Professional Documents
Culture Documents
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%
5%
7%
Nov-12
Dec-12
9%
13%
Oct-12
10%
72%
78%
55%
30%
20%
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
Mar-13
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
Mar-13
Feb-13
Jan-13
Dec-12
Nov-12
Oct-12
Sep-12
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.
1
2
580
www.ccmjournal.org
20
21
Special Article
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
www.ccmjournal.org
581
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.
582
www.ccmjournal.org
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.
www.ccmjournal.org
583
Dellinger et al
www.ccmjournal.org
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
February 2013 Volume 41 Number 2
Special Article
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
585
Dellinger et al
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.
586
www.ccmjournal.org
Special Article
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
587
Dellinger et al
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)
588
www.ccmjournal.org
Special Article
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).
589
Dellinger et al
www.ccmjournal.org
Special Article
4mmol/L
591
Dellinger et al
www.ccmjournal.org
Special Article
593
Dellinger et al
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
594
www.ccmjournal.org
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
February 2013 Volume 41 Number 2
Special Article
595
Dellinger et al
Table 6. Recommendations:
www.ccmjournal.org
Special Article
597
Dellinger et al
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.
www.ccmjournal.org
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;
February 2013 Volume 41 Number 2
Special Article
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).
www.ccmjournal.org
599
Dellinger et al
www.ccmjournal.org
Special Article
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).
www.ccmjournal.org
601
Dellinger et al
Table 8. Recommendations:
www.ccmjournal.org
Special Article
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).
www.ccmjournal.org
603
Dellinger et al
www.ccmjournal.org
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
February 2013 Volume 41 Number 2
Special Article
605
Dellinger et al
www.ccmjournal.org
Special Article
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
Critical Care Medicine
607
Dellinger et al
www.ccmjournal.org
Special Article
609
Dellinger et al
www.ccmjournal.org
Special Article
611
Dellinger et al
www.ccmjournal.org
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
February 2013 Volume 41 Number 2
Special Article
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
Critical Care Medicine
613
Dellinger et al
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)
614
www.ccmjournal.org
Special Article
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
www.ccmjournal.org
615
Dellinger et al
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.
www.ccmjournal.org
Special Article
617
Dellinger et al
www.ccmjournal.org
Special Article
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
www.ccmjournal.org
619
Dellinger et al
REFERENCES
620
www.ccmjournal.org
Special Article
42. Rivers EP, Ahrens T: Improving outcomes for severe sepsis and septic shock: Tools for early identification of at-risk patients and treatment
protocol implementation. Crit Care Clin 2008; 24(3 Suppl):S147
43. Gao F, Melody T, Daniels DF, et al: The impact of compliance with
6-hour and 24-hour sepsis bundles on hospital mortality in patients
with severe sepsis: A prospective observational study. Crit Care
2005; 9:R764R770
44. Schorr C: Performance improvement in the management of sepsis.
Crit Care Clin 2009; 25:857867
45. Girardis M, Rinaldi L, Donno L, et al; Sopravvivere alla Sepsi Group
of the Modena-University Hospital: Effects on management and outcome of severe sepsis and septic shock patients admitted to the
intensive care unit after implementation of a sepsis program: A pilot
study. Crit Care 2009; 13:R143
46. Pestaa D, Espinosa E, Sangesa-Molina JR, et al; REASEP Sepsis Study Group: Compliance with a sepsis bundle and its effect
on intensive care unit mortality in surgical septic shock patients. J
Trauma 2010; 69:12821287
47. Berenholtz SM, Pronovost PJ, Ngo K, et al; Core Sepsis Measurement Team: Developing quality measures for sepsis care in the ICU.
Jt Comm J Qual Patient Saf 2007; 33:559568
48. Black MD, Schorr C, Levy MM: Knowledge translation and the multifaceted intervention in the intensive care unit. Crit Care Med 2012;
40:13241328
49. Suarez D, Ferrer R, Artigas A, et al; Edusepsis Study Group: Costeffectiveness of the Surviving Sepsis Campaign protocol for severe
sepsis: A prospective nation-wide study in Spain. Intensive Care Med
2011; 37:444452
50. Levy MM, Pronovost PJ, Dellinger RP, et al: Sepsis change bundles:
Converting guidelines into meaningful change in behavior and clinical
outcome. Crit Care Med 2004; 32(11 Suppl):S595S597
51. Weinstein MP, Reller LB, Murphy JR, et al: The clinical significance of
positive blood cultures: A comprehensive analysis of 500 episodes of
bacteremia and fungemia in adults. I. Laboratory and epidemiologic
observations. Rev Infect Dis 1983; 5:3553
52. Blot F, Schmidt E, Nitenberg G, et al: Earlier positivity of centralvenous- versus peripheral-blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol 1998; 36:105109
53. Mermel LA, Maki DG: Detection of bacteremia in adults: Consequences of culturing an inadequate volume of blood. Ann Intern Med
1993; 119:270272
54. Guidelines for the management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia. Am J
Respir Crit Care Med 2005; 171:388416
55. Muscedere J, Dodek P, Keenan S, et al; VAP Guidelines Committee and the Canadian Critical Care Trials Group: Comprehensive
evidence-based clinical practice guidelines for ventilator-associated
pneumonia: Diagnosis and treatment. J Crit Care 2008; 23:138147
56. Giamarellos-Bourboulis EJ, Giannopoulou P, Grecka P, et al: Should
procalcitonin be introduced in the diagnostic criteria for the systemic
inflammatory response syndrome and sepsis? J Crit Care 2004;
19:152157
57. Uzzan B, Cohen R, Nicolas P, et al: Procalcitonin as a diagnostic test
for sepsis in critically ill adults and after surgery or trauma: A systematic review and meta-analysis. Crit Care Med 2006; 34:19962003
58. Tang BM, Eslick GD, Craig JC, et al: Accuracy of procalcitonin for
sepsis diagnosis in critically ill patients: Systematic review and metaanalysis. Lancet Infect Dis 2007; 7:210217
59. Tenover FC: Rapid detection and identification of bacterial pathogens
using novel molecular technologies: Infection control and beyond.
Clin Infect Dis 2007; 44:418423
60. Klouche M, Schrder U: Rapid methods for diagnosis of bloodstream
infections. Clin Chem Lab Med 2008; 46:888908
61. Tissari P, Zumla A, Tarkka E, et al: Accurate and rapid identification of bacterial species from positive blood cultures with a DNAbased microarray platform: An observational study. Lancet 2010;
375:224230
62. Alam FF, Mustafa AS, Khan ZU: Comparative evaluation of (1,
3)-beta-D-glucan, mannan and anti-mannan antibodies, and Candida
621
Dellinger et al
Infectious Diseases. Seventh edition. Mandell GL, Bennett JE, Dolin
R (Eds). Philadelphia, Churchill Livingstone, 2010, pp 297307
83. Heyland DK, Johnson AP, Reynolds SC, et al: Procalcitonin for
reduced antibiotic exposure in the critical care setting: A systematic review and an economic evaluation. Crit Care Med 2011;
39:17921799
84. Jensen JU, Hein L, Lundgren B, et al; Procalcitonin And Survival
Study (PASS) Group: Procalcitonin-guided interventions against
infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial. Crit Care Med
2011; 39:20482058
85. Brunkhorst FM, Oppert M, Marx G, et al; German Study Group Competence Network Sepsis (SepNet): Effect of empirical treatment
with moxifloxacin and meropenem vs meropenem on sepsis-related
organ dysfunction in patients with severe sepsis: A randomized trial.
JAMA 2012; 307:23902399
86. Kumar A, Safdar N, Kethireddy S, et al: A survival benefit of combination antibiotic therapy for serious infections associated with sepsis
and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study. Crit Care Med 2010; 38:16511664
87. Kumar A, Zarychanski R, Light B, et al; Cooperative Antimicrobial
Therapy of Septic Shock (CATSS) Database Research Group: Early
combination antibiotic therapy yields improved survival compared
with monotherapy in septic shock: A propensity-matched analysis.
Crit Care Med 2010; 38:17731785
88. Micek ST, Welch EC, Khan J, et al: Empiric combination antibiotic
therapy is associated with improved outcome against sepsis due
to Gram-negative bacteria: A retrospective analysis. Antimicrob
Agents Chemother 2010; 54:17421748
89. Al-Hasan MN, Wilson JW, Lahr BD, et al: Beta-lactam and fluoroquinolone combination antibiotic therapy for bacteremia caused
by gram-negative bacilli. Antimicrob Agents Chemother 2009;
53:13861394
90. Klastersky J: Management of fever in neutropenic patients with
different risks of complications. Clin Infect Dis 2004; 39 Suppl
1:S32S37
91. Martin-Loeches I, Lisboa T, Rodriguez A, et al: Combination antibiotic therapy with macrolides improves survival in intubated patients
with community-acquired pneumonia. Intensive Care Med 2010;
36:612620
92. Rodrguez A, Mendia A, Sirvent JM, et al; CAPUCI Study Group:
Combination antibiotic therapy improves survival in patients with
community-acquired pneumonia and shock. Crit Care Med 2007;
35:14931498
93. Baddour LM, Yu VL, Klugman KP, et al; International Pneumococcal Study Group: Combination antibiotic therapy lowers mortality
among severely ill patients with pneumococcal bacteremia. Am J
Respir Crit Care Med 2004; 170:440444
94. Safdar N, Handelsman J, Maki DG: Does combination antimicrobial
therapy reduce mortality in Gram-negative bacteraemia? A metaanalysis. Lancet Infect Dis 2004; 4:519527
95. Paul M, Silbiger I, Grozinsky S, et al: Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2006; 1:
CD003344
96. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al: Optimal
management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: An observational, multicenter study comparing
monotherapy with combination antibiotic therapy. Crit Care Med
2007; 35:18881895
97. Jain S, Kamimoto L, Bramley AM, et al; 2009 Pandemic Influenza
A (H1N1) Virus Hospitalizations Investigation Team: Hospitalized
patients with 2009 H1N1 influenza in the United States, April-June
2009. N Engl J Med 2009; 361:19351944
98. Writing Committee of the WHO Consultation on Clinical Aspects
of Pandemic (H1N1) 2009 Influenza; Bautista E, Chotpitayasunondh T, Gao Z, et al: Clinical aspects of pandemic 2009 influenza
A (H1N1) virus infection. N Engl J Med 2010; 362:17081719
99. Smith JR, Ariano RE, Toovey S: The use of antiviral agents for
the management of severe influenza. Crit Care Med 2010; 38(4
Suppl):e43e51
622
www.ccmjournal.org
100. Fiore AE, Fry A, Shay D, et al; Centers for Disease Control and
Prevention (CDC): Antiviral agents for the treatment and chemoprophylaxis of influenzarecommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm Rep 2011;
60:124
101. Kalil A: A silent killer: Cytomegalovirus infection in the nonimmunocompromised critically ill patient. Crit Care Med 2008;
36:32613264
102. Ziemann M, Sedemund-Adib B, Reiland P, et al: Increased mortality in long-term intensive care patients with active cytomegalovirus
infection. Crit Care Med 2008; 36:31453150
103. Hotchkiss RS, Opal S: Immunotherapy for sepsisa new approach
against an ancient foe. N Engl J Med 2010; 363:8789
104. Miller GG, Dummer JS: Herpes simplex and varicella zoster viruses:
Forgotten but not gone. Am J Transplant 2007; 7:741747
105. Jimenez MF, Marshall JC; International Sepsis Forum: Source control
in the management of sepsis. Intensive Care Med 2001; 27 Suppl
1:S49S62
106. Moss RL, Musemeche CA, Kosloske AM: Necrotizing fasciitis in children: Prompt recognition and aggressive therapy improve survival.
J Pediatr Surg 1996; 31:11421146
107. Boyer A, Vargas F, Coste F, et al: Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 2009; 35:847853
108. Bufalari A, Giustozzi G, Moggi L: Postoperative intraabdominal
abscesses: Percutaneous versus surgical treatment. Acta Chir Belg
1996; 96:197200
109. OGrady NP, Alexander M, Dellinger EP, et al: Guidelines for the
prevention of intravascular catheter-related infections. Centers for
Disease Control and Prevention. MMWR Recomm Rep 2002;
51(RR-10):129
110. OGrady NP, Alexander M, Dellinger EP, et al: Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis
2002; 35:12811307
111. Mier J, Len EL, Castillo A, et al: Early versus late necrosectomy in
severe necrotizing pancreatitis. Am J Surg 1997; 173:7175
112. van Santvoort HC, Besselink MG, Bakker OJ, et al; Dutch Pancreatitis Study Group: A step-up approach or open necrosectomy for
necrotizing pancreatitis. N Engl J Med 2010; 362:14911502
113. Evans A, Winslow EH: Oxygen saturation and hemodynamic
response in critically ill, mechanically ventilated adults during intrahospital transport. Am J Crit Care 1995; 4:106111
114. Aitken LM, Williams G, Harvey M, et al: Nursing considerations to
complement the Surviving Sepsis Campaign guidelines. Crit Care
Med 2011; 39:18001818
115. Liberati A, DAmico R, Pifferi S, et al: Antibiotic prophylaxis to reduce
respiratory tract infections and mortality in adults receiving intensive
care. Cochrane Collaboration 2010; 9:172
116. de Jonge E, Schultz MJ, Spanjaard L, et al: Effects of selective
decontamination of digestive tract on mortality and acquisition of
resistant bacteria in intensive care: A randomised controlled trial.
Lancet 2003; 362:10111016
117. de Smet AM, Kluytmans JA, Cooper BS, et al: Decontamination of
the digestive tract and oropharynx in ICU patients. N Engl J Med
2009; 360:2031
118. Cuthbertson BH, Francis J, Campbell MK, et al; SuDDICU study
groups: A study of the perceived risks, benefits and barriers to the
use of SDD in adult critical care units (the SuDDICU study). Trials
2010; 11:117
119. de Smet AM, Kluytmans JA, Blok HE, et al: Selective digestive tract
decontamination and selective oropharyngeal decontamination and
antibiotic resistance in patients in intensive-care units: An openlabel, clustered group-randomised, crossover study. Lancet Infect
Dis 2011; 11:372380
120. Oostdijk EA, de Smet AM, Blok HE, et al: Ecological effects of selective decontamination on resistant gram-negative bacterial colonization. Am J Respir Crit Care Med 2010; 181:452457
121. Ochoa-Ardila ME, Garca-Caas A, Gmez-Mediavilla K, et al: Longterm use of selective decontamination of the digestive tract does not
February 2013 Volume 41 Number 2
Special Article
increase antibiotic resistance: A 5-year prospective cohort study.
Intensive Care Med 2011; 37:14581465
122. Guidet B, Martinet O, Boulain T, et al: Assessment of hemodynamic
efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl
fluid replacement in patients with severe sepsis: The CRYSTMAS
study. Crit Care 2012; 16:R94
123. Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42
versus Ringers acetate in severe sepsis. N Engl J Med 2012;
367:124134
124. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group:
Hydroxyethyl starch or saline for fluid resuscitation in intensive care.
N Engl J Med 2012; 367:19011911
125. Perel P, Roberts I: Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2011; 3:
CD000567
126. Schortgen F, Lacherade JC, Bruneel F, et al: Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre
randomised study. Lancet 2001; 357:911916
127. McIntyre LA, Fergusson D, Cook DJ, et al; Canadian Critical Care
Trials Group: Fluid resuscitation in the management of early septic shock (FINESS): A randomized controlled feasibility trial. Can J
Anaesth 2008; 55:819826
128. Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet): Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J Med 2008; 358:125139
129. Finfer S, Bellomo R, Boyce N, et al; SAFE Study Investigators: A
comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:22472256
130. Delaney AP, Dan A, McCaffrey J, et al: The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and metaanalysis. Crit Care Med 2011; 39:386391
131. Marik PE, Monnet X, Teboul JL: Hemodynamic parameters to guide
fluid therapy. Ann Intensive Care 2011; 1:1
132. Marik PE, Cavallazzi R, Vasu T, et al: Dynamic changes in arterial
waveform derived variables and fluid responsiveness in mechanically
ventilated patients: A systematic review of the literature. Crit Care
Med 2009; 37:26422647
133. Hollenberg SM, Ahrens TS, Annane D, et al: Practice parameters for
hemodynamic support of sepsis in adult patients: 2004 update. Crit
Care Med 2004; 32:19281948
134. LeDoux D, Astiz ME, Carpati CM, et al: Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 2000;
28:27292732
135. Martin C, Papazian L, Perrin G, et al: Norepinephrine or dopamine
for the treatment of hyperdynamic septic shock? Chest 1993; 103:
18261831
136. Martin C, Viviand X, Leone M, et al: Effect of norepinephrine on the
outcome of septic shock. Crit Care Med 2000; 28:27582765
137. De Backer D, Creteur J, Silva E, et al: Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic
shock: Which is best? Crit Care Med 2003; 31:16591667
138. Day NP, Phu NH, Bethell DP, et al: The effects of dopamine and
adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection. Lancet 1996; 348:219223
139. Le Tulzo Y, Seguin P, Gacouin A, et al: Effects of epinephrine on right
ventricular function in patients with severe septic shock and right
ventricular failure: A preliminary descriptive study. Intensive Care
Med 1997; 23:664670
140. Bollaert PE, Bauer P, Audibert G, et al: Effects of epinephrine on
hemodynamics and oxygen metabolism in dopamine-resistant septic
shock. Chest 1990; 98:949953
141. Zhou SX, Qiu HB, Huang YZ, et al: Effects of norepinephrine, epinephrine, and norepinephrine-dobutamine on systemic and gastric
mucosal oxygenation in septic shock. Acta Pharmacol Sin 2002;
23:654658
142. Levy B, Bollaert PE, Charpentier C, et al: Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock:
623
Dellinger et al
166. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock.
N Engl J Med 2008; 358:877887
167. Dnser MW, Mayr AJ, Tr A, et al: Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant
vasodilatory shock: Incidence and risk factors. Crit Care Med 2003;
31:13941398
168. Albanse J, Leone M, Delmas A, et al: Terlipressin or norepinephrine
in hyperdynamic septic shock: A prospective, randomized study. Crit
Care Med 2005; 33:18971902
169. Morelli A, Ertmer C, Lange M, et al: Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic
shock: The DOBUPRESS study. Br J Anaesth 2008; 100:494503
170. Morelli A, Ertmer C, Rehberg S, et al: Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): A randomized,
controlled pilot study. Crit Care 2009; 13:R130
171. Bellomo R, Chapman M, Finfer S, et al: Low-dose dopamine in
patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society
(ANZICS) Clinical Trials Group. Lancet 2000; 356:21392143
172. Kellum JA, M Decker J: Use of dopamine in acute renal failure: A
meta-analysis. Crit Care Med 2001; 29:15261531
173. Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic therapy in critically ill patients. Svo2 Collaborative Group. N
Engl J Med 1995; 333:10251032
174. Hayes MA, Timmins AC, Yau EH, et al: Elevation of systemic oxygen
delivery in the treatment of critically ill patients. N Engl J Med 1994;
330:17171722
175. Annane D, Sbille V, Charpentier C, et al: Effect of treatment with
low doses of hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:862871
176. Briegel J, Forst H, Haller M, et al: Stress doses of hydrocortisone
reverse hyperdynamic septic shock: A prospective, randomized,
double-blind, single-center study. Crit Care Med 1999; 27:723732
177. Bollaert PE, Charpentier C, Levy B, et al: Reversal of late septic
shock with supraphysiologic doses of hydrocortisone. Crit Care
Med 1998; 26:645650
178. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group:
Hydrocortisone therapy for patients with septic shock. N Engl J Med
2008; 358:111124
179. Annane D, Bellissant E, Bollaert PE, et al: Corticosteroids in the
treatment of severe sepsis and septic shock in adults: A systematic
review. JAMA 2009; 301:23622375
180. Sligl WI, Milner DA Jr, Sundar S, et al: Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and
meta-analysis. Clin Infect Dis 2009; 49:93101
181. Patel GP, Balk RA: Systemic steroids in severe sepsis and septic
shock. Am J Respir Crit Care Med 2012; 185:133139
182. Oppert M, Schindler R, Husung C, et al: Low-dose hydrocortisone
improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 2005; 33:24572464
183. Yildiz O, Doganay M, Aygen B, et al: Physiological-dose steroid
therapy in sepsis [ISRCTN36253388]. Crit Care 2002; 6:251259
184. Briegel J, Sprung CL, Annane D, et al; CORTICUS Study Group:
Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock. Intensive Care Med
2009; 35:21512156
185. Allolio B, Drr H, Stuttmann R, et al: Effect of a single bolus of etomidate upon eight major corticosteroid hormones and plasma ACTH.
Clin Endocrinol (Oxf) 1985; 22:281286
186. Jabre P, Combes X, Lapostolle F, et al; KETASED Collaborative
Study Group: Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: A multicentre randomised controlled trial.
Lancet 2009; 374:293300
187. Cuthbertson BH, Sprung CL, Annane D, et al: The effects of etomidate on adrenal responsiveness and mortality in patients with septic
shock. Intensive Care Med 2009; 35:18681876
188. Keh D, Boehnke T, Weber-Cartens S, et al: Immunologic and hemodynamic effects of low-dose hydrocortisone in septic shock: A
624
www.ccmjournal.org
Special Article
209. Guidelines for the use of platelet transfusions. Br J Haematol 2003;
122:1023
210. Werdan K, Pilz G, Bujdoso O, et al; Score-Based Immunoglobulin
Therapy of Sepsis (SBITS) Study Group: Score-based immunoglobulin G therapy of patients with sepsis: The SBITS study. Crit Care
Med 2007; 35:26932701
211. Brocklehurst P, Farrell B, King A, et al; INIS Collaborative Group:
Treatment of neonatal sepsis with intravenous immune globulin. N
Engl J Med 2011; 365:12011211
212. Alejandria MM, Lansang MA, Dans LF, et al: Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database
Syst Rev 2002; 1: CD001090
213. Burns ER, Lee V, Rubinstein A: Treatment of septic thrombocytopenia with immune globulin. J Clin Immunol 1991; 11:363368
214. Darenberg J, Ihendyane N, Sjlin J, et al; StreptIg Study Group: Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: A European randomized, double-blind, placebo-controlled
trial. Clin Infect Dis 2003; 37:333340
215. Hentrich M, Fehnle K, Ostermann H, et al: IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic
shock: A randomized, controlled, multiple-center trial. Crit Care Med
2006; 34:13191325
216. Rodrguez A, Rello J, Neira J, et al: Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis
undergoing surgery. Shock 2005; 23:298304
217. Pildal J, Gtzsche PC: Polyclonal immunoglobulin for treatment
of bacterial sepsis: A systematic review. Clin Infect Dis 2004;
39:3846
218. Laupland KB, Kirkpatrick AW, Delaney A: Polyclonal intravenous
immunoglobulin for the treatment of severe sepsis and septic shock
in critically ill adults: A systematic review and meta-analysis. Crit
Care Med 2007; 35:26862692
219. Kreymann KG, de Heer G, Nierhaus A, et al: Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit
Care Med 2007; 35:26772685
220. Turgeon AF, Hutton B, Fergusson DA, et al: Meta-analysis: Intravenous immunoglobulin in critically ill adult patients with sepsis. Ann
Intern Med 2007; 146:193203
221. Angstwurm MW, Engelmann L, Zimmermann T, et al: Selenium in
Intensive Care (SIC): Results of a prospective randomized, placebocontrolled, multiple-center study in patients with severe systemic
inflammatory response syndrome, sepsis, and septic shock. Crit
Care Med 2007; 35:118126
222. Forceville X, Laviolle B, Annane D, et al: Effects of high doses of
selenium, as sodium selenite, in septic shock: A placebo-controlled,
randomized, double-blind, phase II study. Crit Care 2007; 11:R73
223. Manzanares W, Biestro A, Torre MH, et al: High-dose selenium
reduces ventilator-associated pneumonia and illness severity in
critically ill patients with systemic inflammation. Intensive Care Med
2011; 37:11201127
224. Berger MM, Eggimann P, Heyland DK, et al: Reduction of nosocomial pneumonia after major burns by trace element supplementation:
Aggregation of two randomised trials. Crit Care 2006; 10:R153
225. Mishra V, Baines M, Perry SE, et al: Effect of selenium supplementation on biochemical markers and outcome in critically ill patients.
Clin Nutr 2007; 26:4150
226. Andrews PJ, Avenell A, Noble DW, et al; Scottish Intensive care Glutamine or seleNium Evaluative Trial Trials Group: Randomised trial of
glutamine, selenium, or both, to supplement parenteral nutrition for
critically ill patients. BMJ 2011; 342:d1542
227. Wang Z, Forceville X, Van Antwerpen P, et al: A large-bolus injection,
but not continuous infusion of sodium selenite improves outcome in
peritonitis. Shock 2009; 32:140146
228. Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study
group: Efficacy and safety of recombinant human activated protein
C for severe sepsis. N Engl J Med 2001; 344:699709
229. Abraham E, Laterre PF, Garg R, et al; Administration of Drotrecogin
Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study
Group: Drotrecogin alfa (activated) for adults with severe sepsis and
a low risk of death. N Engl J Med 2005; 353:13321341
230. Nadel S, Goldstein B, Williams MD, et al; REsearching severe
Sepsis and Organ dysfunction in children: a gLobal perspective
(RESOLVE) study group: Drotrecogin alfa (activated) in children
with severe sepsis: A multicentre phase III randomised controlled
trial. Lancet 2007; 369:836843
231. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/
ucm277212.htm. Accessed December 18, 2011
232. Bernard GR, Artigas A, Brigham KL, et al: The American-European
Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care
Med 1994; 149(3 Pt 1):818824
233. Ranieri VM, Rubenfeld GD, Thompson BT, et al: Acute respiratory distress syndrome: The Berlin definition. JAMA 2012;
307:2522625233
234. Acute Respiratory Distress Syndrome Network: Ventilation with
lower tidal volumes as compared with traditional tidal volumes for
acute lung injury and the acute respiratory distress syndrome. N
Engl J Med 2000; 342:13011308
235. Amato MB, Barbas CS, Medeiros DM, et al: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.
N Engl J Med 1998; 338:347354
236. Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal
Volume reduction in ARDS. Am J Respir Crit Care Med 1998;
158:18311838
237. Brower RG, Shanholtz CB, Fessler HE, et al: Prospective, randomized, controlled clinical trial comparing traditional versus reduced
tidal volume ventilation in acute respiratory distress syndrome
patients. Crit Care Med 1999; 27:14921498
238. Stewart TE, Meade MO, Cook DJ, et al: Evaluation of a ventilation
strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation
Strategy Group. N Engl J Med 1998; 338:355361
239. Eichacker PQ, Gerstenberger EP, Banks SM, et al: Meta-analysis
of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;
166:15101514
240. Putensen C, Theuerkauf N, Zinserling J, et al: Meta-analysis: Ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009; 151:566576
241. Burns KE, Adhikari NK, Slutsky AS, et al: Pressure and volume
limited ventilation for the ventilatory management of patients with
acute lung injury: A systematic review and meta-analysis. PLoS ONE
2011; 6:e14623
242. Tobin MJ: Culmination of an era in research on the acute respiratory
distress syndrome. N Engl J Med 2000; 342:13601361
243. Marini JJ, Gattinoni L: Ventilatory management of acute respiratory distress syndrome: A consensus of two. Crit Care Med 2004;
32:250255
244. Hager DN, Krishnan JA, Hayden DL, et al; ARDS Clinical Trials Network: Tidal volume reduction in patients with acute lung injury when
plateau pressures are not high. Am J Respir Crit Care Med 2005;
172:12411245
245. Checkley W, Brower R, Korpak A, et al; Acute Respiratory Distress Syndrome Network Investigators: Effects of a clinical trial on
mechanical ventilation practices in patients with acute lung injury.
Am J Respir Crit Care Med 2008; 177:12151222
246. Kallet RH, Jasmer RM, Luce JM, et al: The treatment of acidosis in
acute lung injury with tris-hydroxymethyl aminomethane (THAM). Am
J Respir Crit Care Med 2000; 161(4 Pt 1):11491153
247. Weber T, Tschernich H, Sitzwohl C, et al: Tromethamine buffer modifies the depressant effect of permissive hypercapnia on myocardial
contractility in patients with acute respiratory distress syndrome. Am
J Respir Crit Care Med 2000; 162(4 Pt 1):13611365
248. Determann RM, Royakkers A, Wolthuis EK, et al: Ventilation with
lower tidal volumes as compared with conventional tidal volumes
www.ccmjournal.org
625
Dellinger et al
for patients without acute lung injury: A preventive randomized controlled trial. Crit Care 2010; 14:R1
249. Yilmaz M, Keegan MT, Iscimen R, et al: Toward the prevention of
acute lung injury: Protocol-guided limitation of large tidal volume
ventilation and inappropriate transfusion. Crit Care Med 2007;
35:16606; quiz 1667
250. Gajic O, Dara SI, Mendez JL, et al: Ventilator-associated lung injury
in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004; 32:18171824
251. Schultz MJ: Lung-protective mechanical ventilation with lower tidal
volumes in patients not suffering from acute lung injury: A review of
clinical studies. Med Sci Monit 2008; 14:RA22RA26
252. Marini JJ, Ravenscraft SA: Mean airway pressure: Physiologic determinants and clinical importancePart 1: Physiologic determinants
and measurements. Crit Care Med 1992; 20:14611472
253. Gattinoni L, Marcolin R, Caspani ML, et al: Constant mean airway
pressure with different patterns of positive pressure breathing during the adult respiratory distress syndrome. Bull Eur Physiopathol
Respir 1985; 21:275279
254. Pesenti A, Marcolin R, Prato P, et al: Mean airway pressure vs. positive end-expiratory pressure during mechanical ventilation. Crit Care
Med 1985; 13:3437
255. Mercat A, Richard JC, Vielle B, et al; Expiratory Pressure (Express)
Study Group: Positive end-expiratory pressure setting in adults with
acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2008; 299:646655
256. Meade MO, Cook DJ, Guyatt GH, et al; Lung Open Ventilation Study
Investigators: Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute
lung injury and acute respiratory distress syndrome: A randomized
controlled trial. JAMA 2008; 299:637645
257. Brower RG, Lanken PN, MacIntyre N, et al; National Heart, Lung,
and Blood Institute ARDS Clinical Trials Network: Higher versus
lower positive end-expiratory pressures in patients with the acute
respiratory distress syndrome. N Engl J Med 2004; 351:327336
258. Briel M, Meade M, Mercat A, et al: Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-analysis. JAMA
2010; 303:865873
259. Amato MB, Barbas CS, Medeiros DM, et al: Beneficial effects of
the open lung approach with low distending pressures in acute
respiratory distress syndrome. A prospective randomized study on
mechanical ventilation. Am J Respir Crit Care Med 1995; 152(6 Pt
1):18351846
260. Gattinoni L, Caironi P, Cressoni M, et al: Lung recruitment in patients
with the acute respiratory distress syndrome. N Engl J Med 2006;
354:17751786
261. Pipeling MR, Fan E: Therapies for refractory hypoxemia in acute
respiratory distress syndrome. JAMA 2010; 304:25212527
262. Fan E, Wilcox ME, Brower RG, et al: Recruitment maneuvers for
acute lung injury: A systematic review. Am J Respir Crit Care Med
2008; 178:11561163
263. Stocker R, Neff T, Stein S, et al: Prone postioning and low-volume
pressure-limited ventilation improve survival in patients with severe
ARDS. Chest 1997; 111:10081017
264. Lamm WJ, Graham MM, Albert RK: Mechanism by which the prone
position improves oxygenation in acute lung injury. Am J Respir Crit
Care Med 1994; 150:184193
265. Jolliet P, Bulpa P, Chevrolet JC: Effects of the prone position on gas
exchange and hemodynamics in severe acute respiratory distress
syndrome. Crit Care Med 1998; 26:19771985
266. Guerin C, Gaillard S, Lemasson S, et al: Effects of systematic prone
positioning in hypoxemic acute respiratory failure: A randomized
controlled trial. JAMA 2004; 292:23792387
267. Taccone P, Pesenti A, Latini R, et al; Prone-Supine II Study Group:
Prone positioning in patients with moderate and severe acute respiratory distress syndrome: A randomized controlled trial. JAMA 2009;
302:19771984
626
www.ccmjournal.org
268. Mancebo J, Fernndez R, Blanch L, et al: A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173:12331239
269. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group:
Effect of prone positioning on the survival of patients with acute
respiratory failure. N Engl J Med 2001; 345:568573
270. Sud S, Friedrich JO, Taccone P, et al: Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia:
Systematic review and meta-analysis. Intensive Care Med 2010;
36:585599
271. Sud S, Sud M, Friedrich JO, et al: High frequency oscillation in
patients with acute lung injury and acute respiratory distress syndrome (ARDS): Systematic review and meta-analysis. BMJ 2010;
340:c2327
272. Noah MA, Peek GJ, Finney SJ, et al: Referral to an extracorporeal
membrane oxygenation center and mortality among patients with
severe 2009 influenza A(H1N1). JAMA 2011; 306:16591668
273. Checkley W: Extracorporeal membrane oxygenation as a first-line
treatment strategy for ARDS: Is the evidence sufficiently strong?
JAMA 2011; 306:17031704
274. Peek GJ, Mugford M, Tiruvoipati R, et al; CESAR Trial Collaboration:
Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult
respiratory failure (CESAR): A multicentre randomised controlled
trial. Lancet 2009; 374:13511363
275. Adhikari NK, Burns KE, Friedrich JO, et al: Effect of nitric oxide on
oxygenation and mortality in acute lung injury: Systematic review and
meta-analysis. BMJ 2007; 334:779
276. Drakulovic MB, Torres A, Bauer TT, et al: Supine body position as
a risk factor for nosocomial pneumonia in mechanically ventilated
patients: A randomised trial. Lancet 1999; 354:18511858
277. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et
al: Feasibility and effects of the semirecumbent position to prevent
ventilator-associated pneumonia: A randomized study. Crit Care
Med 2006; 34:396402
278. Antonelli M, Conti G, Rocco M, et al: A comparison of noninvasive
positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 1998;
339:429435
279. Ferrer M, Esquinas A, Leon M, et al: Noninvasive ventilation in severe
hypoxemic respiratory failure: A randomized clinical trial. Am J Respir
Crit Care Med 2003; 168:14381444
280. Rana S, Jenad H, Gay PC, et al: Failure of non-invasive ventilation in
patients with acute lung injury: Observational cohort study. Crit Care
2006; 10:R79
281. Domenighetti G, Moccia A, Gayer R: Observational case-control
study of non-invasive ventilation in patients with ARDS. Monaldi
Arch Chest Dis 2008; 69:510
282. Ely W, Baker AB, Dunagen DP: Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. New Engl J Med 1996; 335:18651869
283. Kress JP, Pohlman AS, OConnor MF, et al: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:14711477
284. Girard TD, Kress JP, Fuchs BD, et al: Efficacy and safety of a paired
sedation and ventilator weaning protocol for mechanically ventilated
patients in intensive care (Awakening and Breathing Controlled
trial): A randomised controlled trial. Lancet 2008; 371:126134
285. Iberti TJ, Fischer EP, Leibowitz AB, et al: A multicenter study of physicians knowledge of the pulmonary artery catheter. Pulmonary Artery
Catheter Study Group. JAMA 1990; 264:29282932
286. Al-Kharrat T, Zarich S, Amoateng-Adjepong Y, et al: Analysis of
observer variability in measurement of pulmonary artery occlusion
pressures. Am J Respir Crit Care Med 1999; 160:415420
287. Connors AF Jr, McCaffree DR, Gray BA: Evaluation of right-heart
catheterization in the critically ill patient without acute myocardial
infarction. N Engl J Med 1983; 308:263267
288. Osman D, Ridel C, Ray P, et al: Cardiac filling pressures are not
appropriate to predict hemodynamic response to volume challenge.
Crit Care Med 2007; 35:6468
February 2013 Volume 41 Number 2
Special Article
289. Richard C, Warszawski J, Anguel N, et al; French Pulmonary Artery
Catheter Study Group: Early use of the pulmonary artery catheter and
outcomes in patients with shock and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2003; 290:27132720
290. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials Network; Wheeler AP, Bernard
GR, Thompson BT, et al: Pulmonary-artery versus central venous
catheter to guide treatment of acute lung injury. N Engl J Med 2006;
354:22132224
291. Sandham JD, Hull RD, Brant RF, et al; Canadian Critical Care Clinical
Trials Group: A randomized, controlled trial of the use of pulmonaryartery catheters in high-risk surgical patients. N Engl J Med 2003; 348:
514
292. Shah MR, Hasselblad V, Stevenson LW, et al: Impact of the pulmonary artery catheter in critically ill patients: Meta-analysis of randomized clinical trials. JAMA 2005; 294:16641670
293. Harvey S, Harrison DA, Singer M, et al; PAC-Man study collaboration: Assessment of the clinical effectiveness of pulmonary artery
catheters in management of patients in intensive care (PAC-Man): A
randomised controlled trial. Lancet 2005; 366:472477
294. Harvey S, Young D, Brampton W, et al: Pulmonary artery catheters
for adult patients in intensive care. Cochrane Database Syst Rev
2006; CD003408
295. Sibbald WJ, Short AK, Warshawski FJ, et al: Thermal dye measurements of extravascular lung water in critically ill patients. Intravascular
Starling forces and extravascular lung water in the adult respiratory
distress syndrome. Chest 1985; 87:585592
296. Martin GS, Mangialardi RJ, Wheeler AP, et al: Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit
Care Med 2002; 30:21752182
297. Mitchell JP, Schuller D, Calandrino FS, et al: Improved outcome
based on fluid management in critically ill patients requiring pulmonary artery catheterization. Am Rev Respir Dis 1992; 145:990998
298. Schuller D, Mitchell JP, Calandrino FS, et al: Fluid balance during
pulmonary edema. Is fluid gain a marker or a cause of poor outcome? Chest 1991; 100:10681075
299. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler
AP, Bernard GR, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:25642575
300. Perkins GD, McAuley DF, Thickett DR, et al: The beta-agonist lung
injury trial (BALTI): A randomized placebo-controlled clinical trial. Am
J Respir Crit Care Med 2006; 173:281287
301. Matthay MA, Brower RG, Carson S, et al: Randomized, placebocontrolled clinical trial of an aerolosolized -2 agonist for treatment of
acute lung injury. Am J Resp Crit Care Med 2011; 184:561568
302. Gao Smith F, Perkins GD, Gates S, et al; BALTI-2 study investigators: Effect of intravenous -2 agonist treatment on clinical outcomes
in acute respiratory distress syndrome (BALTI-2): A multicentre, randomised controlled trial. Lancet 2012; 379:229235
303. Marx WH, DeMaintenon NL, Mooney KF, et al: Cost reduction and
outcome improvement in the intensive care unit. J Trauma 1999;
46:6259; discussion 629
304. MacLaren R, Plamondon JM, Ramsay KB, et al: A prospective evaluation of empiric versus protocol-based sedation and analgesia.
Pharmacotherapy 2000; 20:662672
305. Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation.
Crit Care Med 1999; 27:26092615
306. Shehabi Y, Bellomo R, Reade MC: Early intensive care sedation
predicts long-term mortality in ventilated critically ill patients. Am J
Respir Crit Care Med 2012; 186:724731
307. Strm T, Martinussen T, Toft P: A protocol of no sedation for critically
ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010; 375:475480
308. Devlin JW, Boleski G, Mlynarek M, et al: Motor Activity Assessment
Scale: A valid and reliable sedation scale for use with mechanically
ventilated patients in an adult surgical intensive care unit. Crit Care
Med 1999; 27:12711275
309. De Jonghe B, Cook D, Sharshar T, et al: Acquired neuromuscular disorders in critically ill patients: A systematic review. Groupe
de Reflexion et dEtude sur les Neuromyopathies En Reanimation.
Intensive Care Med 1998; 24:12421250
310. Kollef MH, Levy NT, Ahrens TS, et al: The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest
1998; 114:541548
311. Mehta S, Burry L, Cook D, et al, SLEAP Investigators; Canadian Critical Care Trials Group: Daily sedation interruption in mechanically
ventilated critically ill patients cared for with a sedation protocol: a
randomized controlled trial. JAMA 2012; 308:19851992
312. Kress JP, Vinayak AG, Levitt J, et al: Daily sedative interruption in
mechanically ventilated patients at risk for coronary artery disease.
Crit Care Med 2007; 35:365371
313. Schweickert WD, Pohlman MC, Pohlman AS, et al: Early physical and
occupational therapy in mechanically ventilated, critically ill patients:
A randomised controlled trial. Lancet 2009; 373:18741882
314. Klessig HT, Geiger HJ, Murray MJ, et al: A national survey on the
practice patterns of anesthesiologist intensivists in the use of muscle
relaxants. Crit Care Med 1992; 20:13411345
315. Murray MJ, Cowen J, DeBlock H, et al; Task Force of the American
College of Critical Care Medicine (ACCM) of the Society of Critical
Care Medicine (SCCM), American Society of Health-System Pharmacists, American College of Chest Physicians: Clinical practice
guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2002; 30:142156
316. Hansen-Flaschen JH, Brazinsky S, Basile C, et al: Use of sedating drugs and neuromuscular blocking agents in patients requiring
mechanical ventilation for respiratory failure. A national survey. JAMA
1991; 266:28702875
317. Freebairn RC, Derrick J, Gomersall CD, et al: Oxygen delivery, oxygen consumption, and gastric intramucosal pH are not improved by
a computer-controlled, closed-loop, vecuronium infusion in severe
sepsis and septic shock. Crit Care Med 1997; 25:7277
318. Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators: Neuromuscular blockers in early acute respiratory distress
syndrome. N Engl J Med 2010; 363:11071116
319. Forel JM, Roch A, Marin V, et al: Neuromuscular blocking agents
decrease inflammatory response in patients presenting with acute
respiratory distress syndrome. Crit Care Med 2006; 34:27492757
320. Shapiro BA, Warren J, Egol AB, et al: Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: An
executive summary. Society of Critical Care Medicine. Crit Care
Med 1995; 23:16011605
321. Meyer KC, Prielipp RC, Grossman JE, et al: Prolonged weakness
after infusion of atracurium in two intensive care unit patients. Anesth
Analg 1994; 78:772774
322. Lacomis D, Petrella JT, Giuliani MJ: Causes of neuromuscular weakness in the intensive care unit: A study of ninety-two patients. Muscle Nerve 1998; 21:610617
323. Rudis MI, Sikora CA, Angus E, et al: A prospective, randomized,
controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill
patients. Crit Care Med 1997; 25:575583
324. Frankel H, Jeng J, Tilly E, et al: The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive
care unit. Am Surg 1996; 62:503506
325. Strange C, Vaughan L, Franklin C, et al: Comparison of train-of-four
and best clinical assessment during continuous paralysis. Am J
Respir Crit Care Med 1997; 156:15561561
326. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin
therapy in critically ill patients. N Engl J Med 2001; 345:13591367
327. Van den Berghe G, Wilmer A, Hermans G, et al: Intensive insulin
therapy in the medical ICU. N Engl J Med 2006; 354:449461
328. Arabi YM, Dabbagh OC, Tamim HM, et al: Intensive versus conventional insulin therapy: A randomized controlled trial in medical and
surgical critically ill patients. Crit Care Med 2008; 36:31903197
329. De La Rosa GDC, Hernando Donado J, Restrepo AH: Strict glycaemic control in patients hospitalised in a mixed medical and surgical
www.ccmjournal.org
627
Dellinger et al
intensive care unit: A randomised clinical trial. Critical Care 2008;
12:R120
330. Annane D, Cariou A, Maxime V, et al; COIITSS Study Investigators: Corticosteroid treatment and intensive insulin therapy for
septic shock in adults: A randomized controlled trial. JAMA 2010;
303:341348
331. The NICE-SUGAR Study Investigators: Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;
360:12831297
332. Preiser JC, Devos P, Ruiz-Santana S, et al: A prospective randomised multi-centre controlled trial on tight glucose control by
intensive insulin therapy in adult intensive care units: The Glucontrol
study. Intensive Care Med 2009; 35:17381748
333. Wiener RS, Wiener DC, Larson RJ: Benefits and risks of tight glucose control in critically ill adults: A meta-analysis. JAMA 2008;
300:933944
334. Griesdale DE, de Souza RJ, van Dam RM, et al: Intensive insulin
therapy and mortality among critically ill patients: A meta-analysis
including NICE-SUGAR study data. CMAJ 2009; 180:821827
335. Marik PE, Preiser JC: Toward understanding tight glycemic control
in the ICU: A systematic review and metaanalysis. Chest 2010;
137:544551
336. Friedrich JO, Chant C, Adhikari NK: Does intensive insulin therapy
really reduce mortality in critically ill surgical patients? A reanalysis
of meta-analytic data. Crit Care 2010; 14:324
337. Kansagara D, Fu R, Freeman M, et al: Intensive insulin therapy in
hospitalized patients: A systematic review. Ann Intern Med 2011;
154:268282
338. Peberdy MA, Callaway CW, Neumar RW, et al: Part 9: post-cardiac
arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Circulation 2010; 122(18 Suppl 3):S768S786
339. Qaseem A, Humphrey LL, Chou R, et al; Clinical Guidelines Committee of the American College of Physicians: Use of intensive insulin therapy for the management of glycemic control in hospitalized
patients: A clinical practice guideline from the American College of
Physicians. Ann Intern Med 2011; 154:260267
340. Moghissi ES, Korytkowski MT, DiNardo M, et al; American Association of Clinical Endocrinologists; American Diabetes Association:
American Association of Clinical Endocrinologists and American
Diabetes Association consensus statement on inpatient glycemic
control. Diabetes Care 2009; 32:11191131
341. Jacobi J, Bircher N, Krinsley J, et al: Guidelines for the use of an
insulin infusion for the management of hyperglycemia in critically ill
patients. Crit Care Med 2012; 40:32513276
342. Kauffmann RM, Hayes RM, Jenkins JM, et al: Provision of balanced
nutrition protects against hypoglycemia in the critically ill surgical
patient. JPEN J Parenter Enteral Nutr 2011; 35:686694
343. Egi M, Bellomo R, Stachowski E, et al: Variability of blood glucose
concentration and short-term mortality in critically ill patients. Anesthesiology 2006; 105:244252
344. Krinsley JS: Glycemic variability: A strong independent predictor of
mortality in critically ill patients. Crit Care Med 2008; 36:30083013
345. Mackenzie IM, Whitehouse T, Nightingale PG: The metrics of glycaemic control in critical care. Intensive Care Med 2011; 37:435443
346. Egi M, Bellomo R, Stachowski E, et al: Blood glucose concentration
and outcome of critical illness: The impact of diabetes. Crit Care
Med 2008; 36:22492255
347. Krinsley JS: Glycemic variability and mortality in critically ill patients:
The impact of diabetes. J Diabetes Sci Technol 2009; 3:12921301
348. Nichols JH: Bedside testing, glucose monitoring, and diabetes management. In: Principles of Point of Care Testing. Kost GJ (Ed). Philadelphia, Lippincott Williams & Wilkins, 2002
349. Kanji S, Buffie J, Hutton B, et al: Reliability of point-of-care testing
for glucose measurement in critically ill adults. Crit Care Med 2005;
33:27782785
350. Hoedemaekers CW, Klein Gunnewiek JM, Prinsen MA, et al: Accuracy of bedside glucose measurement from three glucometers in
critically ill patients. Crit Care Med 2008; 36:30623066
628
www.ccmjournal.org
351. Khan AI, Vasquez Y, Gray J, et al: The variability of results between
point-of-care testing glucose meters and the central laboratory analyzer. Arch Pathol Lab Med 2006; 130:15271532
352. Desachy A, Vuagnat AC, Ghazali AD, et al: Accuracy of bedside
glucometry in critically ill patients: Influence of clinical characteristics
and perfusion index. Mayo Clin Proc 2008; 83:400405
353. Fekih Hassen M, Ayed S, Gharbi R, et al: Bedside capillary blood
glucose measurements in critically ill patients: Influence of catecholamine therapy. Diabetes Res Clin Pract 2010; 87:8791
354. Wilson M, Weinreb J, Hoo GW: Intensive insulin therapy in critical
care: A review of 12 protocols. Diabetes Care 2007; 30:10051011
355. Newton CA, Smiley D, Bode BW, et al: A comparison study of continuous insulin infusion protocols in the medical intensive care unit:
Computer-guided vs. standard column-based algorithms. J Hosp
Med 2010; 5:432437
356. Dortch MJ, Mowery NT, Ozdas A, et al: A computerized insulin infusion titration protocol improves glucose control with less hypoglycemia compared to a manual titration protocol in a trauma intensive
care unit. JPEN J Parenter Enteral Nutr 2008; 32:1827
357. Mauritz W, Sporn P, Schindler I, et al: [Acute renal failure in abdominal infection. Comparison of hemodialysis and continuous arteriovenous hemofiltration]. Anasth Intensivther Notfallmed 1986;
21:212217
358. Bartlett RH, Mault JR, Dechert RE, et al: Continuous arteriovenous
hemofiltration: Improved survival in surgical acute renal failure? Surgery 1986; 100:400408
359. Kierdorf H: Continuous versus intermittent treatment: Clinical results
in acute renal failure. Contrib Nephrol 1991; 93:112
360. Bellomo R, Mansfield D, Rumble S, et al: Acute renal failure in critical
illness. Conventional dialysis versus acute continuous hemodiafiltration. ASAIO J 1992; 38:M654M657
361. Bellomo R, Farmer M, Parkin G, et al: Severe acute renal failure: A
comparison of acute continuous hemodiafiltration and conventional
dialytic therapy. Nephron 1995; 71:5964
362. Kruczynski K, Irvine-Bird K, Toffelmire EB, et al: A comparison of continuous arteriovenous hemofiltration and intermittent hemodialysis in
acute renal failure patients in the intensive care unit. ASAIO J 1993;
39:M778M781
363. van Bommel E, Bouvy ND, So KL, et al: Acute dialytic support for
the critically ill: Intermittent hemodialysis versus continuous arteriovenous hemodiafiltration. Am J Nephrol 1995; 15:192200
364. Gurin C, Girard R, Selli JM, et al: Intermittent versus continuous
renal replacement therapy for acute renal failure in intensive care
units: Results from a multicenter prospective epidemiological survey.
Intensive Care Med 2002; 28:14111418
365. Kellum JA, Angus DC, Johnson JP, et al: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intensive Care Med
2002; 28:2937
366. Tonelli M, Manns B, Feller-Kopman D: Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic modality
on mortality and renal recovery. Am J Kidney Dis 2002; 40:875885
367. Mehta RL, McDonald B, Gabbai FB, et al; Collaborative Group for
Treatment of ARF in the ICU: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int
2001; 60:11541163
368. Gasparovic V, Filipovic-Grcic I, Merkler M, et al: Continuous renal
replacement therapy (CRRT) or intermittent hemodialysis (IHD)
what is the procedure of choice in critically ill patients? Ren Fail
2003; 25:855862
369. Augustine JJ, Sandy D, Seifert TH, et al: A randomized controlled
trial comparing intermittent with continuous dialysis in patients with
ARF. Am J Kidney Dis 2004; 44:10001007
370. Uehlinger DE, Jakob SM, Ferrari P, et al: Comparison of continuous
and intermittent renal replacement therapy for acute renal failure.
Nephrol Dial Transplant 2005; 20:16301637
371. Vinsonneau C, Camus C, Combes A, et al; Hemodiafe Study Group:
Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: A multicentre randomised trial. Lancet 2006;
368:379385
February 2013 Volume 41 Number 2
Special Article
372. John S, Griesbach D, Baumgrtel M, et al: Effects of continuous
haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: A
prospective, randomized clinical trial. Nephrol Dial Transplant 2001;
16:320327
373. Misset B, Timsit JF, Chevret S, et al: A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis
and continuous hemofiltration in ICU patients with acute renal failure. Intensive Care Med 1996; 22:742746
374. Ronco C, Bellomo R, Homel P, et al: Effects of different doses in
continuous veno-venous haemofiltration on outcomes of acute renal
failure: A prospective randomised trial. Lancet 2000; 356:2630
375. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, et al: Effects
of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with
acute renal failure: A prospective, randomized trial. Crit Care Med
2002; 30:22052211
376. The VA/NIH Acute Renal Failure Trial Network: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med
2008; 359:720
377. The RENAL Replacement Therapy Study Investigators: Intensity of
continuous renal-replacement therapy in critically ill patients. N Engl
J Med 2009; 361:16271638
378. Cooper DJ, Walley KR, Wiggs BR, et al: Bicarbonate does not
improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med 1990;
112:492498
379. Mathieu D, Neviere R, Billard V, et al: Effects of bicarbonate therapy
on hemodynamics and tissue oxygenation in patients with lactic acidosis: A prospective, controlled clinical study. Crit Care Med 1991;
19:13521356
380. Cade JF: High risk of the critically ill for venous thromboembolism.
Crit Care Med 1982; 10:448450
381. Halkin H, Goldberg J, Modan M, et al: Reduction of mortality in general medical in-patients by low-dose heparin prophylaxis. Ann Intern
Med 1982; 96:561565
382. Pingleton SK, Bone RC, Pingleton WW, et al: Prevention of pulmonary emboli in a respiratory intensive care unit: Efficacy of low-dose
heparin. Chest 1981; 79:647650
383. Belch JJ, Lowe GD, Ward AG, et al: Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981;
26:115117
384. Grdlund B: Randomised, controlled trial of low-dose heparin for
prevention of fatal pulmonary embolism in patients with infectious
diseases. The Heparin Prophylaxis Study Group. Lancet 1996;
347:13571361
385. Samama MM, Cohen AT, Darmon JY, et al: A comparison of enoxaparin with placebo for the prevention of venous thromboembolism
in acutely ill medical patients. Prophylaxis in Medical Patients with
Enoxaparin Study Group. N Engl J Med 1999; 341:793800
386. Dahan R, Houlbert D, Caulin C, et al: Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin:
A randomized double-blind trial. Haemostasis 1986; 16:159164
387. Hirsch DR, Ingenito EP, Goldhaber SZ: Prevalence of deep venous
thrombosis among patients in medical intensive care. JAMA 1995;
274:335337
388. Fraisse F, Holzapfel L, Couland JM, et al: Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The
Association of Non-University Affiliated Intensive Care Specialist
Physicians of France. Am J Respir Crit Care Med 2000; 161(4 Pt
1):11091114
389. Kupfer Y, Anwar J, Seneviratne C, et al: Prophylaxis with subcutaneous heparin significantly reduces the incidence of deep venous
thrombophlebitis in the critically ill. Abstr. Am J Crit Care Med 1999;
159(Suppl):A519
390. Geerts W, Cook D, Selby R, et al: Venous thromboembolism and its
prevention in critical care. J Crit Care 2002; 17:95104
391. Attia J, Ray JG, Cook DJ, et al: Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001; 161:12681279
392. PROTECT Investigators for the Canadian Critical Care Trials Group
and the Australian and New Zealand Intensive Care Society Clinical
Trials Group, Cook D, Meade M, Guyatt G, et al: Dalteparin versus unfractionated heparin in critically ill patients. New Engl J Med
2011; 364:13051314
393. King CS, Holley AB, Jackson JL, et al: Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical
population: A metaanalysis. Chest 2007; 131:507516
394. Douketis J, Cook D, Meade M, et al; Canadian Critical Care Trials Group: Prophylaxis against deep vein thrombosis in critically ill
patients with severe renal insufficiency with the low-molecular-weight
heparin dalteparin: An assessment of safety and pharmacodynamics: The DIRECT study. Arch Intern Med 2008; 168:18051812
395. Vanek VW: Meta-analysis of effectiveness of intermittent pneumatic
compression devices with a comparison of thigh-high to knee-high
sleeves. Am Surg 1998; 64:10501058
396. Turpie AG, Hirsh J, Gent M, et al: Prevention of deep vein thrombosis in potential neurosurgical patients. A randomized trial comparing
graduated compression stockings alone or graduated compression
stockings plus intermittent pneumatic compression with control.
Arch Intern Med 1989; 149:679681
397. Agu O, Hamilton G, Baker D: Graduated compression stockings
in the prevention of venous thromboembolism. Br J Surg 1999;
86:9921004
398. Kakkos SK, Caprini JA, Geroulakos G, et al: Combined intermittent pneumatic leg compression and pharmacological prophylaxis
for prevention of venous thromboembolism in high-risk patients.
Cochrane Database Syst Rev 2008; 4: CD005258
399. German Hip Arthroplasty Trial Group (GHAT): Prevention of deep
vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement: A randomized trial. Arch Orthop Trauma
Surg 1992; 111:110120
400. Colwell CW Jr, Spiro TE, Trowbridge AA, et al: Use of enoxaparin,
a low-molecular-weight heparin, and unfractionated heparin for the
prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 1994; 76:314
401. Geerts WH, Jay RM, Code KI, et al: A comparison of low-dose
heparin with low-molecular-weight heparin as prophylaxis against
venous thromboembolism after major trauma. N Engl J Med 1996;
335:701707
402. Guyatt GH, Akl EA, Crowther M, et al: Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012; 141(Suppl 2):7S47S
403. Basso N, Bagarani M, Materia A, et al: Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients.
Controlled, randomized trial. Am J Surg 1981; 141:339341
404. Bresalier RS, Grendell JH, Cello JP, et al: Sucralfate suspension
versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients. Am J Med 1987;
83(3B):110116
405. Poleski MH, Spanier AH: Cimetidine versus antacids in the prevention of stress erosions in critically ill patients. Am J Gastroenterol
1986; 81:107111
406. Stothert JC Jr, Simonowitz DA, Dellinger EP, et al: Randomized prospective evaluation of cimetidine and antacid control of gastric pH in
the critically ill. Ann Surg 1980; 192:169174
407. Cook DJ, Fuller HD, Guyatt GH, et al: Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials
Group. N Engl J Med 1994; 330:377381
408. Schuster DP, Rowley H, Feinstein S, et al: Prospective evaluation of
the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984; 76:623630
409. Kahn JM, Doctor JN, Rubenfeld GD: Stress ulcer prophylaxis in
mechanically ventilated patients: Integrating evidence and judgment
using a decision analysis. Intensive Care Med 2006; 32:11511158
410. Cook DJ, Reeve BK, Guyatt GH, et al: Stress ulcer prophylaxis in
critically ill patients. Resolving discordant meta-analyses. JAMA
1996; 275:308314
411. Marik PE, Vasu T, Hirani A, et al: Stress ulcer prophylaxis in the new
millennium: A systematic review and meta-analysis. Crit Care Med
2010; 38:22222228
www.ccmjournal.org
629
Dellinger et al
412. Howell MD, Novack V, Grgurich P, et al: Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection.
Arch Intern Med 2010; 170:784790
413. Leonard J, Marshall JK, Moayyedi P: Systematic review of the risk of
enteric infection in patients taking acid suppression. Am J Gastroenterol 2007; 102:204756; quiz 2057
414. Cook D, Guyatt G, Marshall J, et al: A comparison of sucralfate and
ranitidine for the prevention of upper gastrointestinal bleeding in
patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998; 338:791797
415. Lin P, Chang C, Hsu P, et al: The efficacy and safety of proton pump
inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: A meta-analysis. Crit
Care Med 2010; 38:11971205
416. Pongprasobchai S, Kridkratoke S, Nopmaneejumruslers C: Proton
pump inhibitors for the prevention of stress-related mucosal disease
in critically-ill patients: A meta-analysis. J Med Assoc Thai 2009;
92:632637
417. Alhazzani W, Alshahrani M, Moayyedi P, et al: Stress ulcer prophylaxis in critically ill patients: Review of the evidence. Pol Arch Med
Wewn 2012; 122:107114
418. Moore EE, Jones TN: Benefits of immediate jejunostomy feeding
after major abdominal traumaA prospective, randomized study. J
Trauma 1986; 26:874881
419. Chiarelli A, Enzi G, Casadei A, et al: Very early nutrition supplementation in burned patients. Am J Clin Nutr 1990; 51:10351039
420. Eyer SD, Micon LT, Konstantinides FN, et al: Early enteral feeding
does not attenuate metabolic response after blunt trauma. J Trauma
1993; 34:63943; discussion 643
421. Chuntrasakul C, Siltharm S, Chinswangwatanakul V, et al: Early
nutritional support in severe traumatic patients. J Med Assoc Thai
1996; 79:2126
422. Singh G, Ram RP, Khanna SK: Early postoperative enteral feeding in
patients with nontraumatic intestinal perforation and peritonitis. J Am
Coll Surg 1998; 187:142146
423. Kompan L, Kremzar B, Gadzijev E, et al: Effects of early enteral nutrition on intestinal permeability and the development of multiple organ
failure after multiple injury. Intensive Care Med 1999; 25:157161
424. Minard G, Kudsk KA, Melton S, et al: Early versus delayed feeding
with an immune-enhancing diet in patients with severe head injuries.
JPEN J Parenter Enteral Nutr 2000; 24:145149
425. Pupelis G, Selga G, Austrums E, et al: Jejunal feeding, even when
instituted late, improves outcomes in patients with severe pancreatitis and peritonitis. Nutrition 2001; 17:9194
426. Kompan L, Vidmar G, Spindler-Vesel A, et al: Is early enteral nutrition
a risk factor for gastric intolerance and pneumonia? Clin Nutr 2004;
23:527532
427. Nguyen NQ, Fraser RJ, Bryant LK, et al: The impact of delaying
enteral feeding on gastric emptying, plasma cholecystokinin, and
peptide YY concentrations in critically ill patients. Crit Care Med
2008; 36:14691474
428. Marik PE, Zaloga GP: Early enteral nutrition in acutely ill patients: A
systematic review. Crit Care Med 2001; 29:22642270
429. Heyland DK, Dhaliwal R, Drover JW, et al; Canadian Critical Care
Clinical Practice Guidelines Committee: Canadian clinical practice
guidelines for nutrition support in mechanically ventilated, critically ill
adult patients. JPEN J Parenter Enteral Nutr 2003; 27:355373
430. Doig GS, Heighes PT, Simpson F, et al: Early enteral nutrition,
provided within 24h of injury or intensive care unit admission,
significantly reduces mortality in critically ill patients: A meta-analysis of randomised controlled trials. Intensive Care Med 2009;
35:20182027
431. Taylor SJ, Fettes SB, Jewkes C, et al: Prospective, randomized, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering
head injury. Crit Care Med 1999; 27:25252531
432. Ibrahim EH, Mehringer L, Prentice D, et al: Early versus late enteral
feeding of mechanically ventilated patients: Results of a clinical trial.
JPEN J Parenter Enteral Nutr 2002; 26:174181
630
www.ccmjournal.org
433. Rice TW, Mogan S, Hays MA, et al: Randomized trial of initial trophic
versus full-energy enteral nutrition in mechanically ventilated patients
with acute respiratory failure. Crit Care Med 2011; 39:967974
434. National Heart, Lung, and Blood Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials Network, Rice TW, Wheeler AP,
Thompson BT, et al: Trophic vs full enteral feeding in patients with
acute lung injury: The EDEN randomized trial. JAMA 2012; 137:
795803
435. Arabi YM, Tamim HM, Dhar GS, et al: Permissive underfeeding and
intensive insulin therapy in critically ill patients: A randomized controlled trial. Am J Clin Nutr 2011; 93:569577
436. Cerra FB, McPherson JP, Konstantinides FN, et al: Enteral nutrition
does not prevent multiple organ failure syndrome (MOFS) after sepsis. Surgery 1988; 104:727733
437. Heyland DK, MacDonald S, Keefe L, et al: Total parenteral nutrition in the critically ill patient: A meta-analysis. JAMA 1998;
280:20132019
438. Braunschweig CL, Levy P, Sheean PM, et al: Enteral compared
with parenteral nutrition: A meta-analysis. Am J Clin Nutr 2001;
74:534542
439. Gramlich L, Kichian K, Pinilla J, et al: Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill
adult patients? A systematic review of the literature. Nutrition 2004;
20:843848
440. Dhaliwal R, Jurewitsch B, Harrietha D, et al: Combination enteral
and parenteral nutrition in critically ill patients: Harmful or beneficial?
A systematic review of the evidence. Intensive Care Med 2004;
30:16661671
441. Peter JV, Moran JL, Phillips-Hughes J: A metaanalysis of treatment
outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med 2005; 33:213220; discussion 260
442. Simpson F, Doig GS: Parenteral vs. enteral nutrition in the critically ill
patient: A meta-analysis of trials using the intention to treat principle.
Intensive Care Med 2005; 31:1223
443. Koretz RL, Avenell A, Lipman TO, et al: Does enteral nutrition affect
clinical outcome? A systematic review of the randomized trials. Am J
Gastroenterol 2007; 102:412429; quiz 468
444. Casaer MP, Mesotten D, Hermans G, et al: Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365:506517
445. Beale RJ, Bryg DJ, Bihari DJ: Immunonutrition in the critically ill:
A systematic review of clinical outcome. Crit Care Med 1999;
27:27992805
446. Heyland DK, Novak F, Drover JW, et al: Should immunonutrition
become routine in critically ill patients? A systematic review of the
evidence. JAMA 2001; 286:944953
447. Montejo JC, Zarazaga A, Lpez-Martnez J, et al; Spanish Society of
Intensive Care Medicine and Coronary Units: Immunonutrition in the
intensive care unit. A systematic review and consensus statement.
Clin Nutr 2003; 22:221233
448. Marik PE, Zaloga GP: Immunonutrition in critically ill patients: A systematic review and analysis of the literature. Intensive Care Med
2008; 34:19801990
449. Kieft H, Roos AN, van Drunen JD, et al: Clinical outcome of immunonutrition in a heterogeneous intensive care population. Intensive
Care Med 2005; 31:524532
450. Tugrul S, Ozcan PE, Akinci IO, et al: [The effects of immunonutrition
on the development of nosocomial infections and on clinical outcome in critically ill patients]. Ulus Travma Acil Cerrahi Derg 2004;
10:8996
451. Radrizzani D, Bertolini G, Facchini R, et al: Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe
sepsis: A randomized clinical trial. Intensive Care Med 2006;
32:11911198
452. Bertolini G, Iapichino G, Radrizzani D, et al: Early enteral immunonutrition in patients with severe sepsis: Results of an interim analysis
of a randomized multicentre clinical trial. Intensive Care Med 2003;
29:834840
453. Suchner U, Kuhn KS, Frst P: The scientific basis of immunonutrition. Proc Nutr Soc 2000; 59:553563
February 2013 Volume 41 Number 2
Special Article
454. Santora R, Kozar RA: Molecular mechanisms of pharmaconutrients.
J Surg Res 2010; 161:288294
455. Bower RH, Cerra FB, Bershadsky B, et al: Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides,
and fish oil in intensive care unit patients: Results of a multicenter,
prospective, randomized, clinical trial. Crit Care Med 1995;
23:436449
456. Galbn C, Montejo JC, Mesejo A, et al: An immune-enhancing enteral
diet reduces mortality rate and episodes of bacteremia in septic
intensive care unit patients. Crit Care Med 2000; 28:643648
457. Caparrs T, Lopez J, Grau T: Early enteral nutrition in critically ill
patients with a high-protein diet enriched with arginine, fiber, and
antioxidants compared with a standard high-protein diet. The effect
on nosocomial infections and outcome. JPEN J Parenter Enteral
Nutr 2001; 25:299308; discussion 308
458. Preiser JC, Berr PJ, Van Gossum A, et al: Metabolic effects of arginine addition to the enteral feeding of critically ill patients. JPEN J
Parenter Enteral Nutr 2001; 25:182187
459. Novak F, Heyland DK, Avenell A, et al: Glutamine supplementation in
serious illness: A systematic review of the evidence. Crit Care Med
2002; 30:20222029
460. Avenell A: Glutamine in critical care: Current evidence from systematic reviews. Proc Nutr Soc 2006; 65:236241
461. Jiang H, Chen W, Hu W, et al: [The impact of glutamine-enhanced
enteral nutrition on clinical outcome of patients with critical illness: A
systematic review of randomized controlled trials]. Zhonghua Shao
Shang Za Zhi 2009; 25:325330
462. Avenell A: Hot topics in parenteral nutrition. Current evidence and
ongoing trials on the use of glutamine in critically-ill patients and
patients undergoing surgery. Proc Nutr Soc 2009; 68:261268
463. Tian H, Wang KF, Wu TJ: [Effect of total parenteral nutrition with
supplementation of glutamine on the plasma diamine oxidase activity and D-lactate content in patients with multiple organ dysfunction syndrome]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;
18:616618
464. Cai GL, Yan J, Yu YH, et al: [Influence of glutamine and growth hormone intensified nutrition support on immunomodulation in critically
ill elderly patients]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;
18:595598
465. Grau T, Bonet A, Miambres E, et al; Metabolism, Nutrition Working
Group, SEMICYUC, Spain: The effect of L-alanyl-L-glutamine dipeptide supplemented total parenteral nutrition on infectious morbidity
and insulin sensitivity in critically ill patients. Crit Care Med 2011;
39:12631268
466. Wernerman J, Kirketeig T, Andersson B, et al; Scandinavian Critical
Care Trials Group: Scandinavian glutamine trial: A pragmatic multicentre randomised clinical trial of intensive care unit patients. Acta
Anaesthesiol Scand 2011; 55:812818
467 . Fuentes-Orozco C, Anaya-Prado R, Gonzlez-Ojeda A, et al: L-alanyl-L-glutamine-supplemented parenteral nutrition improves infectious morbidity in secondary peritonitis. Clin Nutr 2004; 23:1321
468. Beale RJ, Sherry T, Lei K, et al: Early enteral supplementation with key
pharmaconutrients improves Sequential Organ Failure Assessment
score in critically ill patients with sepsis: Outcome of a randomized,
controlled, double-blind trial. Crit Care Med 2008; 36:131144
469. Trial of glutamine and antioxidant supplementation in critically ill
patients (REDOXS). http://clinicaltrials.gov/ct2/show/NCT001339
78?term=NCT00133978&rank=1
470. Pontes-Arruda A, Demichele S, Seth A, et al: The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: A meta-analysis of outcome data. JPEN J
Parenter Enteral Nutr 2008; 32:596605
471. Pontes-Arruda A, Arago AM, Albuquerque JD: Effects of enteral
feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and
septic shock. Crit Care Med 2006; 34:23252333
472. Gadek JE, DeMichele SJ, Karlstad MD, et al: Effect of enteral feeding
with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants
in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 1999; 27:14091420
631
Dellinger et al
491. Machare Delgado E, Callahan A, Paganelli G, et al: Multidisciplinary
family meetings in the ICU facilitate end-of-life decision making. Am
J Hosp Palliat Care 2009; 26:295302
492. Lautrette A, Darmon M, Megarbane B, et al: A communication strategy and brochure for relatives of patients dying in the ICU. N Engl J
Med 2007; 356:469478
493. Norton SA, Hogan LA, Holloway RG, et al: Proactive palliative
care in the medical intensive care unit: Effects on length of stay for
selected high-risk patients. Crit Care Med 2007; 35:15301535
494. Scheunemann LP, McDevitt M, Carson SS, et al: Randomized, controlled trials of interventions to improve communication in intensive
care: A systematic review. Chest 2011; 139:543554
495. Davidson JE, Powers K, Hedayat KM, et al; American College of
Critical Care Medicine Task Force 2004-2005, Society of Critical
Care Medicine: Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of
Critical Care Medicine Task Force 2004-2005. Crit Care Med 2007;
35:605622
496. Curtis JR, Treece PD, Nielsen EL, et al: Integrating palliative and
critical care: Evaluation of a quality-improvement intervention. Am J
Respir Crit Care Med 2008; 178:269275
497. Odetola FO, Gebremariam A, Freed GL: Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric
sepsis. Pediatrics 2007; 119:487494
498. Typpo KV, Petersen NJ, Hallman DM, et al: Day 1 multiple organ dysfunction syndrome is associated with poor functional outcome and
mortality in the pediatric intensive care unit. Pediatr Crit Care Med
2009; 10:562570
499. Kissoon N, Carcillo JA, Espinosa V, et al; Global Sepsis Initiative
Vanguard Center Contributors: World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med 2011; 12:494503
500. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis: International pediatric sepsis consensus
conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:28
501. Kuch BA, Carcillo JA, Han YY, et al: Definitions of pediatric septic
shock. Pediatr Crit Care Med 2005; 6:501; author reply 501
502. Cam BV, Tuan DT, Fonsmark L, et al: Randomized comparison of oxygen mask treatment vs. nasal continuous positive airway pressure in
dengue shock syndrome with acute respiratory failure. J Trop Pediatr
2002; 48:335339
503. Duke T, Mgone J, Frank D: Hypoxaemia in children with severe
pneumonia in Papua New Guinea. Int J Tuberc Lung Dis 2001;
5:511519
504. Pollard AJ, Britto J, Nadel S, et al: Emergency management of meningococcal disease. Arch Dis Child 1999; 80:290296
505. den Brinker M, Joosten KF, Liem O, et al: Adrenal insufficiency in
meningococcal sepsis: Bioavailable cortisol levels and impact of
interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005; 90:51105117
506. Han YY, Carcillo JA, Dragotta MA, et al: Early reversal of pediatricneonatal septic shock by community physicians is associated with
improved outcome. Pediatrics 2003; 112:793799
507. Carcillo JA, Kuch BA, Han YY, et al: Mortality and functional morbidity after use of PALS/APLS by community physicians. Pediatrics
2009; 124:500508
508. Oliveira CF, Nogueira de S FR, Oliveira DS, et al: Time- and fluidsensitive resuscitation for hemodynamic support of children in septic shock: Barriers to the implementation of the American College
of Critical Care Medicine/Pediatric Advanced Life Support Guidelines in a pediatric intensive care unit in a developing world. Pediatr
Emerg Care 2008; 24:810815
509. Raimer PL, Han YY, Weber MS, et al: A normal capillary refill time of
= 2 seconds is associated with superior vena cava oxygen saturations of = 70%. J Pediatr 2011; 158:968972
510. Brierley J, Carcillo JA, 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
632
www.ccmjournal.org
Special Article
528. Barie PS, Williams MD, McCollam JS, et al; PROWESS Surgical
Evaluation Committee: Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis. Am J Surg 2004;
188:212220
529. Barie PS, Hydo LJ, Shou J, et al: Efficacy and safety of drotrecogin
alfa (activated) for the therapy of surgical patients with severe sepsis. Surg Infect (Larchmt) 2006; 7 Suppl 2:S77S80
530. Marshall JC, Maier RV, Jimenez M, et al: Source control in the management of severe sepsis and septic shock: An evidence-based
review. Crit Care Med 2004; 32(11 Suppl):S513S526
531. Penington AJ, Craft RO, Tilkorn DJ: Plastic surgery management
of soft tissue loss in meningococcal septicemia: Experience of
the Melbourne Royal Childrens Hospital. Ann Plast Surg 2007;
58:308314
532. Wheeler JS, Anderson BJ, De Chalain TM: Surgical interventions
in children with meningococcal purpura fulminansA review of 117
procedures in 21 children. J Pediatr Surg 2003; 38:597603
533. Jackson MA, Colombo J, Boldrey A: Streptococcal fasciitis with toxic
shock syndrome in the pediatric patient. Orthop Nurs 2003; 22:48
534. Xiao-Wu W, Herndon DN, Spies M, et al: Effects of delayed wound
excision and grafting in severely burned children. Arch Surg 2002;
137:10491054
535. Haecker FM, Berger D, Schumacher U, et al: Peritonitis in childhood: Aspects of pathogenesis and therapy. Pediatr Surg Int 2000;
16:182188
536. Gwynne-Jones DP, Stott NS: Community-acquired methicillin-resistant Staphylococcus aureus: A cause of musculoskeletal sepsis in
children. J Pediatr Orthop 1999; 19:413416
537. Wu MH, Tseng YL, Lin MY, et al: Surgical treatment of pediatric lung
abscess. Pediatr Surg Int 1997; 12:293295
538. Murphy JJ, Granger R, Blair GK, et al: Necrotizing fasciitis in childhood. J Pediatr Surg 1995; 30:11311134
539. Jaber MR, Olafsson S, Fung WL, et al: Clinical review of the management of fulminant Clostridium difficile infection. Am J Gastroenterol
2008; 103:3195203; quiz 3204
540. Ananthakrishnan AN: Clostridium difficile infection: Epidemiology,
risk factors and management. Nat Rev Gastroenterol Hepatol 2011;
8:1726
541. Olivas AD, Umanskiy K, Zuckerbraun B, et al: Avoiding colectomy
during surgical management of fulminant Clostridium difficile colitis.
Surg Infect (Larchmt) 2010; 11:299305
542. Ngo NT, Cao XT, Kneen R, et al: Acute management of dengue shock
syndrome: A randomized double-blind comparison of 4 intravenous
fluid regimens in the first hour. Clin Infect Dis 2001; 32:204213
543. Willis BA, Dung NM, Loan HT, et al: Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med
2005; 353:877889
544. Dung NM, Day NP, Tam DT, et al: Fluid replacement in dengue shock
syndrome: A randomized, double-blind comparison of four intravenous-fluid regimens. Clin Infect Dis 1999; 29:787794
545. Booy R, Habibi P, Nadel S, et al; Meningococcal Research Group:
Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001;
85:386390
546. Maat M, Buysse CM, Emonts M, et al: Improved survival of children
with sepsis and purpura: Effects of age, gender, and era. Crit Care
2007; 11:R112
547. Cruz AT, Perry AM, Williams EA, et al: Implementation of goaldirected therapy for children with suspected sepsis in the emergency department. Pediatrics 2011; 127:e758e766
548. Kanter RK, Zimmerman JJ, Strauss RH, et al: Pediatric emergency
intravenous access. Evaluation of a protocol. Am J Dis Child 1986;
140:132134
549. Carcillo JA, Davis AL, Zaritsky A: Role of early fluid resuscitation in
pediatric septic shock. JAMA 1991; 266:12421245
550. Ranjit S, Kissoon N, Jayakumar I: Aggressive management of dengue shock syndrome may decrease mortality rate: a suggested protocol. Pediatr Crit Care Med 2005; 6:412419
633
Dellinger et al
survival in pediatric respiratory failure: a review of the Extracorporeal
Life Support Registry. Pediatr Crit Care Med 2012; 13:1621
574. Bartlett RH: Extracorporeal support for septic shock. Pediatr Crit
Care Med 2007; 8:498499
575. MacLaren G, Butt W, Best D, et al: Central extracorporeal membrane oxygenation for refractory pediatric septic shock. Pediatr Crit
Care Med 2011; 12:133136
576. Flagg A, Danziger-Isakov L, Foster C, et al: Novel 2009 H1N1 influenza virus infection requiring extracorporeal membrane oxygenation
in a pediatric heart transplant recipient. J Heart Lung Transplant
2010; 29:582584
577. Kumar A, Zarychanski R, Pinto R, et al; Canadian Critical Care
Trials Group H1N1 Collaborative: Critically ill patients with
2009 influenza A(H1N1) infection in Canada. JAMA 2009;
302:18721879
578. Pizarro CF, Troster EJ, Damiani D, et al: Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med 2005;
33:855859
579. Riordan FA, Thomson AP, Ratcliffe JM, et al: Admission cortisol and
adrenocorticotrophic hormone levels in children with meningococcal
disease: Evidence of adrenal insufficiency? Crit Care Med 1999;
27:22572261
580. De Kleijn ED, Joosten KF, Van Rijn B, et al: Low serum cortisol in
combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe
meningococcal disease. Pediatr Infect Dis J 2002; 21:330336
581. Markovitz BP, Goodman DM, Watson RS, et al: A retrospective
cohort study of prognostic factors associated with outcome in pediatric severe sepsis: What is the role of steroids? Pediatr Crit Care
Med 2005; 6:270274
582. Pizarro CF, Troster EJ: Adrenal function in sepsis and septic shock. J
Pediatr (Rio J) 2007; 83(5 Suppl):S155S162
583. Zimmerman JJ, Williams MD: Adjunctive corticosteroid therapy in
pediatric severe sepsis: Observations from the RESOLVE study.
Pediatr Crit Care Med 2011; 12:28
584. Lacroix J, Hbert PC, Hutchison JS, et al; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung
Injury and Sepsis Investigators Network: Transfusion strategies
for patients in pediatric intensive care units. N Engl J Med 2007;
356:16091619
585. Karam O, Tucci M, Ducruet T, et al; Canadian Critical Care Trials
Group; PALISI Network: Red blood cell transfusion thresholds
in pediatric patients with sepsis. Pediatr Crit Care Med 2011;
12:512518
586. Church GD, Matthay MA, Liu K, et al: Blood product transfusions
and clinical outcomes in pediatric patients with acute lung injury.
Pediatr Crit Care Med 2009; 10:297302
587. Lpez-Herce Cid J, Bustinza Arriorta A, Alcaraz Romero A, et al:
[Treatment of septic shock with continuous plasmafiltration and
hemodiafiltration]. An Pediatr (Barc) 2003; 59:491496
588. Stegmayr BG, Banga R, Berggren L, et al: Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit
Care Med 2003; 31:17301736
589. El-Nawawy A, Abbassy AA, El-Bordiny M, et al: Evaluation of early
detection and management of disseminated intravascular coagulation among Alexandria University pediatric intensive care patients. J
Trop Pediatr 2004; 50:339347
590. Campanelli A, Kaya G, Ozsahin AH, et al: Purpura fulminans in a
child as a complication of chickenpox infection. Dermatology (Basel)
2004; 208:262264
591. Muntean W: Fresh frozen plasma in the pediatric age group and
in congenital coagulation factor deficiency. Thromb Res 2002; 107
Suppl 1:S29S32
592. Snchez Miralles A, Reig Senz R, Marco Vera P, et al: [Abnormalities in coagulation and fibrinolysis in septic shock with purpura]. An
Esp Pediatr 2002; 56:99103
593. Hazelzet JA, Risseeuw-Appel IM, Kornelisse RF, et al: Age-related
differences in outcome and severity of DIC in children with septic
shock and purpura. Thromb Haemost 1996; 76:932938
634
www.ccmjournal.org
594. Churchwell KB, McManus ML, Kent P, et al: Intensive blood and
plasma exchange for treatment of coagulopathy in meningococcemia. J Clin Apher 1995; 10:171177
595. Ala FA, Greaves M, Jones J, et al: Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force. Curr Vasc Pharmacol
2009; 7:110119
596. Meyer B, Hellstern P: Recommendations for the use of therapeutic
plasma. Semin Nephrol 2008; 28:447456
597. Fortenberry JD: Pediatric critical care management of septic shock
prior to acute kidney injury and renal replacement therapy. Semin
Nephrol 2008; 28:447456
598. OShaughnessy DF, Atterbury C, Bolton Maggs P, et al; British
Committee for Standards in Haematology, Blood Transfusion Task
Force. Practical guidelines for the clinical use of plasma. Thromb
Res 2002; 107(Suppl 1):S53S57
599. Muntean W, Schramm W, Seifried E, Solheim BG: Guideline for
the use of fresh-frozen plasma. Medical Directors Advisory Committee, National Blood Transfusion Council. S Afr Med J 1998;
88:13441347
600. Nguyen TC, Han YY: Plasma exchange therapy for thrombotic microangiopathies. Organogenesis 2011; 7:2831
601. van Deuren M, Brandtzaeg P, van der Meer JW: Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 2000; 13:14466, table of contents
602. Scharfman WB, Tillotson JR, Taft EG, et al: Plasmapheresis for
meningococcemia with disseminated intravascular coagulation. N
Engl J Med 1979; 300:12771278
603. van Deuren M, Santman FW, van Dalen R, et al: Plasma and whole
blood exchange in meningococcal sepsis. Clin Infect Dis 1992;
15:424430
6 04. Bjorvatn B, Bjertnaes L, Fadnes HO, et al: Meningococcal septicaemia treated with combined plasmapheresis and leucapheresis or with blood exchange. Br Med J (Clin Res Ed) 1984;
288:439441
605. Brandtzaeg P, Sirnes K, Folsland B, et al: Plasmapheresis in the
treatment of severe meningococcal or pneumococcal septicaemia
with DIC and fibrinolysis. Preliminary data on eight patients. Scand J
Clin Lab Invest Suppl 1985; 178:5355
606. Drapkin MS, Wisch JS, Gelfand JA, et al: Plasmapheresis for fulminant meningococcemia. Pediatr Infect Dis J 1989; 8:399400
607. Schtt U, Bjrsell-Ostling E: Sonoclot coagulation analysis and
plasma exchange in a case of meningococcal septicaemia. Can J
Anaesth 1995; 42:6468
608. Mok Q, Butt W: The outcome of children admitted to intensive
care with meningococcal septicaemia. Intensive Care Med 1996;
22:259263
609. Kumar A, Kanagasundaram NS, Collyns TA, et al: Plasma exchange
and haemodiafiltration in fulminant meningococcal sepsis. Nephrol
Dial Transplant 1998; 13:484487
610. Munteanu C, Bloodworth LL, Korn TH: Antithrombin concentrate
with plasma exchange in purpura fulminans. Pediatr Crit Care Med
2000; 1:8487
611. Busund R, Koukline V, Utrobin U, et al: Plasmapheresis in severe
sepsis and septic shock: A prospective, randomised, controlled trial.
Intensive Care Med 2002; 28:14341439
612. Randolph AG: Management of acute lung injury and acute respiratory distress syndrome in children. Crit Care Med 2009;
37:24482454
613. Krishnan J, Morrison W: Airway pressure release ventilation: A pediatric case series. Pediatr Pulmonol 2007; 42:8388
614. Ten IS, Anderson MR: Is high-frequency ventilation more beneficial
than low-tidal volume conventional ventilation? Respir Care Clin N
Am 2006; 12:437451
615. Rotta AT, Steinhorn DM: Is permissive hypercapnia a beneficial strategy for pediatric acute lung injury? Respir Care Clin N Am 2006;
12:371387
616. Ben Jaballah N, Khaldi A, Mnif K, et al: High-frequency oscillatory
ventilation in pediatric patients with acute respiratory failure. Pediatr
Crit Care Med 2006; 7:362367
February 2013 Volume 41 Number 2
Special Article
617. Kam PC, Cardone D: Propofol infusion syndrome. Anaesthesia
2007; 62:690701
618. Parke TJ, Stevens JE, Rice AS, et al: Metabolic acidosis and fatal
myocardial failure after propofol infusion in children: Five case
reports. BMJ 1992; 305:613616
619. den Brinker M, Hokken-Koelega AC, Hazelzet JA, et al: One single
dose of etomidate negatively influences adrenocortical performance
for at least 24h in children with meningococcal sepsis. Intensive
Care Med 2008; 34:163168
620. Su F, Hammer GB: Dexmedetomidine: Pediatric pharmacology, clinical uses and safety. Expert Opin Drug Saf 2011; 10:5566
621. Carcillo JA, Doughty L, Kofos D, et al: Cytochrome P450 mediateddrug metabolism is reduced in children with sepsis-induced multiple
organ failure. Intensive Care Med 2003; 29:980984
622. Branco RG, Garcia PC, Piva JP, et al: Glucose level and risk of
mortality in pediatric septic shock. Pediatr Crit Care Med 2005;
6:470472
623. Faustino EV, Apkon M: Persistent hyperglycemia in critically ill children.
J Pediatr 2005; 146:3034
624. Jeschke MG, Kulp GA, Kraft R, et al: Intensive insulin therapy in
severely burned pediatric patients: A prospective randomized trial.
Am J Respir Crit Care Med 2010; 182:351359
625. Day KM, Haub N, Betts H, et al: Hyperglycemia is associated with
morbidity in critically ill children with meningococcal sepsis. Pediatr
Crit Care Med 2008; 9:636640
626. Garcia Branco R, Tasker RC, Ramos Garcia PC, et al: Glycemic
control and insulin therapy in sepsis and critical illness. J Pediatr
(Rio J) 2007; 83(5 Suppl):S128S136
627. Verhoeven JJ, den Brinker M, Hokken-Koelega AC, et al: Pathophysiological aspects of hyperglycemia in children with meningococcal
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
Dellinger et al
Appendix B
Conflict of Interest Process
636
www.ccmjournal.org
Special Article
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.
www.ccmjournal.org
637