member of the Australia and
New Zealand Intensive Care Society Clinical Trials Group for the NICESUGAR Study (no money received); he is a council member of the International Sepsis Forum (as of Oct. 2010); he has held long time research
interests in steroids in sepsis, PI of Corticus study, end-of-life decision making and PI of Ethicus, Ethicatt, and Welpicus studies.
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Dr. Douglas received grants paid to his institution from Eli Lilly (PROWESS
Shock site), Eisai (study site), National Institutes of Health (ARDS Network),
Accelr8 (VAP diagnostics), CCCTG (Oscillate Study), and Hospira (Dexmedetomidine in Alcohol Withdrawal RCT). His institution received an honorarium from the Society of Critical Care Medicine (Paragon ICU Improvement);
he consulted for Eli Lilly (PROWESS Shock SC and Sepsis Genomics
Study) in accordance with institutional policy; he received payment for providing expert testimony (Smith Moore Leatherwood LLP); travel/accommodations reimbursed by Eli Lilly and Company (PROWESS Shock Steering
Committee) and the Society of Critical Care Medicine (Hospital Quality Alliance, Washington DC, four times per year 20092011); he received honoraria from Covidien (non-CME lecture 2010, US$500) and the University
of Minnesota Center for Excellence in Critical Care CME program (2009,
2010); he has a pending patent for a bed backrest elevation monitor.
Dr. Jaeschke has disclosed that he has no potential conflicts of interest.
Dr. Osborn consulted for Sui Generis Health ($200). Her institution
receives grant support from the National Institutes of Health Research,
Health Technology Assessment Programme-United Kingdom (trial doctor for sepsis-related RCT). Salary paid through the NIHR government
funded (nonindustry) grant. Grant awarded to chief investigator from
ICNARC. She is a trial clinician for ProMISe.
Dr. Nunnally received a stipend for a chapter on diabetes mellitus; he is an
author of editorials contesting classic tight glucose control.
Dr. Townsend is an advocate for healthcare quality improvement.
Dr. Reinhart consulted for EISAI (Steering Committee memberless then
US $10,000); BRAHMS Diagnostics (less than US $10,000); and SIRSLab Jena (founding member, less than US $10,000). He received honoraria for lectures including service on the speakers bureau from Biosyn
Germany (less than 10,000) and Braun Melsungen (less than 10,000).
He received royalties from Edwards Life Sciences for sales of central
venous oxygen catheters (~$100,000).
Dr. Kleinpell received monetary compensation for providing expert testimony
(four depositions and one trial in the past year). Her institution receives
grants from the Agency for Healthcare Research and Quality and the Prince
Foundation (4-year R01 grant, PI and 3-year foundation grant, Co-l). She
received honoraria from the Cleveland Clinic and the American Association
of Critical Care Nurses for keynote speeches at conferences; she received
royalties from McGraw Hill (co-editor of critical care review book); travel/
accommodations reimbursed from the American Academy of Nurse Practitioners, Society of Critical Care Medicine, and American Association of
Critical Care Nurses (one night hotel coverage at national conference).
Dr. Angus consulted for Eli Lilly (member of the Data Safety Monitoring
Board, Multicenter trial of a PC for septic shock), Eisai Inc (Anti-TLR4
therapy for severe sepsis), and Idaho Technology (sepsis biomarkers); he
received grant support (investigator, long-term follow-up of phase III trial
of an anti-TLR4 agent in severe sepsis), a consulting income (anti-TRL4
therapy for severe sepsis), and travel/accommodation expense reimbursement from Eisai, Inc; he is the primary investigator for an ongoing National
Institutes of Health-funded study comparing early resuscitation strategies
for sepsis-induced tissue hypoperfusion.
Dr. Deutschman has nonfinancial involvement as a coauthor of the Society
of Critical Care Medicines Glycemic Control guidelines.
Dr. Machado reports unrestricted grant support paid to her institution for
Surviving Sepsis Campaign implementation in Brazil (Eli Lilly do Brasil);
she is the primary investigator for an ongoing study involving vasopressin.
Dr. Rubenfeld received grant support from nonprofit agencies or foundations
including National Institutes of Health ($10 million), Robert Wood Johnson
Foundation ($500,000), and CIHR ($200,000). His institution received grants
from for-profit companies including Advanced Lifeline System ($150,000),
Siemens ($50,000), Bayer ($10,000), Byk Gulden ($15,000), AstraZeneca ($10,000), Faron Pharmaceuticals ($5,000), and Cerus Corporation
($11,000). He received honoraria, consulting fees, editorship, royalties, and
Data and Safety Monitoring Board membership fees paid to him from Bayer
($500), DHD ($1,000), Eli Lilly ($5,000), Oxford University Press ($10,000),
Hospira ($15,000), Cerner ($5,000), Pfizer ($1,000), KCI ($7,500), American Association for Respiratory Care ($10,000), American Thoracic Society
($7,500), BioMed Central ($1,000), National Institutes of Health ($1,500),
and the Alberta Heritage Foundation for Medical Research ($250). He has
database access or other intellectual (non financial) support from Cerner.
Dr. Webb consulted for AstraZeneca (anti-infectives $1,000$5,000) and
Jansen-Cilag (anti-infectives $1,000-$5,000). He received grant support
February 2013 Volume 41 Number 2
Special Article
from a NHMRC project grant (ARISE RECT of EGDT); NHMRC project grant and Fresinius-unrestricted grant (CHEST RCT of voluven vs.
saline); RCT of steroid vs. placebo for septic shock); NHMRC project
grant (BLISS study of bacteria detection by PRC in septic shock) Intensive
Care Foundation-ANZ (BLING pilot RCT of beta-lactam administration
by infusion); Hospira (SPICE programme of sedation delirium research);
NHMRC Centres for Research Excellent Grant (critical illness microbiology observational studies); Hospira-unrestricted grant (DAHlia RCT of
dexmedetomidine for agitated delirium). Travel/accommodations reimbursed by Jansen-Cilag ($5,000$10,000) and AstraZeneca ($1,000$5,000); he has a patent for a meningococcal vaccine. He is chair of the
ANZICS Clinical Trials Group and is an investigator in trials of EGDT, PCR
for determining bacterial load and a steroid in the septic shock trial.
Dr. Beale received compensation for his participation as board member for
Eisai, Inc, Applied Physiology, bioMrieux, Covidien, SIRS-Lab, and Novartis;
consulting income was paid to his institution from PriceSpective Ltd, Easton
Associates (soluble guanylate cyclase activator in acute respiratory distress
syndrome/acute lung injury adjunct therapy to supportive care and ventilation strategies), Eisai (eritoran), and Phillips (Respironics); he provided expert
testimony for Eli Lilly and Company (paid to his institution); honoraria received
(paid to his institution) from Applied Physiology (Applied Physiology PL SAB,
Applied Physiology SAB, Brussels, Satellite Symposium at the ISICEM,
Brussels), bioMrieux (GeneXpert Focus Group, France), SIRS-Lab (SIRSLAB SAB Forum, Brussels and SIRS-LAB SAB, Lisbon), Eli Lilly (CHMP
Hearing), Eisai (eritoran through leader touch plan in Brussels), Eli Lilly
(Lunchtime Symposium, Vienna), Covidien (adult monitoring advisory board
meeting, Frankfurt), Covidien (Global Advisory Board CNIBP Boulder USA),
METHODOLOGY
Definitions
Sepsis is defined as the presence (probable or documented) of
infection together with systemic manifestations of infection.
Severe sepsis is defined as sepsis plus sepsis-induced organ
dysfunction or tissue hypoperfusion (Tables 1 and 2) (6).
Throughout this manuscript and the performance improvement bundles, which are included, a distinction is made
between definitions and therapeutic targets or thresholds. Sepsis-induced hypotension is defined as a systolic blood pressure
(SBP) < 90mm Hg or mean arterial pressure (MAP) < 70mm
Hg or a SBP decrease > 40mm Hg or less than two standard
deviations below normal for age in the absence of other causes
of hypotension. An example of a therapeutic target or typical
threshold for the reversal of hypotension is seen in the sepsis
bundles for the use of vasopressors. In the bundles, the MAP
threshold is 65mm Hg. The use of definition vs. threshold will
be evident throughout this article. Septic shock is defined as
sepsis-induced hypotension persisting despite adequate fluid
resuscitation. Sepsis-induced tissue hypoperfusion is defined
as infection-induced hypotension, elevated lactate, or oliguria.
History of the Guidelines
These clinical practice guidelines are a revision of the 2008
SSC guidelines for the management of severe sepsis and septic
shock (7). The initial SSC guidelines were published in 2004
(8) and incorporated the evidence available through the end
of 2003. The 2008 publication analyzed evidence available
through the end of 2007. The most current iteration is based
on updated literature search incorporated into the evolving
manuscript through fall 2012.
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Grading of Recommendations
We advised the authors to follow the principles of the Grading
of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the
strength of recommendations (Tables 3 and 4). (911). The
SSC Steering Committee and individual authors collaborated
with GRADE representatives to apply the system during the
SSC guidelines revision process. The members of the GRADE
group were directly involved, either in person or via e-mail, in
all discussions and deliberations among the guidelines committee members as to grading decisions.
The GRADE system is based on a sequential assessment of
the quality of evidence, followed by assessment of the balance
between the benefits and risks, burden, and cost, leading to
development and grading of a management recommendation.
Keeping the rating of quality of evidence and strength of
recommendation explicitly separate constitutes a crucial and
defining feature of the GRADE approach. This system classifies
quality of evidence as high (grade A), moderate (grade B), low
(grade C), or very low (grade D). Randomized trials begin
as high-quality evidence but may be downgraded due to
limitations in implementation, inconsistency, or imprecision of
the results, indirectness of the evidence, and possible reporting
bias (Table 3). Examples of indirectness of the evidence
include population studied, interventions used, outcomes
measured, and how these relate to the question of interest.
Well-done observational (nonrandomized) studies begin as
low-quality evidence, but the quality level may be upgraded on
the basis of a large magnitude of effect. An example of this is
the quality of evidence for early administration of antibiotics.
References to supplemental digital content appendices of
GRADEpro Summary of Evidence Tables appear throughout
this document.
The GRADE system classifies recommendations as strong
(grade 1) or weak (grade 2). The factors influencing this determination are presented in Table 4. The assignment of strong
or weak is considered of greater clinical importance than a
difference in letter level of quality of evidence. The committee assessed whether the desirable effects of adherence would
outweigh the undesirable effects, and the strength of a recommendation reflects the groups degree of confidence in
that assessment. Thus, a strong recommendation in favor of
an intervention reflects the panels opinion that the desirable
effects of adherence to a recommendation (beneficial health
outcomes; lesser burden on staff and patients; and cost savings) will clearly outweigh the undesirable effects (harm to
health; more burden on staff and patients; and greater costs).
The potential drawbacks of making strong recommendations in the presence of low-quality evidence were taken into
account. A weak recommendation in favor of an intervention
indicates the judgment that the desirable effects of adherence
to a recommendation probably will outweigh the undesirable
effects, but the panel is not confident about these tradeoffs
either because some of the evidence is low quality (and thus
uncertainty remains regarding the benefits and risks) or the
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Table 1. Diagnostic
benefits and downsides are closely balanced. A strong recommendation is worded as we recommend and a weak recommendation as we suggest.
Throughout the document are a number of statements
that either follow graded recommendations or are listed as
stand-alone numbered statements followed by ungraded
in parentheses (UG). In the opinion of the committee,
these recommendations were not conducive for the GRADE
process.
Critical Care Medicine
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Table 2. Severe
Sepsis
Severe sepsis definition = sepsis-induced tissue hypoperfusion or organ dysfunction (any of the
following thought to be due to the infection)
Sepsis-induced hypotension
Lactate above upper limits laboratory normal
Urine output < 0.5mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
Acute lung injury with Pao2/Fio2 < 250 in the absence of pneumonia as infection source
Acute lung injury with Pao2/Fio2 < 200 in the presence of pneumonia as infection source
Creatinine > 2.0mg/dL (176.8 mol/L)
Bilirubin > 2mg/dL (34.2 mol/L)
Platelet count < 100,000 L
Coagulopathy (international normalized ratio > 1.5)
Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:
12501256.
Underlying methodology
A (high) RCTs
B (moderate) Downgraded RCTs or upgraded observational studies
C (low) Well-done observational studies with control RCTs
D (very low) Downgraded controlled studies or expert opinion based on other evidence
Factors that may decrease the strength of evidence
1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of bias
2. Inconsistency of results, including problems with subgroup analyses
3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison)
4. Imprecision of results
5. High likelihood of reporting bias
Main factors that may increase the strength of evidence
1. Large magnitude of effect (direct evidence, relative risk > 2 with no plausible confounders)
2. Very large magnitude of effect with relative risk > 5 and no threats to validity (by two levels)
3. Dose-response gradient
RCT = randomized controlled trial.
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Table 4. Factors
Recommended Process
The higher the quality of evidence, the more likely a strong recommendation.
The larger the difference between the desirable and undesirable consequences and
the certainty around that difference, the more likely a strong recommendation. The
smaller the net benefit and the lower the certainty for that benefit, the more likely a
weak recommendation.
The more certainty or similarity in values and preferences, the more likely a strong
recommendation.
Resource implications
The lower the cost of an intervention compared to the alternative and other costs related to
(Are resources worth expected benefits?) the decisionie, fewer resources consumedthe more likely a strong recommendation.
they had the least COI. They were required to work within
their group with full disclosure when a topic for which they
had relevant COI was discussed, and they were not allowed
to serve as group head. At the time of final approval of the
document, an update of the COI statement was required. No
additional COI issues were reported that required further
adjudication.
A. Initial Resuscitation
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A. Initial Resuscitation
1. Protocolized, quantitative resuscitation of patients with sepsis- induced tissue hypoperfusion (defined in this document as hypotension
persisting after initial fluid challenge or blood lactate concentration 4 mmol/L). Goals during the first 6 hrs of resuscitation:
a) Central venous pressure 812mm Hg
b) Mean arterial pressure (MAP) 65mm Hg
c) Urine output 0.5 mL/kg/hr
d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C).
2. In patients with elevated lactate levels targeting resuscitation to normalize lactate (grade 2C).
B. Screening for Sepsis and Performance Improvement
1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C).
2. Hospitalbased performance improvement efforts in severe sepsis (UG).
C. Diagnosis
1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s) (grade
1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn
percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted (grade 1C).
2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available and invasive
candidiasis is in differential diagnosis of cause of infection.
3. Imaging studies performed promptly to confirm a potential source of infection (UG).
D. Antimicrobial Therapy
1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe
sepsis without septic shock (grade 1C) as the goal of therapy.
2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or
viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B).
2b. Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B).
3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients
who initially appeared septic, but have no subsequent evidence of infection (grade 2C).
4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, multidrugresistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B). For patients with severe infections
associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an
aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia (grade 2B). A combination of beta-lactam and macrolide for
patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B).
(Continued)
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Table 5.(Continued)
4b. Empiric combination therapy should not be administered for more than 35 days. De-escalation to the most appropriate single
therapy should be performed as soon as the susceptibility profile is known (grade 2B).
5. Duration of therapy typically 710 days; longer courses may be appropriate in patients who have a slow clinical response,
undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including
neutropenia (grade 2C).
6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C).
7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause
(UG).
E. Source Control
1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or
excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is
made, if feasible (grade 1C).
2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until
adequate demarcation of viable and nonviable tissues has occurred (grade 2B).
3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult
should be used (eg, percutaneous rather than surgical drainage of an abscess) (UG).
4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after
other vascular access has been established (UG).
F. Infection Prevention
1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to
reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care
settings and regions where this methodology is found to be effective (grade 2B).
1b. O
ral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated
pneumonia in ICU patients with severe sepsis (grade 2B).
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4mmol/L
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6. We suggest that antiviral therapy be initiated as early as possible in patients with severe sepsis or septic shock of viral
origin (grade 2C).
Rationale. Recommendations for antiviral treatment
include the use of: a) early antiviral treatment of suspected
or confirmed influenza among persons with severe influenza
(eg, those who have severe, complicated, or progressive illness
or who require hospitalization); b) early antiviral treatment
of suspected or confirmed influenza among persons at
higher risk for influenza complications; and c) therapy with a
neuraminidase inhibitor (oseltamivir or zanamivir) for persons
with influenza caused by 2009 H1N1 virus, influenza A (H3N2)
virus, or influenza B virus, or when the influenza virus type or
influenza A virus subtype is unknown (97, 98). Susceptibility
to antivirals is highly variable in a rapidly evolving virus such
as influenza, and therapeutic decisions must be guided by
updated information regarding the most active, strain-specific,
antiviral agents during influenza epidemics (99, 100).
The role of cytomegalovirus (CMV) and other herpesviruses
as significant pathogens in septic patients, especially those not
known to be severely immunocompromised, remains unclear.
Active CMV viremia is common (15%35%) in critically ill
patients; the presence of CMV in the bloodstream has been
repeatedly found to be a poor prognostic indicator (101, 102).
What is not known is whether CMV simply is a marker of disease severity or if the virus actually contributes to organ injury
and death in septic patients (103). No treatment recommendations can be given based on the current level of evidence.
In those patients with severe primary or generalized varicellazoster virus infections, and in rare patients with disseminated
herpes simplex infections, antiviral agents such as acyclovir
can be highly effective when initiated early in the course of
infection (104).
7. We recommend that antimicrobial agents not be used in
patients with severe inflammatory states determined to be
of noninfectious cause (UG).
Rationale. When infection is found not to be present,
antimicrobial therapy should be stopped promptly to minimize the likelihood that the patient will become infected
with an antimicrobial-resistant pathogen or will develop a
drug-related adverse effect. Although it is important to stop
unnecessary antibiotics early, clinicians should be cognizant that blood cultures will be negative in more than 50%
of cases of severe sepsis or septic shock if the patients are
receiving empiric antimicrobial therapy; yet many of these
cases are very likely caused by bacteria or fungi. Thus, the
decisions to continue, narrow, or stop antimicrobial therapy
must be made on the basis of clinician judgment and clinical
information.
E. Source Control
1. We recommend that a specific anatomical diagnosis of
infection requiring consideration for emergent source control (eg, necrotizing soft tissue infection, peritonitis, cholangitis, intestinal infarction) be sought and diagnosed or
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excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).
2. We suggest that when infected peripancreatic necrosis is
identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable
and nonviable tissues has occurred (grade 2B).
3. When source control in a severely septic patient is required,
the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than
surgical drainage of an abscess) (UG).
4. If intravascular access devices are a possible source
of severe sepsis or septic shock, they should be
removed promptly after other vascular access has been
established (UG).
Rationale. The principles of source control in the management of sepsis include a rapid diagnosis of the specific site of
infection and identification of a focus of infection amenable
to source control measures (specifically the drainage of an
abscess, debridement of infected necrotic tissue, removal of a
potentially infected device, and definitive control of a source
of ongoing microbial contamination) (105). Foci of infection readily amenable to source control measures include an
intra-abdominal abscess or gastrointestinal perforation, cholangitis or pyelonephritis, intestinal ischemia or necrotizing
soft tissue infection, and other deep space infection, such as
an empyema or septic arthritis. Such infectious foci should
be controlled as soon as possible following successful initial
resuscitation (106108), and intravascular access devices
that are potentially the source of severe sepsis or septic shock
should be removed promptly after establishing other sites for
vascular access (109, 110).
A randomized, controlled trial (RCT) comparing early
to delayed surgical intervention for peripancreatic necrosis showed better outcomes with a delayed approach (111).
Moreover, a randomized surgical study found that a minimally invasive, step-up approach was better tolerated by
patients and had a lower mortality than open necrosectomy
in necrotizing pancreatitis (112), although areas of uncertainty exist, such as definitive documentation of infection and
appropriate length of delay. The selection of optimal source
control methods must weigh the benefits and risks of the
specific intervention as well as risks of transfer (113). Source
control interventions may cause further complications, such
as bleeding, fistulas, or inadvertent organ injury. Surgical
intervention should be considered when other interventional
approaches are inadequate or when diagnostic uncertainty
persists despite radiologic evaluation. Specific clinical situations require consideration of available choices, the patients
preferences, and the clinicians expertise.
F. Infection Prevention
1a. We suggest that selective oral decontamination (SOD)
and selective digestive decontamination (SDD) should
be introduced and investigated as a method to reduce the
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Table 6. Recommendations:
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Table 7. Norepinephrine
Assumed
Risk
Corresponding
Risk
Dopamine
Norepinephrine
Short-term mortality
Relative
Effect
(95% CI)
Study population
530 per 1000 482 per 1000 (440 to 524)
Study population
82 per 1000 (34 to 195)
Study population
39 per 1000
Quality
No. of
of the
Participants Evidence
(Studies)
(GRADE) Comments
RR 0.91
2043 (6 studies)
(0.83 to 0.99)
moderateb,c
RR 0.47
1931 (2 studies)
(0.38 to 0.58)
moderateb,c
RR 0.35
1931 (2 studies)
(0.19 to 0.66)
moderateb,c
a
The assumed risk is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and
the relative effect of the intervention (and its 95% CI). CI = confidence interval, RR = risk ratio.
b
Strong heterogeneity in the results (I2 = 85%), however this reflects degree of effect, not direction of effect. We have decided not to lower the evidence quality.
c
Effect results in part from hypovolemic and cardiogenic shock patients in De Backer, N Engl J Med 2010. We have lowered the quality of evidence one level for
indirectness.
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has similar effects but is long acting (164). Studies show that
vasopressin concentrations are elevated in early septic shock, but
decrease to normal range in the majority of patients between 24
and 48 hrs as shock continues (165). This has been called relative
vasopressin deficiency because in the presence of hypotension,
vasopressin would be expected to be elevated. The significance
of this finding is unknown. The VASST trial, an RCT comparing
norepinephrine alone to norepinephrine plus vasopressin at
0.03U/min, showed no difference in outcome in the intent-totreat population (166). An a priori defined subgroup analysis
demonstrated that survival among patients receiving < 15 g/
min norepinephrine at the time of randomization was better
with the addition of vasopressin; however, the pretrial rationale
for this stratification was based on exploring potential benefit in
the population requiring 15 g/min norepinephrine. Higher
doses of vasopressin have been associated with cardiac, digital,
and splanchnic ischemia and should be reserved for situations
where alternative vasopressors have failed (167). Information
from seven trials (n = 963 patients with septic shock) comparing
norepinephrine with vasopressin (or terlipressin) does not
support the routine use of vasopressin or its analog terlipressin
(93, 95, 97, 99, 159, 161, 164, 166, 168170). Indeed, the relative
risk of dying was 1.12 (95% CI, 0.961.30; fixed effects; I2 = 0%).
However, the risk of supraventricular arrhythmias was increased
with norepinephrine (RR, 7.25; 95% CI, 2.3022.90; fixed effect;
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J. Corticosteroids
1. We suggest not using intravenous hydrocortisone as a treatment of adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). If this
is not achievable, we suggest intravenous hydrocortisone
alone at a dose of 200mg per day (grade 2C).
Rationale. The response of septic shock patients to fluid
and vasopressor therapy seems to be an important factor in
selection of patients for optional hydrocortisone therapy. One
French multicenter RCT of patients in vasopressor-unresponsive septic shock (hypotension despite fluid resuscitation and
vasopressors for more than 60 mins) showed significant shock
reversal and reduction of mortality rate in patients with relative adrenal insufficiency (defined as postadrenocorticotropic
hormone [ACTH] cortisol increase 9 g/dL) (175). Two
smaller RCTs also showed significant effects on shock reversal
with steroid therapy (176, 177). In contrast, a large, European
multicenter trial (CORTICUS) that enrolled patients without
sustained shock and had a lower risk of death than the French
trial failed to show a mortality benefit with steroid therapy
(178). Unlike the French trial that only enrolled shock patients
with blood pressure unresponsive to vasopressor therapy, the
CORTICUS study included patients with septic shock regardless of how the blood pressure responded to vasopressors; the
study baseline (placebo) 28-day mortality rate was 61% and
31%, respectively. The use of the ACTH test (responders and
nonresponders) did not predict the faster resolution of shock.
In recent years, several systematic reviews have examined the
use of low-dose hydrocortisone in septic shock with contradictory results: Annane et al (179) analyzed the results of 12 studies and calculated a significant reduction in 28-day mortality
with prolonged low-dose steroid treatment in adult septic
shock patients (RR, 0.84; 95% CI, 0.720.97; p = 0.02) (180).
In parallel, Sligl and colleagues (180) used a similar technique,
but only identified eight studies for their meta-analysis, six
of which had a high-level RCT design with low risk of bias
(181). In contrast to the aforementioned review, this analysis
revealed no statistically significant difference in mortality (RR,
1.00; 95% CI, 0.841.18). Both reviews, however, confirmed
the improved shock reversal by using low-dose hydrocortisone
(180, 181). A recent review on the use of steroids in adult septic shock underlined the importance of selection of studies for
systematic analysis (181) and identified only 6 high-level RCTs
as adequate for systematic review (175178, 182, 183). When
only these six studies are analyzed, we found that in low risk
patients from three studies (ie, those with a placebo mortality rate of less than 50%, which represents the majority of all
patients), hydrocortisone failed to show any benefit on outcome (RR, 1.06). The minority of patients from the remaining three studies, who had a placebo mortality of greater than
60%, showed a nonsignificant trend to lower mortality by using
hydrocortisone (see Supplemental Digital Content 4, http://
links.lww.com/CCM/A615, Summary of Evidence Table).
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L. Immunoglobulins
1. We suggest not using intravenous immunoglobulins in
adult patients with severe sepsis or septic shock (grade 2B).
Rationale. One larger multicenter RCT (n = 624) (210) in
adult patients and one large multinational RCT in infants with
neonatal sepsis (n = 3493) (211) found no benefit for intravenous
immunoglobulin (IVIG). (For more on this trial, see the section,
Pediatric Considerations.). A meta-analysis by the Cochrane collaboration, which did not include this most recent RCT, identified 10 polyclonal IVIG trials (n = 1430) and seven trials on
immunoglobulin (Ig) M-enriched polyclonal IVIG (n = 528)
(212). Compared with placebo, IVIG resulted in a significant
reduction in mortality (RR, 0.81 and 95% CI, 0.700.93; and RR,
0.66 and 95% CI, 0.510.85, respectively). Also the subgroup of
IgM-enriched IVIGs (n = 7 trials) showed a significant reduction in mortality rates compared with placebo (RR, 0.66; 95%
CI, 0.510.85). Trials with low risk of bias showed no reduction
in mortality with polyclonal IVIG (RR, 0.97; 95% CI, 0.811.15;
five trials, n = 945). Three of these trials (210, 213, 214) used standard polyclonal IVIG and two IgM-enriched IVIG (215, 216).
These findings are in accordance with those of two older
meta-analyses (217, 218) from other Cochrane authors. One
systematic review (217) included a total of 21 trials and showed
a relative risk of death of 0.77 with immunoglobulin treatment
(95% CI, 0.680.88); however, the results of only high-quality
trials (total of 763 patients) showed a relative risk of 1.02 (95%
CI, 0.841.24). Similarly, Laupland et al (218) found a significant
reduction in mortality with the use of IVIG treatment (OR, 0.66;
95% CI, 0.530.83; p < 0.005). When only high-quality studies
were pooled, the OR for mortality was 0.96 (95% CI, 0.711.3;
p = 0.78). Two meta-analyses, which used less strict criteria to
identify sources of bias or did not state their criteria for the
assessment of study quality, found significant improvement in
patient mortality with IVIG treatment (219, 220). In contrast
to the most recent Cochrane review, Kreymann et al (219) classified five studies that investigated IgM-enriched preparation as
high-quality studies, combining studies in adults and neonates,
and found an OR for mortality of 0.5 (95% CI, 0.340.73).
Most IVIG studies are small, some have methodological
flaws; the only large study (n = 624) showed no effect (210).
Subgroup effects between IgM-enriched and nonenriched formulations reveal substantial heterogeneity. In addition, indirectness and publication bias were considered in grading this
recommendation. The low-quality evidence led to the grading
as a weak recommendation. The statistical information that
comes from the high-quality trials does not support a beneficial effect of polyclonal IVIG. We encourage conducting large
multicenter studies to further evaluate the effectiveness of
other polyclonal immunoglobulin preparations given intravenously in patients with severe sepsis.
M. Selenium
1. We suggest not using intravenous selenium to treat severe
sepsis (grade 2C).
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Table 8. Recommendations:
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Table 8.(Continued)
3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a Pao2/Fio2
< 150 mm Hg (grade 2C).
Q. Glucose Control
1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when
2 consecutive blood glucose levels are >180mg/dL. This protocolized approach should target an upper blood glucose
180mg/dL rather than an upper target blood glucose 110mg/dL (grade 1A).
2. Blood glucose values be monitored every 12 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs
thereafter (grade 1C).
3. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not
accurately estimate arterial blood or plasma glucose values (UG).
R. Renal Replacement Therapy
1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute
renal failure (grade 2B).
2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D).
S. Bicarbonate Therapy
1. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in
patients with hypoperfusion-induced lactic acidemia with pH 7.15 (grade 2B).
T. Deep Vein Thrombosis Prophylaxis
1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). This should
be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C
versus three times daily UFH). If creatinine clearance is <30 mL/min, use dalteparin (grade 1A) or another form of LMWH that
has a low degree of renal metabolism (grade 2C) or UFH (grade 1A).
2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression
devices whenever possible (grade 2C).
3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent
intracerebral hemorrhage) not receive pharmacoprophylaxis (grade 1B), but receive mechanical prophylactic treatment, such
as graduated compression stockings or intermittent compression devices (grade 2C), unless contraindicated. When the risk
decreases start pharmacoprophylaxis (grade 2C).
U. Stress Ulcer Prophylaxis
1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who
have bleeding risk factors (grade 1B).
2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA (grade 2D)
3. Patients without risk factors do not receive prophylaxis (grade 2B).
V. Nutrition
1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only
intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).
2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day),
advancing only as tolerated (grade 2B).
3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in
conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).
4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating
supplementation in patients with severe sepsis (grade 2C).
W. Setting Goals of Care
1. Discuss goals of care and prognosis with patients and families(grade 1B).
2. Incorporategoals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate (grade 1B).
3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission (grade 2C).
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guidelines recommended use of rhAPC in line with the product labeling instructions required by the U.S. and European
regulatory authorities with a grade B quality of evidence (7, 8).
By the time of publication of the 2008 SSC guidelines, additional studies of rhAPC in severe sepsis (as required by regulatory agencies) had shown it ineffective in less severely ill patients
with severe sepsis as well as in children (229, 230). The 2008 SSC
recommendations reflected these findings, and the strength of
the rhAPC recommendation was downgraded to a suggestion
for use in adult patients with a clinical assessment of high risk of
death, most of whom will have Acute Physiology and Chronic
Health Evaluation (APACHE) II scores 25 or multiple organ
failure (grade 2C; quality of evidence was also downgraded from
2004, from B to C) (7). The 2008 guidelines also recommended
against use of rhAPC in low-risk adult patients, most of whom
will have APACHE II scores 20 or single organ failures (grade
1A), and against use in all pediatric patients (grade 1B).
The results of the PROWESS SHOCK trial (1,696 patients)
were released in late 2011, showing no benefit of rhAPC in patients
with septic shock (mortality 26.4% for rhAPC, 24.2% placebo)
with a relative risk of 1.09 and a p value of 0.31 (231). The drug
was withdrawn from the market and is no longer available, negating any need for an SSC recommendation regarding its use.
O. Mechanical Ventilation of Sepsis-Induced Acute
Respiratory Distress Syndrome
1. We recommend that clinicians target a tidal volume of
6 mL/kg predicted body weight in patients with sepsisinduced acute respiratory distress syndrome (ARDS) (grade
1A vs. 12 mL/kg).
2. We recommend that plateau pressures be measured in
patients with ARDS and that the initial upper limit goal for
plateau pressures in a passively inflated lung be 30cm H2O
(grade 1B).
Rationale. Of note, studies used to determine recommendations in this section enrolled patients using criteria from the
American-European Consensus Criteria Definition for Acute
Lung Injury (ALI) and ARDS (232). For this document, we
have used the updated Berlin definition and used the terms
mild, moderate, and severe ARDS (Pao2/Fio2 300, 200, and
100 mm Hg, respectively) for the syndromes previously
known as ALI and ARDS (233). Several multicenter randomized trials have been performed in patients with established
ARDS to evaluate the effects of limiting inspiratory pressure
through moderation of tidal volume (234238). These studies
showed differing results that may have been caused by differences in airway pressures in the treatment and control groups
(233, 234, 239). Several meta-analyses suggest decreased mortality in patients with a pressure- and volume-limited strategy
for established ARDS (240, 241).
The largest trial of a volume- and pressure-limited strategy
showed an absolute 9% decrease in all-cause mortality in patients
with ARDS ventilated with tidal volumes of 6 mL/kg compared
with 12 mL/kg of predicted body weight (PBW), and aiming for
a plateau pressure 30 cm H2O (233). The use of lung-protective
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with established ARDS, some of whom had shock present during the ICU stay, and active attempts to reduce fluid volume
were conducted only outside periods of shock.
12. In the absence of specific indications such as bronchospasm,
we recommend against the use of 2-agonists for treatment
of patients with sepsis-induced ARDS (grade 1B).
Rationale. Patients with sepsis-induced ARDS often develop
increased vascular permeability. Preclinical and early clinical data
suggest that -adrenergic agonists may speed resorption of alveolar edema (300). Two randomized clinical trials studied the effect
of -agonists in patients with ARDS (301, 302). In one, a comparison of aerosolized albuterol and placebo in 282 patients with
ARDS, the trial was stopped for futility (301). Patients receiving albuterol had higher heart rates on day 2, and a trend was
detected toward decreased ventilator-free days (days alive and off
the ventilator). The rates of death before discharge were 23.0% in
the albuterol group vs. 17.7% in placebo-treated patients. More
than half of the patients enrolled in this trial had pulmonary or
nonpulmonary sepsis as the cause of the ARDS (301).
The use of intravenous salbutamol was tested in the
BALTI-2 trial (302). Three hundred twenty-six patients with
ARDS, 251 of whom had pulmonary or nonpulmonary sepsis
as cause, were randomized to intravenous salbutatmol, 15 g/
kg of ideal body weight, or placebo for up to 7 days. Patients
treated with salbutamol had increased 28-day mortality rates
(34% vs. 23%; RR, 1.4; 95% CI, 1.032.08) leading to early termination of the trial (302).
Beta-2 agonists may have specific indications, such as treatment of bronchospasm and hyperkalemia. In the absence of
these conditions, we recommend against the routine use of
-agonists, either in intravenous or aerosolized form, for the
treatment of patients with sepsis-induced ARDS.
P. Sedation, Analgesia, and Neuromuscular Blockade
in Sepsis
1. We recommend that either continuous or intermittent
sedation be minimized in mechanically ventilated sepsis
patients, targeting specific titration endpoints (grade 1B).
Rationale. A growing body of evidence indicates that limiting
the use of sedation in critically ill ventilated patients can
reduce the duration of mechanical ventilation and ICU and
hospital lengths of stay (303305). While studies limiting
sedation have been performed in a wide range of critically ill
patients, there is little reason to assume that septic patients
will not derive benefit from this approach (305). The use of
protocols for sedation is one method to limit sedation use, and
a randomized, controlled clinical trial found that protocolized
sedation compared with usual care reduced duration of
mechanical ventilation, lengths of stay, and tracheostomy
rates (305). Avoidance of sedation is another strategy. A
recent observational study of 250 critically ill patients suggests
that deep sedation is common in mechanically ventilated
patients (306). A randomized, controlled clinical trial found
that patients treated with intravenous morphine boluses
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in treatment effects across subgroups, including the sepsis subjects. Therefore, no studies suggest the superiority of TPN over
enteral alone in the first 24 hrs. In fact, there is a suggestion that
enteral nutrition may in fact be superior to TPN vis--vis infectious complications and possibly requirement for intensive care
and organ support.
Immune system function can be modified through alterations in the supply of certain nutrients, such as arginine, glutamine, or omega-3 fatty acids. Numerous studies have assessed
whether use of these agents as nutritional supplements can
affect the course of critical illness, but few specifically addressed
their early use in sepsis. Four meta-analyses evaluated immuneenhancing nutrition and found no difference in mortality, neither in surgical nor medical patients (445448). However, they
analyzed all studies together, regardless of the immunocomponent used, which could have compromised their conclusions.
Other individual studies analyzed diets with a mix of arginine,
glutamine, antioxidants, and/or omega-3 with negative results
(449, 450) including a small study in septic patients showing a
nonsignificant increase in ICU mortality (451, 452).
Arginine.
Arginine availability is reduced in sepsis, which can lead
to reduced nitric oxide synthesis, loss of microcirculatory
regulation, and enhanced production of superoxide and
peroxynitrite. However, arginine supplementation could lead
to unwanted vasodilation and hypotension (452, 453). Human
trials of l-arginine supplementation have generally been small
and reported variable effects on mortality (454457). The
only study in septic patients showed improved survival, but
had limitations in study design (455). Other studies suggested
no benefit (449, 454, 455) or possible harm (455) in the
subgroup of septic patients. Some authors found improvement
in secondary outcomes in septic patients, such as reduced
infectious complications (454, 455) and length of hospital
stay (454), but the relevance of these findings in the face of
potential harm is unclear.
Glutamine.
Glutamine levels are also reduced during critical illness.
Exogenous supplementation can improve gut mucosal atrophy
and permeability, possibly leading to reduced bacterial translocation. Other potential benefits are enhanced immune cell
function, decreased pro-inflammatory cytokine production,
and higher levels of glutathione and antioxidative capacity
(452, 453). However, the clinical significance of these findings
is not clearly established.
Although a previous meta-analysis showed mortality reduction (428), four other meta-analyses did not (458462). Other
small studies not included in those meta-analyses had similar
results (463, 464). Three recent well-designed studies also failed
to show a mortality benefit in the primary analyses (227, 465,
466), but again, none focused specifically on septic patients.
Two small studies on septic patients showed no benefit in mortality rates (467, 468) but a significant reduction in infectious
complications (467) and a faster recovery of organ dysfunction (468). Some previous individual studies and meta-analyses
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showed positive secondary outcomes, such as reduction in infectious morbidity (461, 462, 465) and organ dysfunction (462).
Beneficial effects were found mostly in trials using parenteral
rather than enteral glutamine. However, recent and well-sized
studies could not demonstrate a reduction of infectious complications (227) or organ dysfunction (465, 466), even with parenteral glutamine. An ongoing trial (REDOXS) of 1,200 patients
will test both enteral and parenteral glutamine and antioxidant
supplementation in critically ill, mechanically ventilated patients
(469). Although no clear benefit could be demonstrated in clinical trials with supplemental glutamine, there is no sign of harm.
The omega-3 fatty acids eicosapentaenoic acid (EPA) and
gamma-linolenic acid (GLA) are eicosanoid precursors. The
prostaglandins, leukotrienes, and thromboxanes produced from
EPA/GLA are less potent than their arachidonic acid-derived
equivalents, reducing the pro-inflammatory impact on the
immune response (452, 453). Three early studies were summarized in a meta-analysis that reported a significant mortality reduction, increased ventilator-free days, and reduced risk of
new organ dysfunction (470). However, only one study was in
septic patients (471), none was individually powered for mortality (472, 473), and all three used a diet with high omega-6 lipid
content in the control group, which is not the usual standard of
care in the critically ill. The authors who first reported reduced
mortality in sepsis (471) conducted a follow-up multicenter
study and again found improvement in nonmortality outcomes,
though notably with no demonstrable effect on mortality (474).
Other studies using enteral (475477) or parenteral (478480)
fish oil failed to confirm these findings in general critical illness
or acute lung injury. Thus, no large, reproducible findings suggest a clear benefit in the use of immunomodulating nutritional
supplements in sepsis, though larger trials are ongoing.
W. Setting Goals of Care
1. We recommend that goals of care and prognosis be discussed with patients and families (grade 1B).
2. We recommend that the goals of care be incorporated into
treatment and end-of-life care planning, utilizing palliative
care principles where appropriate (grade 1B).
3. We suggest that goals of care be addressed as early as feasible,
but no later than within 72 hrs of ICU admission (grade 2C).
Rationale. The majority of ICU patients receive full
support with aggressive, life-sustaining treatments. Many
patients with multiple organ system failure or severe neurologic injuries will not survive or will have a poor quality
of life. Decisions to provide less-aggressive life-sustaining
treatments or to withdraw life-sustaining treatments in these
patients may be in the patients best interest and may be what
patients and their families desire (481). Physicians have different end-of-life practices based on their region of practice,
culture, and religion (482). Although the outcome of intensive care treatment in critically ill patients may be difficult
to prognosticate accurately, establishing realistic treatment
goals is important in promoting patient-centered care in the
ICU (483). Models for structuring initiatives to enhance care
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Table 9. Recommendations:
A. Initial Resuscitation
1. For respiratory distress and hypoxemia start with face mask oxygen or if needed and available, high flow nasal cannula oxygen
or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseus access can be
used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then
cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation (grade 2C).
2. Initial therapeutic end points of resuscitation of septic shock: capillary refill of 2 secs, normal blood pressure for age, normal pulses
with no differential between peripheral and central pulses, warm extremities, urine output >1 mLkg-1hr-1, and normal mental status.
Scvo2 saturation 70% and cardiac index between 3.3 and 6.0L/min/m2 should be targeted thereafter (grade 2C).
3. Follow American College of Critical Care Medicine-Pediatric Life Support ( ACCM-PALS) guidelines for the management of
septic shock (grade 1C).
4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock
(grade 1C).
B. Antibiotics and Source Control
1. Empiric antibiotics be administered within 1hr of the identification of severe sepsis. Blood cultures should be obtained before
administering antibiotics when possible but this should not delay administration of antibiotics. The empiric drug choice should
be changed as epidemic and endemic ecologies dictate (eg H1N1, MRSA, chloroquine resistant malaria, penicillin-resistant
pneumococci, recent ICU stay, neutropenia ) (grade 1D).
2. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension (grade 2D).
3. Early and aggressive source control (grade 1D).
4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease (grade 1A).
C. Fluid Resuscitation
1. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins
with infusion of isotonic crystalloids or albumin with boluses of up to 20mL/kg crystalloids (or albumin equivalent ) over 510
minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and
level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be
implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell
crises) blood transfusion is considered superior to crystalloid or albumin bolusing (grade 2C).
D. Inotropes/Vasopressors/Vasodilators
1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid
resuscitation (grade 2C).
2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given
vasodilator therapies in addition to inotropes (grade 2C).
E. Extracorporeal Membrane Oxygenation (ECMO)
1. Consider ECMO for refractory pediatric septic shock and respiratory failure (grade 2C).
F. Corticosteroids
1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute
(classic) adrenal insufficiency (grade 1A).
G. Protein C and Activated Protein Concentrate
No recommendation as no longer available.
H. Blood Products and Plasma Therapies
1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock
(< 70%), hemoglobin levels of 10g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower
target > 7.0g/dL can be considered reasonable (grade 1B).
2. Similar platelet transfusion targets in children as in adults (grade 2C).
3. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated
intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura (grade 2C).
I. Mechanical Ventilation.
1 Lung-protective strategies during mechanical ventilation (grade 2C)
(Continued)
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Table 9.(continued)
J. Sedation/Analgesia/Drug Toxicities
1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis (grade 1D).
2. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse
drug-related events (grade 1C).
K. Glycemic Control
1. Control hyperglycemia using a similar target as in adults 180mg/dL. Glucose infusion should accompany insulin therapy in
newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant (grade 2C).
L. Diuretics and Renal Replacement Therapy
1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration
(CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload (grade 2C).
M. Deep Vein Thrombosis (DVT) Prophylaxis
No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.
N. Stress Ulcer(SU) Prophylaxis
No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.
O. Nutrition
1. Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot (grade 2C).
4. We recommend evaluating for and reversing pneumothorax, pericardial tamponade, or endocrine emergencies in
patients with refractory shock (grade 1C).
Rationale. Endocrine emergencies include hypoadrenalism and hypothyroidism. In select patients, intra-abdominal
hypertension may also need to be considered (513515).
B. Antibiotics and Source Control
1. We recommend that empiric antimicrobials be administered within 1 hr of the identification of severe sepsis. Blood
cultures should be obtained before administering antibiotics when possible, but this should not delay initiation of
antibiotics. The empiric drug choice should be changed as
epidemic and endemic ecologies dictate (eg, H1N1, methicillin-resistant S. aureus, chloroquine-resistant malaria,
penicillin-resistant pneumococci, recent ICU stay, neutropenia) (grade 1D).
Rationale. Vascular access and blood drawing is more difficult in newborns and children. Antimicrobials can be given
intramuscularly or orally (if tolerated) until intravenous line
access is available (516519).
2. We suggest the use of clindamycin and antitoxin therapies
for toxic shock syndromes with refractory hypotension
(grade 2D).
Rationale. Children are more prone to toxic shock than
adults because of their lack of circulating antibodies to toxins.
Children with severe sepsis and erythroderma and suspected
toxic shock should be treated with clindamycin to reduce
toxin production. The role of IVIG in toxic shock syndrome
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Figure 2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Reproduced from Brierley
J, Carcillo J, Choong K, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666688.
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Rationale. Although there are no data supporting any particular drugs or regimens, propofol should not be used for
long-term sedation in children younger than 3 years because
of the reported association with fatal metabolic acidosis. The
use of etomidate and/or dexmedetomidine during septic shock
should be discouraged, or at least considered carefully, because
these drugs inhibit the adrenal axis and the sympathetic nervous system, respectively, both of which are needed for hemodynamic stability (617620).
2. We recommend monitoring drug toxicity labs because
drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events
(grade 1C).
K. Glycemic Control
O. Nutrition
1. Enteral nutrition should be used in children who can tolerate it, parenteral feeding in those who cannot (grade 2C).
Rationale. Dextrose 10% (always with sodium-containing
solution in children) at maintenance rate provides the glucose delivery requirements for newborns and children (636).
Patients with sepsis have increased glucose delivery needs
which can be met by this regimen. Specific measurement of
caloric requirements are thought to be best attained using a
metabolic cart as they are generally less in the critically ill child
than in the healthy child.
ACKNOWLEDGMENT
The revision process was funded through a grant from the
Gordon and Betty Irene Moore Foundation. We would also
like to acknowledge the dedication and untold hours of
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APPENDIX A
2012 Surviving Sepsis Campaign Guidelines
Committee
Pediatric Subgroup
Jan A. Hazelzet, Adrienne G. Randolph, Margaret M. Parker,
Ann E. Thompson, Paolo Biban, Alan Duncan, Cristina Mangia,
Niranjan Kissoon, and Joseph A. Carcillo (Head).
www.ccmjournal.org
635
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Appendix B
Conflict of Interest Process
636
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Appendix C
ARDSnet Ventilator Management
Assist control modevolume ventilation
Reduce tidal volume to 6mL/kg lean body weight
Keep plateau pressure < 30cm H2O
Reduce tidal volume as low as 4mL/kg predicted body weight to limit plateau pressure
Maintain Sao2/Spo2 between 88% and 95%
Anticipated PEEP settings at various Fio2 requirements
0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0
Fio2
PEEP
5 5
8 8 10 10 10 12 14 14 14 16 18 20-24
Appendix D
Summary of Ventilator Procedures in the Higher PEEP Groups of the ALVEOLI Trial
Procedure
Value
Ventilator mode
Volume assist/control
30cm H2O
1:11:3
Oxygenation goal
Pao2
5580mm Hg
Spo2
88%95%
Weaning
0.3
0.3
0.4
0.4
0.5
0.5
0.50.8
0.8
0.9
PEEP
12
14
14
16
16
18
20
22
22
2224
Note: Complete ventilator procedures and eligibility criteria can be found at www.ardsnet.org.
Spo2 = oxyhemoglobin saturation as measured by pulse oximetry, Fio2 = fraction of inspired oxygen, PEEP = positive end-expiratory pressure.
a
In both study groups (lower and higher PEEP), additional increases in PEEP to 34cm H2O were allowed but not required after Fio2 had been
increased to 1.0, according to the protocol.
Adapted from Brower RG, Lanken PN, MacIntyre N, et al: Higher vs. lower positive end-expiratory pressures in patients with the acute respiratory
distress syndrome.
N Engl J Med. 2004; 351(4):327336.
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