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Citation: Dellinger, R., Levy, M., Rhodes, A., Annane, D., Gerlach, H., Opal, S. M.,
Sevransky, J. E., Sprung, C. L., Douglas, I. S., Jaeschke, R., et al (2013). Surviving Sepsis
Campaign: international guidelines for management of severe sepsis and septic shock,
2012. Intensive Care Medicine, 39(2), pp. 165-228. doi: 10.1007/s00134-012-2769-8

This is the accepted version of the paper.

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Permanent repository link: https://openaccess.city.ac.uk/id/eprint/25920/

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Surviving Sepsis Campaign: International guidelines for

management of severe sepsis and septic shock: 2012

R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Andrew Rhodes, MB BS; Djillali Annane, MD; Joseph A.
Carcillo, MD and the Pediatric Subgroup*; Herwig Gerlach, MD, PhD; Steven Opal, MD; Jonathan
Sevransky, MD; Charles L. Sprung, MD; Ivor S. Douglas, MD; Roman Jaeschke, MD: Tiffany M. Osborn,
MD, MPH; Mark Nunnally, MD; Sean R. Townsend, MD; Konrad Reinhart, MD; Ruth M. Kleinpell, PhD,
RN-CS; Derek C. Angus, MD, MPH; Clifford S. Deutschman, MD, MS; Flavia R. Machado, MD, PhD;
Gordon Rubenfeld, MD; Steven Webb, MD: Richard J. Beale, MB BS; Jean-Louis Vincent, MD, PhD; Rui
Moreno, MD; and the Surviving Sepsis Campaign Guidelines Committee*

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 29 international organizations.

Nominal groups were assembled at key international meetings (for those committee members attending

the conference). A stand-alone meeting was held for all sub-group 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.

Methods: We advised the authors to follow the priniciples 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., and the potential

drawbacks of making strong recommendations in the presence of low quality evidence were emphasized

strong (1) or weak (2). Recommendations are in 3 groups: 1) those directly targeting severe sepsis; 2)

recommendations targeting general care of the critically ill patient that are considered high priority in

severe sepsis; and 3) pediatric considerations. A formal conflict of interest policy (COI) was developed at

the onset of the process and enforced throughout. The entire guidelines process was conducted

independent of any industry funding.Results: Key recommendations and suggestions, listed by category,

include early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C);

blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm potential

source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of

1
septic shock (1B) and severe sepsis without septic shock (1C); reassessment of antimicrobial therapy

daily for de-escalation, when appropriate (1B); 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

(1A) with consideration of the addition of albumin in patients who continue to require boluses of crystalloid

to maintain adequate mean arterial pressure (2B) and the avoidance of hetastarch formulations (1B);

initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia

to achieve a minimum of 30 ml/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 there is

hemodynamic improvement based on either dynamic or static variables (UG); norepinephrine as the first

choice vasopressor to maintain MAP ≥ 65 mm HG (1B); epinephrine when an additional agent is needed

to maintain adequate blood pressure (1B); vasopressin 0.03 units/min can be added to high dose

norepinephrine to either raise MAP to target or to decrease NE dose but should not be used as the initial

vasopressor (UG); dopamine is not recommended except in highly selected fcircumstances (2C);

dobutamine infusion administered or added to vasopressor (if in use) 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); not using intravenous hydrocortisone in adult septic shock patients if adequate fluid

resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); target a

hemoglobin of 7-9 g/dLin the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute

hemorrhage(1B); a low tidal volume (1A) and limitation of inspiratory plateau pressure strategy (1B) for

acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-

expiratory pressure (PEEP) in acute lung injury (1B); higher rather than lower level of PEEP for patients

with sepsis-induced 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

<100 in facilities that have experience with such practices (2C); head of bed elevation in mechanically

ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established

ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A);

minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific

2
titration endpoints (1B); avoiding neuromuscular blockers if possible in the septic patient without ARDS

(1C); a short course of neuromuscular blocker of not greater than 48 hrs for patients with early, severe

ARDS (2C); a protocolized approach to blood glucose management commencing insulin dosing when 2

consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose <180 mg/dL (1A);

equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for

deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding (1B);

administering oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or

provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock

(2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate)

(1B), as early as feasible, but no later than within 72 hrs of ICU admission (2C). Recommendations

specific to pediatric severe sepsis include: in the presence of respiratory distress and/or hypoxemia,

beginning therapy with face mask oxygen, high flow nasal cannula oxygen or nasopharyngeal continuous

PEEP (2C), greater use of physical examination therapeutic end points such as capillary refill (2C); for

septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 ml/kg

of crystalloids(or albumin equivalent) over 5-10 minutes (2C); more common use of inotropes and

vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance

(2C); use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency

(2C); and more common use of ECMO for refractory respiratory failure associated with septic shock (2C).

Conclusions: Strong agreement existed among a large cohort of international experts regarding many

level 1 recommendations for the best current care of patients with severe sepsis. Although a significant

number of aspects of care have relatively weak evidence, evidence-based recommendations regarding

the acute management of sepsis and septic shock are the foundation of improved outcomes for this

important group of critically ill patients.

KEY WORDS: sepsis; severe sepsis; septic shock; sepsis syndrome; infection; Grading of

Recommendations Assessment, Development and Evaluation criteria; GRADE; guidelines; evidence-

based medicine; Surviving Sepsis Campaign; sepsis bundles

3
From Cooper University Hospital, Camden NJ (RPD); Warren Alpert Medical School of Brown University,
Providence RI (MML); St. George’s Hospital, London, UK (AR); Hôpital Raymond Poincaré, Garches,
France (DA); Children’s Hospital of Pittsburgh, Pittsburgh, PA (JAC); Vivantes-Klinikum Neukölln, Berlin,
Germany (HG); Memorial Hospital of Rhode Island, Pawtucket, RI (SMO); Emory University Hospital,
Atlanta, GA (JES); Hadassah Hebrew University Medical Center, Jerusalem, Israel (CLS); Denver Health
Medical Center, Denver, CO (ISD); McMaster University, Hamilton, Ontario, Canada (RJ); Barnes-Jewish
Hospital, St. Louis (TMO); University of Chicago Medical Center, Chicago, IL (MEN); California Pacific
Medical Center, San Francisco, CA (SRT); Friedrich Schiller University Jena, Jena, Germany (KR); Rush
University Medical Center, Chicago, IL (RMK); University of Pittsburgh, Pittsburgh, PA (DCA); Perelman
School of Medicine at the University of Pennsylvania, Philadelphia, PA (CSD); Federal University of Sao
Paulo, Sao Paulo, Brazil (FRM); Sunnybrook Health Sciences Center, Toronto, ON, Canada (GDR);
Royal Perth Hospital, Perth, Western Australia (SW); Guy’s and St. Thomas’ Hospital Trust, London, UK
(RJB); Erasme University Hospital, Brussels, Belgium (JLV); UCINC, Hospital de São José, Centro
Hospitalar de Lisboa Central, E.P.E. , Lisbon, Portugal (RM).

Sponsoring organizations: American Association of Critical-Care Nurses, American College of Chest

Physicians, American College of Emergency Physicians, American Thoracic Society, Asia Pacific
Association of Critical Care Medicine, Australian and New Zealand Intensive Care Societies, Brazilian
Society of Critical Care, Canadian Critical Care Society, Chinese Society of Critical Care Medicine,
Chinese Society of Critical Care Medicine - China Medical Association, Emirates Intensive Care Society,
European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases,
European Society of Intensive Care Medicine, European Society of Pediatric and Neonatal Intensive Care,
Infectious Diseases Society of America, Indian Society of Critical Care Medicine, International Pan
Arabian Critical Care Medicine Society, Japanese Association for Acute Medicine, Japanese Society of
Intensive Care Medicine, Pediatric Acute Lung Injury and Sepsis Investigators, Society for Academic
Emergency Medicine, Society of Critical Care Medicine, Society of Hospital Medicine, Surgical Infection
Society, World Federation of Critical Care Nurses, World Federation of Pediatric Intensive and Critical
Care Societies; World Federation of Societies of Intensive and Critical Care Medicine. Participation and
endorsement by the German Sepsis Society and the Latin American Sepsis Institute.

*Members of the 2012 SSC Guidelines Committee and Pediatric Subgroup are listed in Appendix A.
Author disclosures appear as Appendix A of the online supplemental material,

For information regarding this article, E-mail: Dellinger-Phil@CooperHealth.edu

Copyright © 2013 by the Society of Critical Care Medicine and European Society of Intensive Care

Medicine

Contents
Introduction
Methodology
Definitions
History
Committee Composition and Meetings
Search Techniques
Grading of Recommendations

4
 Conflict of Interest Policy
I. Management of Severe Sepsis
Initial Resuscitation and Infection Issues
A. Initial Resuscitation
B. Screening for Sepsis and Sepsis Performance Improvement
C. Diagnosis
D. Antimicrobial Therapy
E. Source Control
F. Infection Prevention
Hemodynamic Support and Adjunctive Therapy
G. Fluid Therapy of Severe Sepsis
H. Vasopressors
I. Inotropic Therapy
J. Corticosteroids
K. Blood Product Administration
L. Immunoglobulins
M. Selenium
N. History of Recommendations Regarding Use of Recombinant Activated Protein C
II. Supportive Therapy of Severe Sepsis
O. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis
Q. Glucose Control
R. Renal Replacement Therapy
S. Bicarbonate Therapy
T. Deep Vein Thrombosis Prophylaxis
U. Stress Ulcer Prophylaxis
V. Nutrition
W. Setting Goals of Care
III. Pediatric Considerations in Severe Sepsis
A. Initial Resuscitation
B. Antibiotics and Source Control
C. Fluid Resuscitation
D. Inotropes/Vasopressors/Vasodilators
E. Extracorporeal Membrane Oxygenation (ECMO) and Inhaled Nitric Oxide

5
 F. Corticosteroids
G. Protein C and Activated Protein Concentrate
H. Blood Products and Plasma Therapies
I. Mechanical Ventilation
J. Sedation/Analgesia/Drug Toxicities
K. Glycemic Control
L. Diuretics and Renal Replacement Therapy
M. DVT Prophylaxis
N. Stress Ulcer Prophylaxis
O.. Nutrition
Summary and Future Directions
Acknowledgments
References
Appendices
A. 2012 SSC Guidelines Committee
B. COI Disclosure Process
C. ARDSNET Ventilator Management
D. Summary of Ventilator Procedures in the Higher-PEEP Groups of the ALVEOLI Trial
Tables
1. Diagnostic Criteria for Sepsis
2. Severe Sepsis Definition = Sepsis-Induced Tissue Hypoperfusion or Organ Dysfunction
3. Determination of the Quality of Evidence
4. Factors Determining Strong vs. Weak Recommendation
5. Recommendations: Initial Resuscitation and Infection Issues
6. Norepinephrine Compared to Dopamine in Severe Sepsis
7. Recommendations: Hemodynamic Support and Adjunctive Support
8. Recommendations: Other Supportive Therapy of Severe Sepsis
9. Recommendations: Special Considerations in Pediatrics
Figures
1. Surviving Sepsis Campaign Care Bundles
2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic
support in infants and children
Online Appendices
A. SSC Conflict of Interest Policy/Disclosure

6
 B. Supplemental Bibliography of Quantitative Resuscitation
C. Summary of Evidence Table - Combined Topical Digestive Tract Antibiotics (Includes
Chlorhexidine) Versus No Prophylaxis for Mechanical Ventilation > 48 hours
D. Summary of Evidence Table - Low Dose Long Term Glucocorticosteroids for Severe
Sepsis and Septic Shock
E. Summary of Evidence Table - Neuromuscular Blocking Agents (NMBA) Compared to
Placebo in Patients with Acute Respiratory Distress Syndrome (ARDS)
F. Summary of Evidence Table - Histamine-2 Receptor Antagonists (H2RA) Compared To
Placebo for Prevention of GI Bleeding
G. Summary of Evidence Table - Proton Pump Inhibitors (PPI) Compared to Histamine-2
Receptor Antagonists (H2RA) for Prevention of GI Bleeding
H. Mortality in Clinical Trials of Intensive Insulin Therapy by High or Moderate Control
Groups

Introduction

Sepsis is a systemic, deleterious host response to infection leading to severe sepsis (acute organ

dysfunction secondary to documented or suspected infection) and septic shock (severe sepsis

plus hypotension not reversed with fluid resuscitation. Severe sepsis and septic shock are major

healthcare problems, affecting millions of people around the world each year, killing 1 in 4 (and often

more), and increasing in incidence (1-5). Similar to polytrauma, acute myocardial infarction, or stroke, the

speed and appropriateness of therapy administered in the initial hours after severe sepsis develops are

likely to influence outcome.

The recommendations in this document are intended to provide guidance for the clinician caring for a

patient with severe sepsis or septic shock. Recommendations from these guidelines cannot replace the

clinician’s decision-making capability when he or she is presented with a patient’s unique set of clinical

variables. Most of these recommendations are appropriate for the severe sepsis patient in the intensive

care unit (ICU) and non-ICU settings. In fact, the committee believes that currently the greatest outcome

improvement can be made through education and process change for those caring for severe sepsis

patients in the non-ICU setting and across the spectrum of acute care. It should also be noted that

resource limitations in some institutions and countries may prevent physicians from accomplishing

7
particular recommendations. These recommendations are intended to be best practice (what the

committee considers a goal for clinical practice) and not created to represent standard of care... The

Surviving Sepsis Campaign (SSC) Guidelines Committee hopes that over time, particularly through

education programs and formal audit and feedback performance improvement initiatives, the guidelines

will influence bedside healthcare practitioner behavior that will reduce the burden of sepsis worldwide. .

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, there is a distinction between definitions and therapeutic

targets or thresholds .Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) < 90 mm

Hg or mean arterial pressure <70 mm Hg or a SBP decrease >40 mm Hg or < 2 SD 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 vaspopressors. In the bundles,

the threshold for mean arterial pressure is ≥65 mm Hg. The different use of definition versus threshold

will be evident throughout this manuscript. 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 - The current clinical practice guidelines are a revision of the 2008 SSC

guidelines for the management of severe sepsis and septic shock (7). The first SSC guidelines were

published in 2004 (8). The 2004 publication incorporated the evidence available through the end of 2003;

the 2008 publication considered evidence through the end of 2007. The current publication is based on

an updated literature search into 2012.

Selection of Committee Members - Selection of committee members was based on interest and expertise

in specific aspects of sepsis. Co-chairs and executive committee members were appointed by the

Society of Critical Care Medicine and European Society of Intensive Care Medicine governing bodies.

Each sponsoring organization appointed a representative who had sepsis expertise. Additional

8
committee members were appointed by the co-chairs and executive committee based on creating

continuity with the previous guidelines committee membership and content needs for the development

process. Four evidence-based medicine experts were selected by the GRADE group.

The guidelines development process began with appointment of group heads and assignment of

committee members to groups according to their specific expertise. Each group was responsible for

drafting the initial update to the 2008 edition in their assigned area (with major additional elements of

information incorporated into the evolving manuscript through year-end 2011 and early 2012).

Under the guidance of the evidence-based medicine experts, an initial group meeting was held to

establish procedures for literature review and development of tables for evidence analysis. Committees

and their subgroups continued work via phone and internet. Several subsequent meetings of subgroups

and key individuals occurred at major international meetings (“nominal groups”), with work continuing via

teleconferences and electronic-based discussions among subgroups and members of the entire

committee. Ultimately, a meeting of all group heads, executive committee members, and other key

committee members was held to finalize the draft document for submission to reviewers.

Search Techniques - A separate search was performed for each clearly defined question. The committee

chairs worked with subgroup heads to identify pertinent search terms that were to include, at a minimum,

sepsis, severe sepsis, septic shock, and sepsis syndrome crossed against the general topic area of the

subgroup, as well as appropriate key words of the specific question posed. All questions of the previous

guidelines publications were searched, as were pertinent new questions generated by general topic-

related searches or recent trials. The authors were specifically asked to look for existing meta-analyses

related to their question and search a minimum of one general data base (ie, MEDLINE, EMBASE), and

Cochrane Library (both The Cochrane Database of Systematic Reviews [CDSR] and Database of

Abstract of Reviews of Effectiveness [(DARE]). Other databases were optional (ACP Journal Club,

Evidence- Based Medicine Journal, Cochrane Registry of Controlled Clinical Trials, http://www.controlled-

trials.com/isrctn/ or http://www.controlled-trials.com/mrct/. ).Available evidence was summarized using a

review manager program in the form of summary of evidence tables.

Grading of Recommendations

9
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). The grading of the

2012 guidelines recommendations is based on the Grading of Recommendations Assessment,

Development and Evaluation (GRADE) system, a structured system for rating quality of evidence and

grading strength of recommendations in clinical practice (9-11). The SSC Steering Committee and

individual authors collaborated with GRADE representatives to apply the GRADE 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 and, based on the preceding,

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 (see Table 3). Examples of indirectness of the evidence

include population studied, interventions used, outcomes measured, and how these relate to the question

of interest. 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 online 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 the judgment of strong versus weak recommendation are presented in Table 4. The

grade 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 will outweigh the

undesirable effects, and the strength of a recommendation reflects the group’s degree of confidence in

10
that assessment. A strong recommendation in favor of an intervention reflects the panel’s opinion that the

desirable effects of adherence to a recommendation (beneficial health outcomes; less 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 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.

The implications of calling a recommendation strong are that most well-informed patients would

accept that intervention and that most clinicians should use it in most situations. Circumstances may exist

in which a strong recommendation cannot or should not be followed for an individual patient because of

that patient’s preferences or clinical characteristics that make the recommendation less applicable. A

strong recommendation does not automatically imply standard of care. For example, the strong

recommendation for administering antibiotics within 1 hr of the diagnosis of severe sepsis as well as the

recommendation for achieving a CVP of 8 mm Hg and an ScvO2 of 70% in the first 6 hours of

resuscitation of sepsis-induced tissue hypoperfusion, although deemed desirable, are not yet standards

of care as verified by current practice data (see those respective sections of the guidelines for additional

information).

Significant education of committee members on the GRADE approach built on the process

conducted during 2008 efforts. Several members of the committee were trained in the use of GRADEpro

software allowing more formal use of the GRADE system (12). Rules were distributed concerning

assessing the body of evidence, and GRADE representatives were available for advice throughout the

11
process. Subgroups agreed electronically on draft proposals that were presented for general discussion

among subgroup heads, Surviving Sepsis Campaign (SSC) steering committee (2 co-chairs, 2 co-vice

chairs, and an at-large committee member), and several selected key committee members met in July

2011 in Chicago. The results of that discussion were incorporated into the next version of

recommendations and again discussed with the whole group using electronic mail. Draft

recommendations were distributed to the entire committee and finalized during an additional nominal

group meeting in Berlin in October 2011. Deliberations and decisions were then recirculated to the entire

committee for approval. At the discretion of the chairs and following discussion, competing proposals for

wording of recommendations or assigning strength of evidence were resolved by formal voting within

subgroups and at nominal group meetings. The manuscript was edited for style and form by the writing

committee with final approval by subgroup heads for their respective group assignment and then by the

entire committee.

Conflict of Interest Policy

Since the inception of the SSC guidelines in 2004, no members of the committee were from industry;

there was no industry input into guidelines development;; and no industry representatives were present at

any of the meetings. Industry awareness or comment on the recommendations was not allowed. No

member of the guidelines committee received any honoraria for any role in the 2004, 2008, or 2012

guidelines process.

Appendix B shows a flowchart of the COI disclosure process. Committee members who were

judged to have either financial or non-financial/academic competing interests were recused during the

closed discussion session and voting session on that topic. Full disclosure and transparency of all

committee members’ potential conflicts were sought A detailed description of the disclosure process and

all author disclosures appear in online Appendix A in the online supplemental materials to this document.

On initial review, 68 financial conflict of interest (COI) disclosures and 54 non-financial disclosures were

submitted by committee members. Declared COIs from 19 membersmembers were determined by the

COI subcommittee to be not relevant to the guidelines content process. Nine who were determined to

12
have COI (financial and non-financial) were adjudicated by group reassignment and requirement to

adhere to SSC COI policy regarding discussion or voting at any committee meetings where content

germane to their COI was discussed. Nine were judged as having COI that could not be resolved solely

by reassignment. One of these individuals was asked to step down from the committee. The other 8

people were assigned to the groups in which they had the least COI. They were required to work within

their group with full disclosure as to their conflict of interest when a topic for which they had relevant COI

was discussed and 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.

MANAGEMENT OF SEVERE SEPSIS –

Initial Resuscitation and Infection Issues (Table 5)

A. Initial Resuscitation

1. We recommend the 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). This protocol should be initiated as soon as hypoperfusion is

recognized and should not be delayed pending ICU admission. During the first 6 hrs of resuscitation, the

goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following as one part

of a treatment protocol (grade 1C):

(a) Central venous pressure 8–12 mm Hg

(b) Mean arterial pressure (MAP) ≥65 mm Hg

(c) Urine output ≥ 0.5 mL·kg-1·hr-1

(d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively.

2. We suggest, in patients with elevated lactate levels as a marker of tissue hypoperfusion, targeting

resuscitation to normalize lactate as rapidly as possible (grade 2C).

Rationale. Early quantitative resuscitation has been shown to improve survival for emergency department

patients presenting with septic shock in a randomized, controlled, single-center study

(13). Resuscitation targeting the physiologic goals expressed in recommendation 1, above, for the initial

6-hr period was associated with a 15.9% absolute reduction in 28-day mortality rate. This strategy,

13
termed “early goal-directed therapy” was evaluated in a multicenter trial of 314 patients with severe

sepsis in 8 Chinese centers (14). This trial reported a 17.7% absolute reduction in 28-day mortality

(survival rates, 75.2% vs. 57.5%, P=0.001). A large number of other observational studies using similar

forms of early quantitative resuscitation in similar patient populations have shown significant mortality

reduction compared to historical controls at that institution (See Online Appendix B, Supplemental

Bibliography of Quantitative Resuscitation). Phase III of the SSC activities, the international performance

improvement program, showed that the mortality of septic patients presenting with both hypotension and

lactate ≥4 mmol/L was 46.1%, similar to the 46.6% mortality found in the first trial alluded to above (15).

Although as part of performance improvement programs some hospitals have lowered the lactate

threshold for triggering quantitative resuscitation in the patient with severe sepsis, these thresholds have

not been subjected to randomized trials.

The consensus panel judged use of central venous and mixed venous oxygen saturation targets

to be recommended physiologic targets for resuscitation. Although there are limitations to CVP as a

marker of intravascular volume status and response to fluids, a low CVP, in general, can be relied upon

as supporting positive response to fluid loading. Either intermittent or continuous measurements of

oxygen saturation were judged to be acceptable. During the first six hours of resuscitation, if ScvO2

< 70% or SvO2 equivalent of <65% persists with what is judged to be adequate intravascular volume

repletion in the presence of persisting tissue hypoperfusion, then dobutamine infusion (to a maximum of

20/μg/kg/min) or transfusion of packed red blood cells to achieve a hematocrit of ≥30% in attempts to

achieve the ScvO2 or SvO2 goal are options. The strong recommendation for achieving a CVP of

8 mm Hg and an ScvO2 of 70% in the first 6 hours of resuscitation of sepsis-induced tissue

hypoperfusion, although deemed desirable, are not yet standard of care as verified by current practice

data. The publication of the initial results of the international SSC performance improvement program

demonstrated that adherence to CVP and Scv02 targets for initial resuscitation was low (15).

In mechanically ventilated patients or patients with known pre-existing decreased ventricular

compliance, a higher target central venous pressure of 12–15 mm Hg should be achieved to account for

the impediment in filling (16). Similar consideration may be warranted in circumstances of increased

abdominal pressure (17). Elevated central venous pressures may also be seen with pre-existing clinically

14
significant pulmonary artery hypertension making use of this variable untenable for judging intravascular

volume status. Although the cause of tachycardia in septic patients may be multifactorial, a decrease in

elevated pulse rate with fluid resuscitation is often a useful marker of improving intravascular filling.

Recently published observational studies have demonstrated an association between good clinical

outcome in septic shock and MAP ≥65 mm Hg as well as central venous oxygen saturation (ScvO2,

measured in superior vena cava, either intermittently or continuously) of ≥70% (18). Many recent studies

support the value of early protocolized resuscitation in severe sepsis and sepsis-induced tissue

hypoperfusion (19-24). Studies of patients with shock indicate that mixed venous oxygen saturation

(SvO2) runs 5–7% lower than ScvO2 (25). While the committee recognized the controversy surrounding

resuscitation targets, an early quantitative resuscitation protocol using CVP and venous blood gasses can

be readily established in both ED and ICU settings (26). Recognized limitations to static ventricular filling

pressure estimates exist as surrogates for fluid resuscitation (27, 28). However, measurement of central

venous pressure is currently the most readily obtainable target for fluid resuscitation. Targeting dynamic

measures of fluid responsiveness during resuscitation including flow and possibly volumetric indices and

microcirculatory changes may have advantages (29-32). Currently available technologies allow

measurement of flow at the bedside (33, 34); however, the efficacy of these monitoring techniques to

influence clinical outcomes from early sepsis resuscitation remains incomplete and requires further study

before endorsement.

The global prevalence of patients initially presenting with either hypotension with lactate ≥ 4

mmol//L, hypotension alone, or lactate ≥ 4 mmol/L alone, is reported as 16.6%, 49.5%, and 5.4%,

respectively (15). The mortality is high in septic patients with both hypotension and lactate

≥ 4 mmol/L (46.1%) (15). Mortality is also increased in severely septic patients with hypotension alone

(36.7%) and lactate ≥ 4 mmol/L alone (30%) (15). If ScvO2 is not available, lactate normalization may be

a feasible option in the patient with severe sepsis-induced tissue hypoperfusion. ScvO2 and lactate

normalization may also be used as a combined endpoint when both are available. Two recent multi-

center randomized trials evaluated a resuscitation strategy that included lactate reduction as a single

target or a target combined with ScvO2 normalization (35, 36). The first trial reported that early

quantitative resuscitation based on lactate clearance (decrease by at least 10%) was noninferior to early

15
quantitative resuscitation based on achieving ScvO2 of 70% or more (37). The intention-to-treat group

was 300; however the number of patients actually requiring either ScvO2 normalization or lactate

clearance was small (n=30). The second trial included 348 patients with lactate ≥3 mmol/L (36). The

strategy in this trial was based on a 20% or more decrease in lactate levels per 2 hours of the first 8 hours

in addition to ScvO2 target achievement and was associated with a 9.6% absolute reduction in mortality

(P= 0.067; adjusted hazard ratio, .61; 95% confidence interval, 0.43-0.87; P= 0.006).

B. Screening for Sepsis and Performance Improvement

1. We recommend routine screening of seriously ill patients for severe sepsis to increase the early

identification of sepsis and allow implementation of early sepsis therapy (grade 1C).Rationale. The early

identification of sepsis and implementation of early evidence-based therapies have been documented to

improve outcomes and decrease sepsis-related mortality (15). Reducing the time to diagnose severe

sepsis is thought to be a critical component of reducing mortality from sepsis-related multiple organ

dysfunction (35). Lack of early recognition of sepsis is a major obstacle to sepsis bundle initiation.

Sepsis screening tools have been developed to monitor ICU patients (37-41). Implementation of these

sepsis screening tools has been associated with decreased sepsis-related mortality (15).

2. Performance improvement efforts in severe sepsis should be used to improve patient outcomes (UG).

Rationale. Performance improvement efforts in sepsis have been associated with improved patient

outcomes (19, 43-46). Improvement in the process of care through increasing compliance with sepsis

quality indicators is the goal of a severe sepsis performance improvement program (47). Sepsis

management requires a multidisciplinary team (physicians, nurses, pharmacy, respiratory, dietetics, and

administration) and a multispecialty collaboration (medicine, surgery, and emergency medicine) to

maximize the chance for success. Evaluation of process change requires consistent education, protocol

development and implementation, data collection, measurement of indicators, and feedback to facilitate

16
the continuous performance improvement. Ongoing educational sessions provide feedback of indicator

compliance and can help identify areas for additional performance improvement efforts. In addition to

traditional continuing medical education efforts to introduce guidelines into clinical practice, knowledge

translation efforts have recently been introduced as a means to promote the use of high-quality evidence

in changing behavior (48). Protocol implementation associated with education and performance feedback

has been shown to change clinician behavior and areis associated with improved outcomes and cost

effectiveness in severe sepsis (19, 23, 24, 49). In partnership with the Institute for Healthcare

Improvement, Phase III of the Surviving Sepsis Campaign targeted the implementation of a core set

(“bundle”) of recommendations in hospital environments where change in behavior and clinical impact

were measured (50). The Surviving Sepsis Campaign Guidelines and Bundles can be used as the basis

of a sepsis performance improvement program.

Application of the SSC sepsis bundles led to sustained, continuous quality improvement in sepsis care

and was was associated with reduced mortality (15). Analysis of the data from nearly 32,000 patient

charts gathered from 239 hospitals in 17 countries through September 2011 as part of Phase III of the

Campaign informed the revision of the bundles in conjunction with the 2012 edition of the guidelines. As

a result, for the 2012 version, management bundle was dropped and the resuscitation bundle was

broken into 2 parts as shown in Figure 1. Note that target measures are not considered in scoring

compliance with the bundles. The targets per the original protocol are included with the bundles for

reference purposes (13).

. .

C. Diagnosis

1. We recommend obtaining appropriate cultures before antimicrobial therapy is initiated if such cultures

do not cause significant delay (>45 minutes) in the start of antimicrobial(s) administration ( grade 1C). To

optimize identification of causative organisms, we recommend 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

hr.) inserted. These blood cultures can be drawn at the same time if they are obtained from different sites.

17
Cultures of other sites (preferably quantitative where appropriate), such as urine, cerebrospinal fluid,

wounds, respiratory secretions, or other body fluids that may be the source of infection should also be

obtained before antimicrobial therapy if not associated with significant delay in antibiotic administration

(grade 1C).

Rationale. Although sampling should not delay timely administration of antimicrobial agents in patients

with severe sepsis (eg, lumbar puncture in suspected meningitis), obtaining appropriate cultures before

administration of antimicrobials is essential to confirm infection and the responsible pathogens and to

allow de-escalation of antimicrobial therapy after receipt of the susceptibility profile. Samples can be

refrigerated or frozen if processing cannot be performed immediately.Because rapid sterilization of blood

cultures can occur within a few hours after the first anti-infective dose, obtaining those cultures before

starting therapy is essential if the causative organism is to be identified. Two or more blood cultures are

recommended (51). In patients with indwelling catheters (for >48 hr), at least one blood culture should be

drawn through each lumen of each vascular access device (if feasible, especially for vascular devices

with signs of inflammation, catheter dysfunction, or indicators of thrombus formation). Obtaining blood

cultures peripherally and through a vascular access device is an important strategy. If the same organism

is recovered from both cultures, the likelihood that the organism is causing the severe sepsis is enhanced.

In addition, if equivalent volumes of blood drawn for culture through the vascular access device is positive

much earlier than the peripheral blood culture (ie, >2 hr earlier), the data support the concept that the

vascular access device is the source of the infection (3651, 52). Quantitative cultures of catheter and

peripheral blood may also be useful for determining whether the catheter is the source of infection. The

volume of blood drawn with the culture tube should be ≥10 mL (53). Quantitative (or semi-quantitative)

cultures of respiratory tract secretions are often recommended for the diagnosis of ventilator-associated

pneumonia (54), but their diagnostic value remains unclear (55).

The Gram stain can be useful, in particular for respiratory tract specimens, to determine if inflammatory

cells are present (>5 PMN/high powered field and <10 squamous cells/ low powered field) and if culture

of the sample will be informative of lower respiratory pathogens. Rapid influenza antigen testing during

18
periods of increased influenza activity in the community is also recommended. A focused history can

provide vital information about potential risk factors for infection and likely pathogens at specific tissue

sites. The potential role of biomarkers for diagnosis of infection in patients presenting with severe sepsis

remains undefined. The utility of procalcitonin levels or other biomarkers (such as C reactive protein) to

discriminate the acute inflammatory pattern of sepsis from other causes of generalized inflammation (eg,

postoperative, other forms of shock) has not been demonstrated; no recommendation can be given at

present for the use of these markers to distinguish between severe infection from other acute

inflammatory states (56-58).

In the near future, rapid, non-culture-based diagnostic methods (polymerase chain reaction, mass

spectroscopy, microarrays) might be extremely helpful for a quicker identification of pathogens and major

antimicrobial resistance determinants (59). These methodologies could be particularly useful for difficult to

culture pathogens or in clinical situations where empiric antimicrobial agents have already been

administered before culture samples have been obtained. Clinical experience remains limited to date and

more clinical studies are needed before recommending these non-culture molecular methods as a

replacement for standard blood culture methods (60, 61).

.2. We suggest the use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody

assays (2C), if available, for the early diagnosis of invasive candidiasis.

Rationale. The diagnosis of systemic fungal infection (usually candidiasis) in the critically ill patient can

be challenging and rapid diagnostic methodologies such as antigen and antibody detection assays can be

helpful in detecting candidiasis in the ICU patient. These suggested tests have been shown to become

positive significantly earlier than standard culture methods (62-67), but false positive reactions can occur

with colonization alone and their diagnostic utility in managing fungal infection in the ICU needs additional

study (65).

3. We recommend that imaging studies be performed promptly in attempts to confirm a potential

source of infection (grade1C). Sampling of potential sources of infection should occur as they are

19
identified and in consideration of patient risk for transport and invasive procedures(for example careful

coordination and aggressive monitoring if decision is made to transport for a CT guided needle aspiration).

Bedside studies, such as ultrasound, may avoid patient transport.

Rationale. Diagnostic studies may identify a source of infection that requires removal of a foreign body or

drainage to maximize the likelihood of a satisfactory response to therapy. Even in the most organized and

well-staffed healthcare facilities, however, transport of patients can be dangerous, as can be placing

patients in outside-unit imaging devices that are difficult to access and monitor. Balancing risk and benefit

is therefore mandatory in those settings.

D. Antimicrobial Therapy

1. We recommend that intravenous antimicrobial therapy be started as early as possible and

within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock

(grade 1C). Appropriate cultures should be obtained before initiating antibiotic therapy, but should not

prevent prompt administration of antimicrobial therapy.

Rationale. Establishing vascular access and initiating aggressive fluid resuscitation are the first priorities

when managing patients with severe sepsis or septic shock. Prompt infusion of antimicrobial agents

should also be a priority and may require additional vascular access ports (68, 69). In the presence of

septic shock, each hour delay in achieving administration of effective antibiotics is associated with a

measurable increase in mortality in a number of recent studies (15, 68, 70-72). One study done in

emergency department patients showed that if antibiotics were given prior versus after onset of shock

outcome was influenced (improved survival) butshowed no incremental benefit on survival based on time

of antibiotic administration (73). Overall, data support giving antibiotics as soon as possible in patients

with severe sepsis with or without septic shock (15, 68, 70-72, 74-78). Administration of antimicrobial

agents with a spectrum of activity likely to treat the responsible pathogen(s) effectively should begin

within 1 hr after the diagnosis of severe sepsis and septic shock is made. This should be the target goal

when managing patients with septic shock whether they are located within the hospital ward, the

20
emergency department, or within the intensive care unit. The strong recommendation for administering

antibiotics within 1 hr of the diagnosis of severe sepsis and septic shock, although judged to be desirable,

is not yet standard of care as verified by current published practice data (15).

If antimicrobial agents cannot be mixed and delivered promptly from the pharmacy, establishing a supply

of premixed antibiotics for such urgent situations is an appropriate strategy for ensuring prompt

administration. Many antibiotics will not remain stable for long if premixed in a solution. This risk must be

taken into consideration in institutions that rely on premixed solutions for rapid availability of antibiotics. In

choosing the antimicrobial regimen, clinicians should be aware that some antimicrobial agents have the

advantage of bolus administration, while others require a lengthy infusion. Thus, if vascular access is

limited and many different agents must be infused, bolus drugs may offer an advantage.

2a. We recommend that initial empiric anti-infective therapy include one or more drugs that have

activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate

concentrations into the tissues presumed to be the source of sepsis (grade 1B).

Rationale. The choice of empirical antimicrobial therapy depends on complex issues related to the

patient’s history, including drug intolerances, recent receipt of antibiotics (previous 3 months), underlying

disease, the clinical syndrome, and susceptibility patterns of pathogens in the community, in the hospital,

and that previously have been documented to colonize or infect the patient. The most common pathogens

that cause septic shock in hospitalized patients are Gram-positive bacteria followed by Gram-negative

and mixed bacterial microorganisms. Candidiasis, toxic shock syndromes and an array of uncommon

pathogens should be considered in selected patients. An especially wide range of potential pathogens

exists for neutropenic patients. Recently used anti-infective agents should generally be avoided. When

choosing empirical therapy, clinicians should be cognizant of the virulence and growing prevalence of

oxacillin (methicillin)-resistant Staphylococcus aureus (ORSA or MRSA), and resistance to broad-

spectrum beta-lactams and carbapenem among Gram-negative bacilli in some communities and

21
healthcare settings. Within regions in which the prevalence of such drug-resistant organisms is

significant, empiric therapy adequate to cover these pathogens is warranted.

Clinicians should also consider whether candidemia is a likely pathogen when choosing initial

therapy. When deemed warranted, the selection of empirical antifungal therapy (eg, an echinocandin,

triazoles such as fluconazole, or a formulation of amphotericin B) should be tailored to the local pattern of

the most prevalent Candida species and any recent exposure to antifungal drugs(79). Recent Infectious

Diseases Society of America (IDSA) guidelines recommend either fluconazole or an echinocandin.

Empiric use of an echinocandin is preferred in most patients with severe illness, especially in those

patients who have recently been treated with antifungal agents, or if C. glabrata infection is suspected

from earlier culture data.Knowledge of local resistance patterns to antifungal agents should guide drug

selection until fungal susceptibility test results, if available, are performed. Risk factors for candidemia

such as immunosupressed or neutropenic state, prior intense antibiotic therapy, or colonization in multiple

sites should also be considered when choosing initial therapy.

Because patients with severe sepsis or septic shock have little margin for error in the choice of therapy,

the initial selection of antimicrobial therapy should be broad enough to cover all likely pathogens.

Antibiotic choices should be guided by local prevalence patterns of bacterial pathogens and susceptibility

data , There is ample evidence that failure to initiate appropriate therapy (ie, therapy with activity against

the pathogen that is subsequently identified as the causative agent) correlates with increased morbidity

and mortality in patients with severe sepsis or septic shock (68, 71, 80,81). Recent exposure to

antimicrobials (within last 6 months) should be considered in choosing an empiric antibacterial regimen.

Patients with severe sepsis or septic shock warrant broad-spectrum therapy until the causative organism

and its antimicrobial susceptibilities are defined. Although a global restriction of antibiotics is an

important strategy to reduce the development of antimicrobial resistance and to reduce cost, it is not an

appropriate strategy in the initial therapy for this patient population. However, as soon as the causative

pathogen has been identified, de-escalation should be performed by selecting the most appropriate

22
antimicrobial agent that covers the pathogen and is safe and cost effective. Collaboration with

antimicrobial stewardship programs, where they exist, is encouraged to ensure appropriate choices and

rapid availability of effective antimicrobials for treating septic patients. All patients should receive a full

loading dose of each antimicrobial agent. Patients with sepsis often have abnormal and often vacillating

renal or hepatic function or may have abnormally high volumes of distribution due to aggressive fluid

resuscitation, requiring dose adjustment. Drug serum concentration monitoring can be useful in an ICU

setting for those drugs that can be measured promptly. Significant expertise is required to ensure that

serum concentrations are attained that maximize efficacy and minimize toxicity (82, 83).

2b. The antimicrobial regimen should be reassessed daily for potential de-escalation to prevent the

development of resistance, to reduce toxicity, and to reduce costs (1B).

Rationale. Once the causative pathogen has been identified, the most appropriate antimicrobial agent

should be chosen that covers the pathogen and is safe and cost effective. On occasion, continued use of

specific combinations of antimicrobials might be indicated even after susceptibility testing is available (eg,

Pseudomonas spp. only susceptible to aminoglycosides; Enterococcal endocarditis; Acinetobacter spp.

infections susceptible only to polymyxins, etc). Decisions on definitive antibiotic choices need to be made

based on the type of pathogen, patient characteristics, and favored hospital treatment regimens.

Narrowing the spectrum of antimicrobial coverage and reducing the duration of antimicrobial therapy will

reduce the likelihood that the patient will develop superinfection with other pathogenic or resistant

organisms such as Candida species, Clostridium difficile, or vancomycin-resistant Enterococcus faecium.

However, the desire to minimize superinfections and other complications should not take precedence

over the need to give the patient an adequate course of therapy to cure the infection that caused the

severe sepsis or septic shock.

23
3. We suggest the use of low procalcitonin levels or similar biomarkers to assist the clinician in the

discontinuation of empiric antibiotics in patients who appeared septic, but have no subsequent evidence

of infection (grade 2C).

Rationale. This suggestion is predicated on the preponderance of the published literature to date relating

to the use of procalcitonin as a tool to discontinue unnecessary antimicrobials (58, 84). However, clinical

experience with this strategy is limited and the potential for harm remains a concern (84). No evidence

exists to demonstrate this practice reduces the prevalence of antimicrobial resistance or the risk of

antibiotic-related diarrhea from C. difficile. One recent study failed to show benefit of daily PCT

measurement as a guide to early antibiotic therapy or survival benefit (85).

4a. Empiric therapy should attempt to provide antimicrobial activity against the most likely pathogens

based upon each patient’s presenting illness and local patterns of infection.

We suggest combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for

patients with difficult to treat, multidrug- resistant bacterial pathogens such as Acinetobacter and

Pseudomonas spp. (grade 2B). For selected 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 suggested for P. aeruginosa bacteremia (grade 2B). Similarly, a

more complexcombination of beta-lactam and a macrolide is suggested for patients with septic shock

from bacteremic Streptococcus pneumoniae infections (grade 2B).

Rationale: Complex combinations might be needed in settings where highly antibiotic-resistant pathogens

are prevalent with regimens containing carbapenems, colistin, rifampin, or other agents. However, a

recent controlled trial suggested that adding a fluoroquinolone to a carbapenem did not improve

outcome as empiric therapy in a population at low risk for infection with resistant microorganisms (86).

4b. When used empirically in patients with severe sepsis, we suggest that combination therapy should not

be administered for >3–5 days. De-escalation to the most appropriate single therapy should be performed

as soon as the susceptibility profile is known (grade 2B). Exceptions would include aminoglycoside

24
monotherapy,which should be generally avoided, particularly for P. aeruginosa sepsis, and for selected

forms of endocarditis where prolonged courses of combinations of antibiotics are warrented.

Rationale. A recent propensity-matched analysis, meta-analysis, and meta-regression analysis along with

additional observational studies have demonstrated that combination therapy produces a superior clinical

outcome in severely ill, septic patients with a high risk of death (87-91). In light of the increasing

frequency of resistance to antimicrobial agents in many parts of the world, broad spectrum coverage

generally requires initial use of combinations of antimicrobial agents. Combination therapy used in this

context connotes at least 2 different classes of antibiotics (usually a beta-lactam agent with a macrolide,

fluoroquinolone, or aminoglycoside for select patients). A recent controlled trial however suggest that

when using a carbapenem as empiric therapy in a population at low risk for infection with resistant

microorganisms, the addition of a fluoroquinolone does not improve outcomes of patients. A number of

other recent observational studies and some small, prospective trials support initial combination therapy

for selected patients with specific pathogens (eg, pneumococcal sepsis, multi-drug resistant gram

negative pathogens) (92-94), but evidence from adequately powered, randomized clinical trials is not

available to support combination over monotherapy other than in septic patients at high risk of death. In

some clinical scenarios, combination therapies are biologically plausible and are likely clinically useful

even if evidence has not demonstrated improved clinical outcome (90, 91, 95, 96). Combination therapy

for suspected or known Pseudomonas aeruginosa or other multi-resistant gram-negative pathogens,

pending susceptibility results, increases the likelihood that at least one drug is effective against that strain

and positively affects outcome (89, 97).

5. We suggest that the duration of therapy typically be 7–10 days if clinically indicated; 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. We suggest that antiviral therapy be initiated as early as possible in patients with severe sepsis or

septic shock of viral origin (grade 2C). Appropriate viral cultures and real-time polymerase chain reaction

25
(PCR) (more sensitive and specific) should be obtained but should not delay prompt administration of

antiviral therapy.

overt sepsis resulting from mixed bacterial/viral infection Rationale. Recommendations for antiviral

treatment include the use of 1) 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); 2) early antiviral treatment of suspected or confirmed influenza among persons at

higher risk for influenza complications; and 3) 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 (98,99). Susceptibility to

antivirals is highly variable in a rapidly evolving virus such as influenza and therapeutic decisions need to

be guided with updated information regarding the most active, strain-specific, antiviral agents during

influenza epidemics (100, 101).

The role of cytomegalovirus (CMV) and other herpes viruses as significant pathogens in septic patients,

especially those not known to be severely immunocompromised, remains unclear. Active CMV viremia is

quite common (15-35%) in critically ill patients; the presence of CMV in the blood stream has been

repeatedly found to be a poor prognostic indicator (102,103). 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

(104). No recommendations on treatment can be given, based on the current level of evidence. In those

patients with severe primary or generalized varicella-zoster 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 (105).

7. We recommend that antimicrobial agents not be used in patients with severe inflammatory states

determined to be of noninfectious cause (grade 1C).

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

26
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 >50% of cases of severe sepsis or

septic shock if they 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 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 peri-pancreatic 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 on 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) (106). 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 (107-109) and removing

27
intravascular access devices that are potentially the source of severe sepsis or septic shock promptly

after establishing other sites for vascular access (110,111).

A randomized, controlled trial comparing early versus delayed surgical intervention for peri-pancreatic

necrosis showed better outcomes with a delayed approach (112). Moreover, a recent, 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 (113). However, 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 (114). Source control interventions may cause further complications, such as bleeding,

fistulas, or inadvertent organ injury. Surgical intervention should be considered when lesser interventional

approaches are inadequate or when diagnostic uncertainty persists despite radiologic evaluation. Specific

clinical situations require consideration of available choices, patient’s preferences, and clinician’s

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 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. We suggest oral chlorhexidine gluconate (CHG) be used as a form of oropharyngeal decontamination

to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B).

Rationale: Careful infection control practices (eg, hand washing, expert nursing care, catheter care,

barrier precautions, airway management, elevation of the head of the bed, subglottic suctioning, etc)

should be instituted during the care of septic patients as recently reviewed in the nursing considerations

for the Surviving Sepsis Campaign (115). The role of selective decontamination of the digestive tract

28
(SDD) with systemic antimicrobial prophylaxis and its variants (eg, selective oral decontamination [SOD],

or oral chlorhexidine gluconate [CHG]) continues to be a contentious issue ever since the concept was

first developed more than 30 years ago. The notion of limiting the acquisition of opportunistic, often multi-

resistant, healthcare-associated microorganisms has its appeal by promoting “colonization resistance”

from the resident microbiome existing along mucosal surfaces of the alimentary tract. However, the

efficacy of SDD, its safety, propensity to prevent or promote antibiotic resistance, and cost-effectiveness

remain debatable despite a number of favorable meta-analyses and controlled clinical trials (116). The

data indicate an overall reduction in ventilator-associated pneumonia (VAP) but no consistent

improvement in mortality, except for selected populations in some studies. Most of the available literature

do not specifically address the efficacy of SDD in patients who present with sepsis, but some do (117-

119).

Oral CHG is relatively easy to apply, decreases risk of nosocomial infection, and reduces the potential

concern over promotion of antimicrobial resistance by SDD regimens. This remains a subject of

considerable debate, despite the recent evidence that the incidence of antimicrobial resistance does not

change appreciably with current SDD regimens (120-122). The grading is 2B for both SOD and CHG as

the group felt the risk was less with CHG and is better accepted despite less published literature than with

SOD.

Online Appendix C shows a GRADEpro Summary of Evidence Table regarding the use of topical

digestive tract antibiotics and chlorhexidine for prophylaxis against VAP.

Hemodynamic Support and Adjunctive Therapy

G. Fluid Therapy of Severe Sepsis

1. We recommend crystalloids be used as the initial fluid of choice in the resuscitation of severe sepsis

and septic shock (grade 1B).

2. We recommend against the use of hydroxy ethyl starches for fluid resuscitation of severe sepsis and

septic shock (grade 1B).

29
3. We suggest the use of albumin in the fluid resuscitation of severe sepsis and septic shock when

patients require repeated boluses of crystalloids (grade 2C).

Rationale. The absence of any clear benefit following the administration of colloid solutions when

compared to crystalloid solutions, together with the expense associated with colloid solutions, supports a

high grade recommendation for the use of crystalloid solutions in the initial resuscitation of patients with

severe sepsis and septic shock. It also supports a high grade recommendation advising against the

routine use of colloid solutions in the initial resuscitation of this patient group.

Three recent multicenter randomized controlled trials evaluating HES 6%130/0.4 solutions (tetra

starches) have been published. CRYSTMAS demonstrated no difference in mortality with HES versus

0.9% normal saline (31% versus 25.3%, P=0.37) in the resuscitation of septic shock patients; however

the study was underpowered to detect the 6% difference in absolute mortality observed. In a sicker

patient cohort, a Scandinavian multicenter study in septic patients (6S Trial Group) showed increased

mortality rates with HES 130/0.42 fluid resuscitation compared to Ringer's acetate (51% versus 43%.

P=0.03) (123, 124). In a heterogenous population of patients admitted to intensive care the CHEST

study (HES vs isotonic saline n=7000 critically ill patients) showed no difference in 90-day mortality

between resuscitation with 6% HES with a molecular weight of 130 kD/0.40 and isotonic saline (18%

versus 17%, P=0.26) . In this trial, the need for renal replacement therapy was higher in the HES group

(7.0 versus 5.8%, RR 1.21; 95% CI 1.00-1.45, p=0.04) (125). A meta-analysis of 56 randomized trials

found no overall difference in mortality between crystalloids and artificial colloids (modified gelatins,

hydroxyethyl starches, dextran) when used for initial fluid resuscitation (126). Information from 3

randomized trials (n=704 patients with severe sepsis/septic shock) did not show survival benefit with use

of heta-, hexa-, or pentastarches when compared to other fluids (RR=1.15; > 95% CI: 0.95 to 1.39,

random effect; I2= 0%) (127-129). However, these solutions increased substantially the risk of acute

kidney injury (RR=1.60, 95% CI: 1.26 to 2.04; I2= 0%) (127-129).

The evidence of harm observed in the 6S and CHEST studies and the meta-analysis supports a high

30
level recommendation advising against the use of HES solutions in patients with severe sepsis and septic

shock.

The SAFE study indicated that albumin administration was safe and equally as effective as 0.9% saline

(130). A recent meta-analysis aggregated data from 17 randomized trials (n=1977) of albumin versus

other fluid solutions in patients with severe sepsis/septic shock (131). There were 279 deaths among 961

albumin-treated patients vs 343 deaths among 1016 patients treated with other fluids, thus favoring

albumin (OR= 0.82, 95%CI: 0.67 to 1.00; I2= 0%). When compared to crystalloids (7 trials, n=1441), the

OR of dying was significantly reduced for albumin-treated patients, 0.78 (95%CI: 0.62 to 0.99, I2= 0%). A

recent multicenter randomized trial (n=794) in patients with septic shock, compared intravenous albumin

(20 g, 20%) every 8 hours for 3 days to intravenous saline solution (131). In this trial, albumin therapy

was associated with 2.2% absolute reduction in 28-day mortality (from 26.3 to 24.1%), which did not

achieve statistical significance. These data support a low level recommendation regarding the use of

albumin in patients with sepsis and septic shock. See GRADEpro Summary of Evidence Table in online

supplemental material

5. We recommend that a fluid challenge technique be applied wherein fluid administration is continued as

long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure,

stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG).

Rationale. Dynamic tests to assess patients’ responsiveness to fluid replacement have become very

popular in recent years in the ICU (132). These tests are based on monitoring changes in stroke volume

during mechanical ventilation or after passive leg raising in spontaneously breathing patients. A recent

systematic review (29 trials, n=685 critically ill patients) has analyzed the association between stroke

volume variation, pulse pressure variation, and/or stroke volume variation and the change in stroke

volume/cardiac index after a fluid or positive end-expiratory pressure challenge (133). The diagnostic OR

of fluid responsiveness was 59.86 (14 trials, 95%CI: 23.88–150.05) and 27.34 (5 trials, 95%CI: 3.46–

31
55.53) for the pulse pressure variation (PPV) and the stroke volume variation (SVV), respectively. Utility

of PPV and SVV is limited in the presence of atrial fibrillation, spontaneous breathing, and low pressure

support breathing.These techniques generally require sedation.

H. Vasopressors

1. We recommend that vasopressor therapy initially target a mean arterial pressure (MAP) of 65 mm Hg

(grade 1C).

Rationale. Vasopressor therapy is required to sustain life and maintain perfusion in the face of life-

threatening hypotension, even when hypovolemia has not yet been resolved. Below a threshold mean

arterial pressure, auto-regulation in critical vascular beds can be lost, and perfusion can become linearly

dependent on pressure. Thus, some patients may require vasopressor therapy to achieve a minimal

perfusion pressure and maintain adequate flow (134,135). The titration of norepinephrine to a MAP as low

as 65 mm Hg has been shown to preserve tissue perfusion (135). Note that the consensus definition of

sepsis-induced hypotension for use of MAP for the diagnosis of severe sepsis is different (MAP < 70 mm

Hg) from the evidence-based medicine target of 65 mm Hg used in this recommendation. In any case, the

optimal MAP should be individualized as it may be higher in patients with atherosclerosis and/or previous

hypertension than in young patients without cardiovascular comorbidity. For example, a MAP of 65 mm

Hg might be too low in a patient with severe uncontrolled hypertension, and in a young, previously

normotensive patient, a lower MAP might be adequate. Supplementing end points, such as blood

pressure, with assessment of regional and global perfusion, such as blood lactate concentrations, skin

perfusion, mental status, and urine output, is important. Adequate fluid resuscitation is a fundamental

aspect of the hemodynamic management of patients with septic shock and should ideally be achieved

before vasopressors and inotropes are used, but using vasopressors early as an emergency measure in

patients with severe shock is frequently necessary, for instance when diastolic blood pressure is too low.

When that occurs, great effort should be directed to weaning vasopressors with continuing fluid

resuscitation.

2. We recommend norepinephrine as the first choice vasopressor (grade 1B).

32
3. We suggest epinephrine (added to and potentially substituted for norepinephrine) when an additional

agent is needed to maintain adequate blood pressure (grade 2B).

4. Vasopressin up to 0.03 units/minute can be added to norepinephrine (NE) with the intent of raising

MAP to target or decreasing NE dosage (UG)

5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-

induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for

salvage therapy (failure to achieve adequate MAP with other vasopressor agents). (UG).

6. We suggest dopamine as an alternative vasopressor agent to norepinephrine only in highly selected

patients (eg, patients with low risk of arrhythmias and/or low heart rate). (grade 2C).

7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a)

norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood

pressure persistently low, or (c) as salvage therapy when combined inotrope/vasopressor drugs and low

dose vasopressin have failed to achieve MAP target (grade 1C).

Rationale. An extensive literature contrasts the physiologic effects of vasopressor and combined

inotrope/vasopressors selection in septic shock (Table 6) (136-148). Table 6 depicts a

GRADEproSummary of Evidence Table comparing dopamine and norepinephrinethe treatment of septic

shock. Dopamine increases mean arterial pressure and cardiac output, primarily due to an increase in

stroke volume and heart rate. Norepinephrine increases mean arterial pressure due to its vasoconstrictive

effects, with little change in heart rate and lesser increase in stroke volume compared with dopamine.

Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in

patients with septic shock. Dopamine may be particularly useful in patients with compromised systolic

function but causes more tachycardia and may be more arrhythmogenic (149). It may also influence the

endocrine response via the hypothalamic pituitary axis and have immunosuppressive effects. However,

information from 5 randomized trials (n=1993 patients with septic shock) comparing norepinephrine to

dopamine, does not support the routine use of dopamine in the management of septic shock (137,150-

153). Indeed, the relative risk of short term mortality was 0.91 (95% CI:0.84 to 1.00;fixed effect; I2=0%) in

33
favor of norepinephrine. . A recent meta-analysis showed dopamine was associated with an increased

risk. (relative risk 1.10[1.01-1.20], P=0.035). In the two trials that reported arrhythmias, these were more

frequent with dopamine than with norepinephrine (relative risk 2.34[1.46-3.77], P=0.001) (154).

Although some human and animal studies suggest epinephrine has deleterious effects on splanchnic

circulation and produces hyperlactemia, there is no clinical evidence that epinephrine results in worse

outcomes, and it should be the first chosen alternative to norepinephrine. Indeed, information from 4

randomized trials (n=540) comparing norepinephrine to epinephrine found no evidence for differences in

the risk of dying (RR=0.96; 0.77 to 1.21; fixed effect; I2=0%) (143, 148, 155, 156). Epinephrine may

increase aerobic lactate production via stimulation of skeletal muscles’ beta-2 adrenergic receptors and

thus may prevent the use of lactate clearance to guide resuscitation. With its almost pure alpha-

adrenergic effects, phenylephrine is the adrenergic agent least likely to produce tachycardia, but it may

decrease stroke volume and is therefore not recommended for use in the treatment of septic shock

except in circumstances where norepinephrine is (a) associated with serious arrhythmias or (b) cardiac

output is known to be high or (c) as salvage therapy when other vasopressor agents have failed to

achieve target MAP (157).. Vasopressin levels in septic shock have been reported to be lower than

anticipated for a shock state (158). Low doses of vasopressin may be effective in raising blood pressure

in patients refractory to other vasopressors and may have other potential physiologic benefits (159164).

Terlipressin has similar effects but is long acting (165).. Studies show that vasopressin concentrations are

elevated in early septic shock, but with continued shock the concentration decreases to normal range in

the majority of patients between 24 and 48 hrs (166). 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, a randomized, controlled trial comparing norepinephrine

alone to norepinephrine plus vasopressin at 0.03 units/min, showed no difference in outcome in the intent

to treat population (167). An a priori defined subgroup analysis demonstrated that survival among patients

receiving <15 µg/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 ≥15 µg/min norepinephrine requirement population. Higher doses of vasopressin have been

associated with cardiac, digital, and splanchnic ischemia and should be reserved for situations where

34
alternative vasopressors have failed (168). Information from 7 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 (94, 96, 98, 100,160,162,165,167,169-171). Indeed, the relative risk

of dying was 1.12 (95%CI: 0.96 to 1.30; fixed effects; I2=0%). See GRADEpro Summary of Evidence

Tables in online supplement. However, the risk of supraventricular arrhythmias was increased with

norepinephrine (RR=7.25; 95%CI: 2.30 to 22.90; fixed effect; I2=0%). Cardiac output measurement

targeting maintenance of a normal or elevated flow is desirable when these pure vasopressors are

instituted.

8. We recommend that low-dose dopamine not be used for renal protection (grade 1A).

Rationale. A large randomized trial and meta-analysis comparing low-dose dopamine to placebo found no

difference in either primary outcomes (peak serum creatinine, need for renal replacement, urine output,

time to recovery of normal renal function) or secondary outcomes (survival to either ICU or hospital

discharge, ICU stay, hospital stay, arrhythmias) (172,173). Thus, the available data do not support

administration of low doses of dopamine solely to maintain renal function.

9. We recommend that all patients requiring vasopressors have an arterial catheter placed as soon as

practical if resources are available (UG).

Rationale. In shock states, estimation of blood pressure using a cuff is commonly inaccurate; use of an

arterial cannula provides a more appropriate and reproducible measurement of arterial pressure. These

catheters also allow continuous analysis so that decisions regarding therapy can be based on immediate

and reproducible blood pressure information.

I. Inotropic Therapy

1. We recommend that a trial of dobutamine infusion up to 20 μg/kg/min be administered or added to

vasopressor (if in use) 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 (grade 1C).

35
2. We recommend against the use of a strategy to increase cardiac index to predetermined supranormal

levels (grade 1B).

Rationale. Dobutamine is the first choice inotrope for patients with measured or suspected low cardiac

output in the presence of adequate left ventricular filling pressure (or clinical assessment of adequate fluid

resuscitation) and adequate mean arterial pressure. Septic patients who remain hypotensive after fluid

resuscitation may have low, normal, or increased cardiac outputs. Therefore, treatment with a combined

inotrope/vasopressor, such as norepinephrine or epinephrine, is recommended if cardiac output is not

measured. When the capability exists for monitoring cardiac output in addition to blood pressure, a

vasopressor, such as norepinephrine, may be used separately to target specific levels of mean arterial

pressure and cardiac output. Large prospective clinical trials that included critically ill ICU patients

who had severe sepsis failed to demonstrate benefit from increasing oxygen delivery to supranormal

targets by use of dobutamine (174,175). These studies did not specifically target patients with severe

sepsis and did not target the first 6 hrs of resuscitation. If evidence of tissue hypoperfusion persists

despite adequate intravascular volume and adequate MAP, a viable alternative (other than reversing

underlying insult) is to add inotropic therapy.

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). In case this is not achievable, we suggest intravenous hydrocortisone at a

dose of 200 mg per day (grade 2C).

Rationale. The response of septic shock patients to fluid and vasopressor therapy seems to be an

important factor for selection of patients for an optional hydrocortisone therapy. One French multicenter,

randomized controlled trial (RCT) of patients in vasopressor-unresponsive septic shock (hypotension

despite fluid resuscitation and vasopressors for more than 60 min) showed a significant shock reversal

and reduction of mortality rate in patients with relative adrenal insufficiency (defined as

postadrenocorticotropic hormone [ACTH] cortisol increase ≤9 µg/dL) (176). Two additional smaller RCTs

also showed significant effects on shock reversal with steroid therapy (177,178). In contrast, a large,

36
European multicenter trial (CORTICUS) that enrolled patients without sustained shock and having a lower

risk of death than in the French trial failed to show a mortality benefit with steroid therapy (179). 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, resulting in baseline (placebo) 28-day mortality of respectively 61% and 31%

in the former and latter trial. The use of the ACTH test (responders and nonresponders) did not predict

the faster resolution of shock. In recent years, there have been several systematic reviews on the use of

low-dose hydrocortisone in septic shock with contradictory results: Annane analyzed 12 studies in a

meta-analysis and calculated a significant reduction of 28-day mortality by prolonged low-dose steroid

treatment in adult septic shock patients (RR: 0.84; 95% CI: 0.72-0.97, p=0.02) (180). In parallel, Sligl

used a similar technique, but only 81). In contrast to the aforementioned review, this analysis revealed no

statistically significant difference in mortality (RR: 1.00; 95% CI: 0.84-1.18). 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 (182), and identified only 6 high-level RCTs as adequate for systematic review (176-

170,183,184), thus confirming the lack of evidence that the use of low-dose hydrocortisone improves the

patients’ outcome (182). When only these 6 studies are analyzed, we found that in “low risk” patients from

3 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 3 studies, who had a placebo mortality of more than 60%, showed a non-significant trend to

lower mortality by using hydrocortisone. . See Online Appendix D Summary of Evidence Table.

2. We suggest not using the ACTH stimulation test to identify the subset of adults with septic shock who

should receive hydrocortisone (grade 2B).

Rationale.In The observation of a potential interaction between steroid use and ACTH test was not

statistically significant (176). Furthermore, there was no evidence of this distinction between responders

and nonresponders in a recent multicenter trial (179). Random cortisol levels may still be useful for

absolute adrenal insufficiency; however, for septic shock patients who suffer from relative adrenal

insufficiency (no adequate stress response), random cortisol levels have not been demonstrated to be

37
useful.Cortisol immunoassays may over- or underestimate the actual cortisol level, affecting the

assignment of patients to responders or nonresponders (185). Although the clinical significance is not

clear, it is now recognized that etomidate, when used for induction for intubation, will suppress the

hypothalamic-pituitary-adrenal axis (186. 187). Moreover, a sub-analysis of the CORTICUS trial (179)

revealed that the use of etomidate before application of low-dose steroids was associated with an

increased 28-day mortality (188).An inappropriately low random cortisol level (< 18 μg/dL) in a patient

with shock would be considered an indication for steroid therapy along traditional adrenal insufficiency

guidelines.

3. We suggest that clinicians taper the patient from steroid therapy when vasopressors are no longer

required (grade 2D).

Rationale. There has been no comparative study between a fixed-duration and clinically guided regimen

or between tapering and abrupt cessation of steroids. Three RCTs used a fixed-duration protocol

for treatment (176,178,179), and in 2 RCTs, therapy was decreased after shock resolution (177,183). In 4

RCTs steroids were tapered over several days (177-179,183), and in 2 RCTs (176,184), steroids were

withdrawn abruptly. One crossover study showed hemodynamic and immunologic rebound effects after

abrupt cessation of corticosteroids (189). Moreover, a recent study revealed that there is no difference in

outcome of septic shock patients if low dose hydrocortisone is used for 3 or 7 days; hence, no

recommendation can be given with regard to the optimal time of hydrocortisone therapy (190).

4. We recommend that corticosteroids not be administered for the treatment of sepsis in the absence of

shock (grade 1D).

Rationale.. Steroids may be indicated in the presence of a history of steroid therapy or adrenal

dysfunction. However, whether low-dose steroids have a preventive potency in reducing the incidence of

severe sepsis and saptic shock in critically ill patients still cannot be answered. A preliminary study of

stress-dose level steroids in community acquired pneumonia showed improved outcome measures in a

small population (191), and a recent confirmatory RCT revealed reduced hospital length of stay without

38
affecting mortality (192). 5. When low-dose hydrocortisone is given, we suggest using continuous infusion

rather than repetitive bolus injections (2C).

Rationale: Several randomized trials on the use of low-dose hydrocortisone in septic shock patients

revealed a significant increase of hyperglycemia and hypernatremia (176) as side effects. A small

prospective study demonstrated that repetitive bolus application of hydrocortisone leads to a significant

increase of blood glucose; this peak effect was not detectable during continuous infusion. Furthermore, it

was shown that there is a considerable inter-individual variability of this blood glucose peak after the

hydrocortisone bolus (193). Although an association of hyperglycemia and hypernatremia with outcome

measures of patients could not be shown so far, good practice includes strategies for avoiding and/or

detection of these side effects.

K. Blood Product Administration

1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as

myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic coronary artery disease, we

recommend that red blood cell transfusion occur when hemoglobin concentration decreases to <7.0 g/dL

to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults (grade 1B).

Rationale. Although the optimum hemoglobin concentration for patients with severe sepsis has not been

specifically investigated, the Transfusion Requirements in Critical Care trial suggested that a hemoglobin

level of 7–9 g/dL when compared with 10–12 g/dL was not associated with increased mortality in critically

ill adults (194). There were no significant differences in 30-day mortality between treatment groups in the

subgroup of patients with severe infections and septic shock (22.8 percent and 29.7 percent, respectively;

P=0.36),

39
Although less applicable to septic patients, a randomized trial in patients undergoing cardiac surgery with

cardiopulmonary bypass supports a restrictive transfusion strategy using a threshold hematocrit of <24%

(hemoglobin approximately 8 g/dL) as equivalent to a transfusion threshold of hematocrit of <30%

(hemoglobin approximately 10 g/dL) (195). Red blood cell transfusion in septic patients increases oxygen

delivery but does not usually increase oxygen consumption (196-198). The transfusion threshold of 7 g/dL

contrasts with early goal-directed resuscitation protocols that use a target hematocrit of 30% in patients

with low ScvO2 during the first 6 hrs of resuscitation of septic shock (13).

2. We recommend not using erythropoietin as a specific treatment of anemia associated with severe

sepsis (grade 1B).

Rationale. No specific information regarding erythropoietin use in septic patients is available, but clinical

trials of erythropoietin administration in critically ill patients show some decrease in red cell transfusion

requirement with no effect on clinical outcome (199, 200). The effect of erythropoietin in severe sepsis

and septic shock would not be expected to be more beneficial than in other critical conditions. Patients

with severe sepsis and septic shock may have co-existing conditions that meet indications for use of

erythropoietin.

3. We suggest that fresh frozen plasma not be used to correct laboratory clotting abnormalities in the

absence of bleeding or planned invasive procedures (grade 2D).

Rationale. Although clinical studies have not assessed the impact of transfusion of fresh frozen plasma

on outcomes in critically ill patients, professional organizations have recommended fresh frozen plasma

for coagulopathy when there is a documented deficiency of coagulation factors (increased prothrombin

time, international normalized ratio, or partial thromboplastin time) and the presence of active bleeding or

before surgical or invasive procedures (201-204). In addition, transfusion of fresh frozen plasma in

nonbleeding patients with mild abnormalities of prothrombin time usually fails to correct the prothrombin

time (205, 206). There are no studies to suggest that correction of more severe coagulation abnormalities

benefits patients who are not bleeding.

40
4. We recommend against antithrombin administration for the treatment of severe sepsis and septic

shock (grade 1B).

Rationale. A Phase III clinical trial of high-dose antithrombin did not demonstrate any beneficial effect on

28-day all cause mortality in adults with severe sepsis and septic shock. High-dose antithrombin was

associated with an increased risk of bleeding when administered with heparin (207). Although a post hoc

subgroup analysis of patients with severe sepsis and high risk of death showed better survival in patients

receiving antithrombin, antithrombin cannot be recommended until further clinical trials are performed

(208).

5. In patients with severe sepsis, we suggest that platelets be administered prophylactically when counts

are <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet

transfusion when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding.

Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive

procedures (grade 2D).

Rationale. Guidelines for transfusion of platelets are derived from consensus opinion and experience in

patients with chemotherapy-induced thrombocytopenia. Patients with severe sepsis are likely to have

some limitation of platelet production similar to chemotherapy-treated patients, but they also are likely to

have increased platelet consumption. Recommendations take into account the etiology of

thrombocytopenia, platelet dysfunction, risk of bleeding, and presence of concomitant disorders (201,

203,204,209,210). Factors that may increase the bleeding risk and indicate the need for a higher platelet

count are frequently present in patients with severe sepsis. Sepsis itself is considered to be a risk factor

for bleeding in patients with chemotherapy-induced thrombocytopenia. Other factors considered to

increase the risk of bleeding that may be relevant to patients with severe sepsis include fever >38° C,

recent minor hemorrhage, rapid decrease in platelet count, and other coagulation abnormalities (204,

209,210).

L. Immunoglobulins

41
1. We suggest not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock

(grade 2B)

Rationale: One larger multi-center RCT (n=624) (211) in adult patients and one large multi-national RCT

in infants with neonatal sepsis (n=3493) (212) found no benefit for intravenous immunoglobulin (IVIG).

For pediatric considerations based on this trial see Section III. A recent meta-analysis by the Cochrane

collaboration (213) which did not include this most recent RCT identified 10 polyclonal intravenous

immunoglobulin (IVIG) trials (n=1430) and 7 trials on IgM enriched polyclonal IVIG (n=528). Overall

compared to placebo, IVIG resulted in a significant reduction in mortality (RR 0.81, 95% Cl 0.70. to 0.93

and 0.66; 95 Cl 0.51-0.85, respectively). Also the subgroup of IgM enriched IVIG’s (n=7 trials) showed a

significant reduction in mortality in comparison to placebo (RR 0.66; 95% Cl 0.51 to 0.85). However, trials

with low risk of bias showed no reduction in mortality with polyclonal IVIG (RR 0.97; 95 Cl 0.81-1.15; 5

trials n=945). Three of these trials (211,214,215) used standard polyclonal IVIG, and two IgM enriched IV

(216,217).

These findings are in accordance with 2 older meta-analyses (218, 219) from other Cochrane authors.

One systematic review (218) included a total of 21 trials and showed a relative risk of death with

immunoglobulin treatment of 0.77 (95% Cl 0.68-0.88); however, including only high quality trials with a

total of 763 patients showed a relative risk of 1.02 (95% Cl 0.84-1.24). Similarly, Laupland et al (219)

found a significant reduction in mortality with the use of IVIG treatment OR 0.66 (95% confidence interval

0.53-0.83; p<0.005). When only high quality studies were pooled, the OR for mortality was 0.96 (Cl 0.71-

1.3; p=0.78). Two meta-analyses, which used less strict criteria to identify sources of bias or did not

discuss their criteria for the assessment of study quality, found significant improvement of patient mortality

by IVIG treatment (220,221). Kreymann et al (220), who in contrast to the most recent Cochrane review

classified 5 studies that investigated IgM enriched-preparation as high quality studies combinino studies

in adult and neonate studies, found an OR for mortality of 0.5 (95% Cl 0.34-0.73).

Most studies on IVIG are small studies; some of them have methodological flaws, the only larger study

(n=624) showed no effect. There is substantial heterogeneity with subgroup effects between IgGM-

42
enriched and nonenriched formulations. 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).

Rationale. Selenium was hoped to correct the known reduction of selenium concentration observed in

sepsis patients and further provide a pharmacologic effect through antioxidant defense in humans.

Although there are some randomized controlled trials available, the evidence on the use of intravenous

application of selenium is still very weak. Only one larger clinical trial has examined the impact of

selenium supplementation on mortality and reported no significant impact on the intent-to-treat

populationwith severe SIRS, sepsis, or septic shock (OR 0.66, 95% CI: 0.39-1.10, p=0.109) (222).

Overall, there was a trend toward a concentration-dependent reduction in mortality; no differences in

secondary outcomes or adverse events were detected. Finally, there was no comment on standardization

of sepsis management in this study, which recruited 249 patients over a time period of 6 years (1999-

2004) (222).

A French RCT in a smaller population revealed no effect on primary (shock reversal) or secondary (days

on mechanical ventilation, ICU mortality) endpoints (223). A smaller RCT investigating the effect of

selenium on the development of VAP revealed less early VAP in the selenium group (p=0.04), but no

difference in late VAP or secondary outcomes such as ICU or hospital mortality (224). This is in

accordance with 2 RCTs that resulted in reduced number of infectious episodes (225) or glutathione

peroxidase concentrations (227); both studies, however, could not show a beneficial effect on secondary

outcome measures (renal replacement, ICU mortality) (225, 226).

43
A recent large RCT tried to determine if addition of relatively low doses of supplemental selenium

(glutamine was also tested in a 2-factorial design) to parenteral nutrition in critically ill patients is able to

reduce infections and improve outcome (227). Selenium supplementation did not significantly affect

patients developing a new infection (OR 0.81, 95% CI: 0.57-1.15), and 6- month mortality was not

different (OR 0.89, 95% CI 0.62-1.29). In addition, length of stay, days of antibiotic use, and modified

SOFA score were not significantly affected by selenium (228).

Besides the lack of evidence, the questions of optimal dosing and application mode still remain

unanswered. Reported high-dose regimens have involved a loading dose followed by an infusion, while

animal trials suggest that bolus dosing could be more effective (228)); this, however, has not been tested

in humans. Altogether, these unsolved problems require additional trials, and we encourage conducting

large multicenter studies to further evaluate the effectiveness of intravenous selenium in patients with

severe sepsis. This recommendation does not exclude the use of low-dose selenium as part of the

standard minerals and oligo-elements used during total parenteral nutrition.

N. History of Recommendations Regarding Use of Recombinant Activated Protein C

Recombinant activated protein C (rhAPC) was approved for use in adult patients in a number of countries

in 2001 following the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in

Severe Sepsis) trial, which enrolled 1,690 severe sepsis patients and showed a significant reduction in

mortality (mortality 24.7 % in patients given rhAPC and 30.8% in placebo, p 0.005) (229). The 2004 SSC

guidelines recommended use of rhAPC in line with the product labeling instructions required by the US

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 rhAPC ineffective in less severely ill patients with severe

sepsis as well as in children (230,231). The 2008 SSC recommendations reflected these findings and the

44
strength of the rhAPC recommendation for adults was downgraded to a suggestion for use in adult

patients with a clinical assessment of high risk of death, most of whom will have APACHE II scores ≥25 or

multiple organ failure (grade 2C; quality of evidence was also downgraded from 2004, from B to C) (6).

The 2008 guidelines also recommended against use of rhAPC in lower risk adult patients, most of whom

will have APACHE II score ≤20 or single organ failures (grade 1A), as well as recommending 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 % in patients given rhAPC and 24.2 % in

placebo group) with a relative risk of 1.09 and a p value of 0.31(232). The drug was withdrawn from the

market and is no longer available, negating any need for SSC recommendation regarding its use.

SUPPORTIVE THERAPY OF SEVERE SEPSIS

O. Mechanical Ventilation of Sepsis-Induced Respiratory Distress Syndrome (ARDS)

1. We recommend that clinicians target a tidal volume of 6 mL/kg rather than 12 ml/kg predicted body

weight in patients with sepsis-induced ARDS (grade 1A).

2. We recommend that plateau pressures be measured in patients withARDS and that the initial upper

limit goal for plateau pressures in a passively inflated lung be ≤30 cm 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 Acute

Respiratory Distress Syndrome (ARDS) (233). For this document, we have used the updated Berlin

definition and used the term ARDS as an inclusive term for the syndromes previously known as ALI and

ARDS (234).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 (235-

239).. These studies showed differing results that may have been caused by differences between airway

45
pressures in the treatment and control groups (234(235, 240). Several meta-analyses suggest decreased

mortality in patients with a pressure and volume limited strategy for established ARDS (241, 242).

The largest trial of a volume- and pressure limited strategy showed an absolute 9% decrease of all-cause

mortality in patients with ALI or 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(234). The use of lung-

protective strategies for patients with ARDS is supported by clinical trials and has been widely accepted,

but the precise choice of tidal volume for an individual patient with ARDS may require adjustment for such

factors as the plateau pressure achieved, the level of positive end-expiratory pressure chosen, the

compliance of the thoracoabdominal compartment, and the vigor of the patient’s breathing effort. Patients

with profound metabolic acidosis, high obligate minute ventilations, or short stature may require additional

manipulation of tidal volumes. Some clinicians believe it may be safe to ventilate with tidal volumes >6

mL/kg PBW as long as the plateau pressure can be maintained ≤30 cm H2O (243. 244) The validity of

this ceiling value will depend on the breathing effort, as patients who are actively inspiring generate

higher transalveolar pressures for a given plateau pressure than patients who are passively inflated.

Conversely, patients with very stiff chest walls may require plateau pressures >30 cm H2O to meet vital

clinical objectives. A retrospective study suggested that tidal volumes should be lowered even with

plateau pressures ≤30 cm H2O(245) as lower plateau pressures were associated with decreased in-

hospital mortality (246).

High tidal volumes that are coupled with high plateau pressures should be avoided in ARDS. Clinicians

should use as a starting point the objective of reducing tidal volume over 1–2 hrs from its initial value

toward the goal of a “low” tidal volume (≈6 mL/kg PBW) achieved in conjunction with an end-inspiratory

plateau pressure ≤30 cm H2O. If the plateau pressure remains >30 cm H2Oafter reduction of tidal volume

to 6 mL/kg PBW, tidal volume may be reduced further to as low as 4 mL/kg PBW per protocol .

(Appendix C provides ARDSNet ventilator management and formulas to calculate PBW.) Using volume

and pressure limited ventilation may lead to hypercapnia with maximum tolerated set respiratory rates. In

such cases, hypercapnia that is otherwise not contraindicated (eg, high ICP) and appears to be tolerated

46
should be allowed. Sodium bicarbonate or tromethamine (THAM) infusion may be considered in selected

patients to facilitate use of limited ventilator conditions that result in permissive hypercapnia (247,248).

A A number of observational trials in mechanically ventilated patients have demonstrated a decreased

risk of developing ARDS when smaller trial volumes are used (249-252). Accordingly, high tidal volumes

and plateau pressures should be avoided in mechanically ventilated patients at risk for developing ARDS,

including patients with sepsis.

No single mode of ventilation (pressure control, volume control) has consistently been shown to be

advantageous when compared with any other that respects the same principles of lung protection.

3. We recommend that positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at

end expiration (atelectotrauma) (grade 1B).

4. We suggest strategies based on higher rather than lower levels of PEEP for patients with sepsis

induced severe ARDS (grade 2C).

Rationale. Raising PEEP in ALI/ARDS keeps lung units open to participate in gas exchange. This will

increase PaO2 when PEEP is applied through either an endotracheal tube or a face mask (253-255).. In

animal experiments, avoidance of end-expiratory alveolar collapse helps minimize ventilator-induced lung

injury when relatively high plateau pressures are in use. Three large multicenter trials using higher versus

lower levels of PEEP in conjunction with low tidal volumes did not show benefit or harm (256-258)).A

meta-analysis using individual patient data showed no benefit in all patients with ALI; however, patients

with ARDS had decreased mortality with the use of higher PEEP, whereas those with ALI but not ARDS

did not.(259). Two options are recommended for PEEP titration. One option is to titrate PEEP (and tidal

volume) according to bedside measurements of thoracopulmonary compliance with the objective of

obtaining the best compliance, reflecting a favorable balance of lung recruitment and overdistension

(260). The second option is to titrate PEEP based on severity of oxygenation deficit and guided by the

FIO2 required to maintain adequate oxygenation (235,256,257). A PEEP >5 cm H20 is usually required to

avoid lung collapse (261). ARDSnet standard PEEP strategy is shown in Appendix C. The higher PEEP

strategy as recommended for ARDS in Recommendation 4 above is shown in Appendix D and comes

from the ALVEOLI trial (258)

47
5. We suggest recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS

(grade 2C).

6. We suggest prone positioning in sepsis-induced ARDS patients with a PaO2/FiO2 ratio ≤ 100 mm HG

in facilities that have experience with such practices (grade 2B).

Rationale. Many strategies exist for treating refractory hypoxemia in patients with severe ARDS (262).

Temporarily raising transpulmonary pressure may facilitate opening atelectatic alveoli to permit gas

exchange (261). Such maneuvers, however, could also overdistend aerated lung units leading to

ventilator induced lung injury and cause temporary hypotension. The application of transient sustained

use of continuous positive airway pressure appears to improve oxygenation in patients initially, but these

effects are transient in some studies (263). While selected patients with severe hypoxemia may benefit

from recruitment maneuvers in conjunction with higher levels of PEEP, there is little evidence to support

their routine use in all ARDS patients.(263). Blood pressure and oxygenation should be monitored and

recruitment maneuvers discontinued if deterioration in these variables is observed.

Several small studies and one larger study in patients with hypoxemic respiratory failure or acute lung

injury have shown that a majority of patients respond to the prone position with improved oxygenation

(264-267) None of the individual trials of prone positioning in patients with ALI/ARDS or hypoxemic

respiratory failure demonstrated a mortality benefit (268-271). A recent meta-analysis suggested potential

benefits for prone positioning in patients with profound hypoxemia with a PaO2/;FiO2 ratio ≤100 mm HG,

but not in those with less severe hypoxemia.(271) Prone positioning may be associated with potentially

life-threatening complications, including accidental dislodging of the endotracheal and chest tubes; these

complications occur more frequently in patients in the prone compared with supine positionv(271)

Other methods to treat refractory hypoxemia include the use of High Frequency Oscillatory Ventilation,

Airway Pressure Release Ventilation and Extracorporeal Membrane Oxygenation (272). These therapies

may be considered as rescue therapies in centers with expertise and experience with their use (262,272-

275).Inhaled nitric oxide does not improve mortality in patients with ARDS and should not be routinely

used (276)...

48
7, We recommend that mechanically ventilated sepsis patients be maintained with the head of the bed

elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated

pneumonia (grade 1B)..

Rationale. The semi-recumbent position has been demonstrated to decrease the incidence of ventilator-

associated pneumonia (VAP)(277). Enteral feeding increased the risk of developing VAP; 50% of the

patients who were fed enterally in the supine position developed VAP compared with 9% of those fed in

the semi-recumbant position (277). However, the bed position was only monitored once a day, and

patients who did not achieve the desired bed elevation were not included in the analysis (277). A recent

study did not show a difference in incidence of VAP between patients maintained in supine and

semirecumbent positions (278). In this study, patients assigned to the semi-recumbent group did not

consistently achieve the desired head of the bed elevation, and the head of bed elevation in the supine

group approached that of the semi-recumbent group by day 7 (278). When necessary, patients may be

laid flat for procedures, hemodynamic measurements, and during episodes of hypotension. Patients

should not be fed enterally while supine.

8. We suggest that noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced

ALI/ARDS patients in whom the benefits of NIV have been carefully considered and are thought to

outweigh the risks (grade 2B).

Rationale. Obviating the need for airway intubation confers multiple advantages: better communication,

lower incidence of infection, reduced requirements for sedation. Two RCTs in patients with acute

respiratory failure demonstrate improved outcome with the use of NIV in patients when it can be used

successfully (279,280). Unfortunately, only a small percentage of patients with sepsis life-threatening

hypoxemia can be managed in this way (281,282).

Patients should be considered for NIV in sepsis-induced ALI/ARDS if responsive to relatively low levels of

pressure support and PEEP with stable hemodynamics, can be made comfortable, and are easily

arousable; who are able to protect the airway and spontaneously clear the airway of secretions; and who

49
are anticipated to recover rapidly from the precipitating insult (281,282,). A low threshold for airway

intubation should be maintained.

9. We recommend that a weaning protocol be in place and that mechanically ventilated patients with

severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue

mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable

(without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-

expiratory pressure requirements; and e) low FIO2 requirements which can be met safely delivered with a

face mask or nasal cannula If the spontaneous breathing trial is successful, consideration should be given

for extubation (grade 1A).

Rationale. Spontaneous breathing trial (SBT) options include a low level of pressure support, continuous

positive airway pressure (≈5 cm H2O), or a T-piece. Recent studies demonstrate that daily spontaneous

breathing trials in appropriately selected patients reduce the duration of mechanical ventilation (283, 284).

These spontaneous breathing trials should be conducted in conjunction with a spontaneous awakening

trial (SAT) (285). Successful completion of spontaneous breathing trials leads to a high likelihood of

successful early discontinuation of mechanical ventilation.

10. We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-

induced ALI/ARDS (grade 1A).

Rationale. While insertion of a pulmonary artery (PA) catheter may provide useful information on a

patient’s volume status and cardiac function, potential benefits of such information may be confounded by

differences in interpretation of results (286-288), lack of correlation of PA occlusion pressures with clinical

response (289), and absence of a proven strategy to use catheter results to improve patient outcomes

(174). Two multicenter randomized trials, one in patients with shock or acute lung injury (290) and one in

patients with acute lung injury (291), failed to show benefit with the routine use of pulmonary artery

catheters in patients with acute lung injury. In addition, other studies in different types of critically ill

patients have failed to show definitive benefit with routine use of the PA catheter (292-294). Well-

selected patients remain appropriate candidates for PA catheter insertion only when the answers to

50
important management decisions depend on information solely obtainable from direct measurements

made within the PA (293,295).

11. We recommend a conservative rather than liberal fluid strategy for patients with established sepsis-

induced acute lung injury who do not have evidence of tissue hypoperfusion (grade 1C).

Rationale. Mechanisms for the development of pulmonary edema in patients with acute lung injury

include increased capillary permeability, increased hydrostatic pressure, and decreased oncotic pressure

(296). Small prospective studies in patients with critical illness and acute lung injury have suggested that

less weight gain is associated with improved oxygenation (297) and fewer days of mechanical ventilation

(298,299). Use of a fluid-conservative strategy directed at minimizing fluid infusion and weight gain in

patients with acute lung injury based on either a central venous catheter (central venous pressure <4mm

Hg) or a PA catheter (pulmonary artery wedge pressure <8mm Hg) along with clinical variables to guide

treatment strategies led to fewer days of mechanical ventilation and reduced length of ICU stay without

altering the incidence of renal failure or mortality rates (300). Of note, this strategy was only used in

patients with established acute lung injury, some of whom had shock present during the ICU stay and

active attempts to reduce fluid volume were conducted only during periods free from shock.

12. In the absence of specific indications such as bronchospasm, we recommend against the

use of beta 2-agonists for treatment of ALI/ARDS in patients with sepsis- induced ARDS.

(grade 1B)

Rationale. Patients with sepsis –induced acute lung injury often develop increased vascular permeability.
Preclincial and early clinical data suggest that beta-adrenergic agonists may speed resorption of alveolar
edema(301). Two randomized clinical trials studied the affect of beta-agonists in patients with acute lung
injury (302, 303). A randomized controlled trial of aerosolized albuterol versus placebo in 282 patients
with acute lung injury was stopped for futility (302). Patients receiving albuterol had higher heart rates on
day 2, and a trend toward decreased ventilator –free days (days alive and off the ventilator). The number
of patients who died before discharge was (23.0 versus 17.7) in the albuterol versus placebo treated
patients. Of note, more than half of the patients enrolled in this trial had pulmonary or nonpulmonary
sepsis as the cause of their ALI (302).

The use of intravenous salbutamol was tested in the BALTI-2 trial. 326 Patients with ARDS, 251 of whom
had pulmonary or nonpulmonary sepsis as cause, were randomized to get intravenous salbutatmol , 15
μg/kg of ideal body weight or placebo for up to 7 days (303). Patients treated with salbutamol had
increased 28 day mortality rates ( 34 vs. 23% RR 1.4( 95% CI 1.03-2.08)) leading to early termination of
the trial. (303)
Beta-2 agonists have specific indications such as treatment of bronchospasm, auto-PEEP and
hyperkalemia. In the absence of these conditions, we recommend against the routine use of beta-

51
agonists, either in intravenous or aerosolized form, for the treatment of patients with sepsis induced ALI
(285).

P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis

1. We recommend 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 length of stay (304-306).

The use of protocols for sedation is one method to limit sedation use and a randomized, controlled clinical

trial found that protocol use reduced duration of mechanical ventilation, lengths of stay, and tracheostomy

rates (306).While these 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

(306). A randomized, controlled clinical trial found that patients treated with intravenous morphine boluses

preferentially, with short-term propofol infusions for rescue therapy only, had significantly more days

without ventilation, shorter stay in ICU and hospital, than patients who received propofol infusions in

addition to bolus morphine (307). However, agitated delirium was more frequent in the intervention group.

Several studies have used a specific sedation scale to titrate sedative use (308,309).

Although not specifically studied in patients with sepsis, the administration of intermittent sedation, daily

sedative interruption, and systematic titration to a predefined end point have been demonstrated to

decrease the duration of mechanical ventilation (285,306, 311)). Patients receiving neuromuscular

blocking agents (NMBAs) must be individually assessed regarding discontinuation of sedative drugs

because neuromuscular blocking drugs must first be discontinued. The use of intermittent vs continuous

methods for the delivery of sedation in critically ill patients has been examined in an observational study

of mechanically ventilated patients that showed that patients receiving continuous sedation had

significantly longer durations of mechanical ventilation and ICU and hospital lengths of stay (311).

Similarly, a prospective, controlled study in 128 mechanically ventilated adults receiving continuous

intravenous sedation demonstrated that a daily interruption in the continuous sedative infusion until the

patient was awake decreased the duration of mechanical ventilation and ICU length of stay (312)

52
Although the patients did receive continuous sedative infusions in this study, the daily interruption and

awakening allowed for titration of sedation, in effect making the dosing intermittent. In addition, a paired

spontaneous awakening trial combined with a spontaneous breathing trial decreased the duration of

mechanical ventilation, length of ICU and hospital stay, and one-year mortality (285). Many patients may

tolerate mechanical ventilation without the use of continuous infusion of sedatives (307). Systematic

(protocolized) titration to a predefined end point has also been shown to alter outcome (306). Additionally,

a randomized prospective blinded observational study demonstrated that although myocardial ischemia is

common in critically ill ventilated patients, daily sedative interruption is not associated with an increased

occurrence of myocardial ischemia (313). Thus, the benefits of daily interruption of sedation appear to

outweigh the risks. These benefits includeshorter duration of mechanical ventilation and ICU

stay,decreased mortality, better assessment of neurologic function, increased ability to participate in early

physical rehabilitation, and reduced costs (285,314).

2. We recommend that NMBAs be avoided if possible in the septic patient without ALI/ARDS due to the

risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either

intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade

should be used (grade 1C).

3. We suggest a short course of NMBA of not greater than 48 hours for patients with early, severe sepsis-

induced ARDS (grade 2C).

Rationale. Although NMBAs are often administered to critically ill patients, their role in the ICU is not well

defined. No evidence exists that neuromuscular blockade in this general patient population reduces

mortality or major morbidity. In addition, no studies have been published that specifically address the use

of NMBAs in septic patients.

The most common indication for NMBA use in the ICU is to facilitate mechanical ventilation (315). When

appropriately used, NMBAs may improve chest wall compliance, prevent respiratory dyssynchrony, and

reduce peak airway pressures (316). Muscle paralysis may also reduce oxygen consumption by

decreasing the work of breathing and respiratory muscle blood flow (317). However, a randomized,

placebo-controlled clinical trial in patients with severe sepsis demonstrated that oxygen delivery, oxygen

consumption, and gastric intramucosal pH were not improved during deep neuromuscular blockade (318).

53
A recent randomized clinical trial of continuous infusions of cisatracurium in patients with early, severe

ARDS showed improved adjusted survival rates and more organ failure-free days compared with placebo

treated patients (319) without an increased risk in ICU-acquired weakness. Of note, the investigators

used a high fixed dose of cisatracurium without train-of-four monitoring, and half of the patients in the

placebo group received at least a single dose of NMBA (319,320). It is not known whether another NMBA

would have similar effects. While many of the patients enrolled into this trial appear to meet sepsis

criteria, it is not clear whether similar results would occur in sepsis patients.A GRADEpro Summary of

Evidence Table regarding use of NMBA in ARDS appears online..

An association between NMBA use and myopathies and neuropathies has been suggested by case

studies and prospective observational studies in the critical care population (316, 321-323). The

mechanisms by which NMBAs produced or contribute to myopathies and neuropathies in critically ill

patients are presently unknown. Although no studies exist specific to the septic patient population, it

seems clinically prudent based on existing knowledge that NMBAs not be administered unless there is a

clear indication for neuromuscular blockade that cannot be safely achieved with appropriate sedation and

analgesia (316).

Only one prospective RCT has evaluated peripheral nerve stimulation vs standard clinical assessment in

ICU patients. Rudis (324) randomized 77 critically ill patients requiring neuromuscular blockade in the ICU

to receive dosing of vecuronium based on train-of-four stimulation or on clinical assessment (control

group). The peripheral nerve stimulation group received less drug and recovered neuromuscular function

and spontaneous ventilation faster than the control group. Nonrandomized observational studies have

suggested that peripheral nerve monitoring reduces or has no effect on clinical recovery from NMBAs in

the ICU (325-326).

Benefits to neuromuscular monitoring, including faster recovery of neuromuscular function and shorter

intubation times, appear to exist. A potential for cost savings (reduced total dose of NMBAs and shorter

intubation times) also may exist, although this has not been studied formally.

54
Q. Glucose Control

1. We recommend a protocolized approach to blood glucose management in ICU patients with severe

sepsis commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This

protocolized approach should target an upper blood glucose < 180 mg/dL rather than an upper target

blood glucose < 110 mg/dL (grade 1A).

2. We recommendblood glucose values be monitored every 1–2 hrs until glucose values and insulin

infusion rates are stable and then every 4 hrs thereafter (grade 1C).

3. We recommend thatglucose levels obtained with point-of-care testing of capillary blood be interpreted

withcaution, as such measurements may not accurately estimate arterial blood or plasma glucose values.

Rationale. One large RCT single center trial in a predominantly cardiac surgical ICU demonstrated a

reduction in ICU mortality with intensive intravenous insulin (Leuven protocol) targeting blood glucose to

80–110 mg/dL (327). (A second randomized trial of intensive insulin therapy using the Leuven protocol

enrolled medical ICU patients with an anticipated ICU LOS of more than3 days in three medical ICUs and

overall mortality was not reduced. [328].

Since these studies (327,328) and the previous Surviving Sepsis Guidelines (7), several RCTs (129, 329-

333) and meta-analyses (334,335) of intensive insulin therapy have been performed. The RCTs studied

mixed populations of surgical and medical ICU patients (128,329-333). The studies found that intensive

insulin therapy did not significantly decrease mortality (129,186,329-331,334) whereas the NICE-SUGAR

trial demonstrated an increased mortality (332). All studies reported a much higher incidence of severe

hypoglycemia (glucose ≤40mg/dL) (6-29%) with intense insulin therapy. Several meta-analyses confirmed

that intense insulin therapy was not associated with a mortality benefit in surgical, medical or mixed ICU

patients (335-337). The Griesdale meta-analysis (335) using between trial comparisons driven mainly by

the van den Berghe Study (327) found that intense insulin therapy was beneficial in surgical ICU patients

[risk ratio 0.63 (0.44-0.91)], whereas the Friedrich meta-analysis (337) using within trial comparisons

showed no benefit for surgical patients in mixed medical-surgical ICUs [risk ratio 0.99 (0.82-1.11)] and no

subgroup of surgical patients who benefited from intense insulin therapy. Interestingly, the RCTs that

noted benefit from intense insulin therapy (129,327-330) compared intensive insulin therapy to high

55
controls (180-200mg/dL) [odds ratio 0.89 (0.73-1.09)], whereas those that did not demonstrate benefit

(331,333,334) compared intensive therapy to moderate control (108-180 mg/dL) [odds ratio 1.14 (1.02-

1.26) Online Appendix H.

The trigger to start an insulin protocol for blood glucose levels >180 mg/dL with an upper target blood

glucose < 180 mg/dL derive from the NICE-SUGAR study (332) which used these values for commencing

and stopping therapy. The NICE-SUGAR trial is the largest, most compelling study to date on glucose

control in ICU patients given its inclusion of multiple ICUs and hospitals and a general patient population.

Several medical organizations including the American Association of Clinical Endocrinologists, the

American Diabetes Association, the American Heart Association, the American College of

Physicians,,and the Society of Critical Care Medicine have recently published consensus statements for

glycemic control of hospitalized patients (338-342). These statements usually targeted glucose levels

between 140 and 180 mg/dL. As there is no evidence that targets of 140-180 mg/d are different from

targets of 110 to140 mg/dl, the present recommendations use an upper target blood glucose <180 mg/dL

without a lower target other than hypoglycemia. Treatment should be aimed to avoid hyperglycemia

(>180 mg/dL), hypoglycemia, and wide swings in glucose levels. The continuation of insulin infusions

especially with the cessation of nutrition has been identified as a risk factor for hypoglycemia (333).

Balanced nutrition may be associated with a reduced risk of hypoglycemia (343). Recent studies have

suggested that the importance of variability in glucose levels over time is an important determinant of

mortality (344-346). Hyperglycemia and glucose variability seem to be unassociated with increased

mortality in diabetic patients as compared to non-diabetic patients (347, 348).

Several factors may affect the accuracy and reproducibility of point-of-care testing of blood capillary blood

glucose, including the type and model of the device used, user expertise, and patient factors,

including hematocrit (false elevation with anemia), PaO2, and drugs (349). Plasma glucose values by

capillary point of care testing have been found to be inaccurate with frequent false elevations (350,351)

over the range of glucose levels (351) but especially in the hypoglycemic (350, 352) and hyperglycemic

glucose ranges (352) and in hypotensive patients (353) or patients receiving catecholamines (354). A

56
review of 12 published insulin infusion protocols for critically ill patients showed wide variability in insulin

dose recommendations and variable glucose control (355). This lack of consensus about optimal dosing

of intravenous insulin may reflect variability in patient factors (severity of illness, surgical vs medical

settings), or practice patterns (eg, approaches to feeding, intravenous dextrose) in the environments in

which these protocols were developed and tested. Alternatively, some protocols may be more effective

than others. This conclusion is supported by the wide variability in hypoglycemia rates reported with

protocols (129,327-334). Thus, the use of established insulin protocols is important not only for clinical

care but also for the conduct of clinical trials to avoid hypoglycemia, adverse events, and premature

termination of these trials before the efficacy signal, if any, can be determined. Recently, several studies

have suggested that computer-based algorithms result in tighter glycemic control with a reduced risk of

hypoglycemia (356,357). Further study of protocols that have been validated to be safe and effective for

controlling blood glucose concentrations and blood glucose variability in the severe sepsis population is

needed.

R. Renal Replacement Therapy

1. We suggest that continuous renal replacement therapies and intermittent hemodialysis are equivalent

in patients with severe sepsis and acute renal failure because they achieve similar short-term survival

rates (grade 2B).

2. We suggest the use of continuous therapies to facilitate management of fluid balance in

hemodynamically unstable septic patients (grade 2D).

Rationale. Although numerous nonrandomized studies have reported a nonsignificant trend toward

improved survival using continuous methods (358-364), 2 meta-analyses (366,367) reported the absence

of significant difference in hospital mortality between patients who receive continuous and intermittent

renal replacement therapies. This absence of apparent benefit of one modality over the other persists

even when the analysis is restricted to only RCT studies (367). To date, 5 prospective RCTs have been

published (368-372). Four of them found no significant difference in mortality (369-372). One study found

significantly higher mortality in the continuous treatment group (368), but imbalanced randomization had

led to a higher baseline severity of illness in this group. When a multivariable model was used to adjust

for severity of illness, no difference in mortality was apparent between the groups (368). Most studies

57
comparing modes of renal replacement in the critically ill have included a small number of patients and

some major weaknesses (randomization failure, modifications of therapeutic protocol during the study

period, combination of different types of continuous renal replacement therapies, small number of

heterogeneous groups of patients enrolled). The most recent and largest RCT (372) enrolled 360 patients

and found no significant difference in survival between the 2 groups. Moreover, there is no current

evidence to support the use of continuous therapies in sepsis independent of renal replacement needs.

Concerning the hemodynamic tolerance of each method, no current evidence exists to support a better

tolerance with continuous treatments. Only 3 prospective studies (370,373) have reported a better

hemodynamic tolerance with continuous treatment, with no improvement in regional perfusion (373) and

no survival benefit (370). Four other prospective studies did not find any significant difference in mean

arterial pressure or drop in systolic pressure between the two methods (369,371,372,374). Concerning

fluid balance management, 2 studies reported a significant improvement in goal achievement with

continuous methods (368,370). In summary, current evidence is insufficient to draw strong conclusions

regarding the mode of replacement therapy for acute renal failure in septic patients.

Four RCTs have addressed whether the dose of continuous renal replacement affects outcomes in

patients with acute renal failure (375-378). Three found improved mortality in patients receiving higher

doses of renal replacement (375,377,378), while one (376) did not. None of these trials was conducted

specifically in patients with sepsis. Although the weight of current evidence suggests that higher doses of

renal replacement may be associated with improved outcomes, these results may not be easily

generalizable. Two large multicenter randomized trials comparing the dose of renal replacement (ATN in

the United States and RENAL in Australia and New Zealand) failed to show benefit of more aggressive

renal replacement dosing. A typical dose for CRRT, would be 20-25 ml/kg/hr of effluent generation.

S. Bicarbonate Therapy

1. We recommend against the use of 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).

58
Rationale. Although bicarbonate therapy may be of utility in some situations during utilization of

permissive hypercapnia in limiting tidal volume in ARDS (see Mechanical Ventilation of ARDS section), no

evidence supports the use of bicarbonate therapy in the treatment of hypoperfusion-induced lactic

academia associated with sepsis. Two blinded, crossover RCTs that compared equimolar saline and

bicarbonate in patients with lactic acidosis failed to reveal any difference in hemodynamic variables or

vasopressor requirements (379,380). The number of patients with pH <7.15 in these studies was small.

Bicarbonate administration has been associated with sodium and fluid overload, an increase in lactate

and PCO2, and a decrease in serum ionized calcium, but the relevance of these variables to outcome is

uncertain. The effect of bicarbonate administration on hemodynamics and vasopressor requirements at

lower pH as well as the effect on clinical outcomes at any pH is unknown. No studies have examined the

effect of bicarbonate administration on outcomes.

T. Deep Vein Thrombosis Prophylaxis

1. We recommend that patients with severe sepsis receive daily pharmacoprophylaxis against

venous thromboembolism (VTE) (grade 1B). We recommend that this be accomplished with daily

subcutaneous low-molecular weight heparin (LMWH) (grade 1B) versus twice daily UFH and

versus three times daily UFH (grade 2C) .

. If creatinine clearance is <30 ml/min and LMWH is used, we recommend use of dalteparin (grade

1A) or another form ofof LMWH that has a low degree ofof renal metabolism (grade 2C) or UFH

(grade 1A).

2. We suggest that patients with severe sepsis be treated with a combination of pharmacologic

therapy and intermittent pneumatic compression devices whenever possible (grade 2C).

3. We recommend that septic patients who have a contraindication for heparin use (eg,,

thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not

59
 receive pharmacoprophylaxis (grade 1B), but suggest they receive mechanical prophylactic

treatment, such as graduated compression stockings or intermittent compression devices (grade

2C), unless contraindicated. When the risk decreases, we suggest starting pharmacoprophylaxis

(grade 2C)..

Rationale. ICU patients are at risk for DVT (381). It is logical that patients with severe sepsis would be

similar to or at higher risk than the general ICU population. The consequences of VTE in the setting of

sepsis(increased risk of potentially fatal PEs in an already hemodynamically compromised patient) are

dire. Therefore, prevention of VTE is highly desirable, especially if it can be done safely and effectively.

VTE prophylaxis is generally effective. In particular, nine placebo-controlled RCTs ofVTE prophylaxis in

general populations of acutely ill patients exist (382-390). All 9 trials showed reduction in DVT or

pulmonary embolism, a benefit that is also supported by meta-analyses (391, 392).Thus, the evidence

strongly supports the value of VTE prophylazxis (grade 1A). The prevalence of infection/sepsis was 17%

in those studies in which this could be ascertained. One study investigated ICU patients only, In that trial,

52% of those enrolled had infection/ sepsis.The need to extrapolate from general, acutely ill patients to

critically ill patients to septic patients downgrades the evidence. That the effect is pronounced and the

data are robust somewhat mitigate against the extrapolation, leading to a grade of B. Because the risk of

administration to the patient is small, the gravity of not administeringmay be great, and the cost is low, the

strength of the recommendation is strong (1).

Deciding how to provide prophylaxis is decidedly more difficult. A recently published RCT by the

Canadian Critical Care Trials Group compared UFH (5000U twice daily) to LMWH (dalteparin, 5000U

once per day and a second placebo injection to ensure parallel-group equivalence) (393).There was not a

statistically significant difference in asymptomatic DVTs between the 2 groups (hazard ratio: 0.92, 95%

CI: 0.68-1.23. P = 0.57). However, the proportion of patients with pulmonary embolism diagnosed when

patients had CT scans showing filling defects, high-probability VQ scans, or on autopsy, was significantly

lower in the LMWH group (hazard ratio: 0.51, 95% CI: 0.30-0.88, P = 0.01).The study did not account for

the use of other forms of LMWH. These data suggest that LMWH (dalteparin) is the treatment of choice

60
in critically ill patients when compared to UFH administered twice daily. The study included septic patients.

Therefore, the evidence supporting the use of dalteparin over twice daily UFH in critically ill, and perhaps

septic, patiens is strong (A). Similarly, a meta-analysis of acutely ill, general medical patients comparing

UFH 2 times daily and 3 times daily demonstrated that UFH administered three times daily more

effectively prevented VTE but twice daily dosing produced less bleeding(394). There are critically ill and,

indeed, septic patients included in these analyses but the numbers are unclear. Nonetheless, the

evidence supporting the use of three times daily, as opposed to twice daily, UFH dosing in preventing

VTE in acutely ill medical patients is strong (A). However, comparing LMWH to twice daily UFH or twice

daily UFH to three times daily UFH in sepsis requires extrapolation, downgrading the data (B). There are

no data directly comparing LMWH to UFH administered 3 times a day nor are there studies directly

comparing twice daily and three times daily UFH dosing in septic or critically ill patients. Therefore, it is

not possible to state that LMWH is superior to three times daily UFH or that three times daily dosing is

superior to twice daily administration in sepsis. This downgrades the quality of the evidence and

therefore the recommendation.

Douketis et al conducted a study of 120 critically ill patients with acute kidney injury (creatinine clearance

< 30 ml/min) who received VTE prophylaxis with dalteparin 5000IU daily for between 4 and 14 days and

had at least one trough anti-factor Xa level measured. None of the patients had bio-accumulation (trough

anti-factor Xa level lower than 0,06 IU/ml). The incidence of major bleeding was somewhat higher than in

trials of other agents, but most other studies did not involve critically ill patients, in whom the bleeding risk

is higher. Further, bleeding did not correlate with detectable trough levels (395). Therefore, we

recommend that dalteparin can be administered to critically ill patients with acute renal failure (A).Data on

other LMWHs are lacking. Consequently, these forms should probably be avoided or, if used, anti-factor

Xa levels should be monitored (grade 2C). UFH is not renally clear and is safe (grade 1A)..

Mechanical methods (intermittent compression devices and graduated compression stockings) are

recommended when anticoagulation is contraindicated (396-398). A meta-analysis of 11 studies,

including 6 RCTs, published in the Cochrane Library concluded that the combination of pharmacologic

and mechanical prophylaxis was superior to either modality alone in preventing DVT and was better than

compression alone in preventing pulmonary embolism (399). The included studies were underpowered to

61
determine if combined therapy were superior to pharmacologic therapy alone. This analysis did not focus

on sepsis or critically ill patients but included studies of prophylaxis for patients after orthopedic, pelvic,

and cardiac surgery. In addition, the type of pharmacologic prophylaxis varied, including UFH, LMWH,

aspirin, and warfarin. Nonetheless, the minimal risk associated with compression devices lead us to

recommend combination therapy in most cases. In very high-risk patients, LMWH is preferred over UFH

(393,400-402). Patients receiving heparin should be monitored for development of heparin-induced

thrombocytopenia.These recommendations are consistent with those developed by the American College

of Chest Physicians (403)..

U. Stress Ulcer Prophylaxis

1. We recommend that 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, we suggest the use of proton pump inhibitors rather than

histamine 2 receptor antagonists (H2RA) (grade 2C)

3. We suggest that patients without risk factors do not receive prophylaxis (grade 2B).

Rationale. Although no study has been performed specifically in patients with severe sepsis, trials

confirming the benefit of stress ulcer prophylaxis in reducing upper GI bleeds in general ICU populations

enrolled 20- 25% of patients with sepsis (404-407). This benefit should be applicable to patients with

severe sepsis and septic shock. In addition, the risk factors for gastrointestinal bleeding (coagulopathy,

mechanical ventilation for at least 48 hours, possibly hypotension) are frequently present in patients with

severe sepsis and septic shock (408,409). Patients without these risk factors are unlikely (0.2%, 95% CI

0.02-0.5%) to have clinically important bleeding (408).

Both old and new meta-analyses show prophylaxis-induced reduction in clinically significant upper GI

bleeding, which we consider significant even in the absence of proven mortality benefit (410-412). The

benefit of prevention of upper GI bleed must be weighed against the potential (not proven) effect of

increased stomach pH on greater incidence of ventilator-associated pneumonia and Clostridium difficile

infection (410,413,414) (See online Summary of Evidence Tablesfor effects of treatments on specific

outcomes). We considered the possibility of less benefit and more harm of prophylaxis among patients

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receiving enteral nutrition as an exploratory hypothesis (as did the authors of the meta-analysis

suggesting such a possibility) (412) but decided to provide one recommendation while lowering quality of

evidence (412). The balance of benefits and risks may thus depend on the individual patient’s

characteristics as well as on local epidemiology of VAP and C. difficile infections. The rationale for

considering only suppression of acid production (and not sulcrafate) is based on the study of 1,200

patients by Cook comparing H2 blockers and sulcrafate (415). Recent meta-analyses provide low quality

evidence suggesting more effective GI bleeding protection with the use of proton pump inhibitors (PPI) in

comparison to H2RA (416-418). Patients should be periodically evaluated for continued need for

prophylaxis.

HV. Nutrition

1. We suggest administering 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. We suggest avoiding mandatory full caloric feeding in the first week, but rather suggest low dose

feeding (eg, up to 500 kilocalories per day), advancing only as tolerated (grade 2B).

3. We suggest using 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 sepis/septic shock (grade 2B).

4. We suggest using nutrition with no specific immunomodulating supplementation rather than nutrition

providing specific immunomodulating supplementation in patients with severe sepsis (grade 2C).

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Rationale.There are theoretical advantages to early enteral nutrition regarding integrity of gut mucosa and

prevention of bacterial translocation and organ dysfunction. However, there is also some concern about

the risk of ischemia with early feeding, mainly in hemodynamically unstable patients.

Unfortunately, no clinical trial specifically addressed early feeding in septic patients. Studies on different

subpopulations of critically ill patients, mostly surgical patients, are not consistent, with great variability in

intervention and control groups, all with low methodological quality (419-428). None of those trials was

individually powered for mortality, with very low mortality rates (419-421,424,427). Previously published

meta- analyses of optimal nutrition strategies for the critically ill all reported that the studies they included

had high heterogeneity and low quality (419-431).. Of note, although there was no consistent effect on

mortality, there was some evidence of benefit from some early enteral feeding on secondary outcomes,

such as reduced incidence of infectious complications (419,423,427,429-431), reduced length of

mechanical ventilation (422,428) and reduced ICU (422, 428) and hospital stay (429). No evidence of

harm was demonstrated in any of those studies.

Therefore, there is insufficient evidence to issue a strong recommendation, but the suggestion of some

benefit and absence of harm supports a suggestion that some enteral feeding is warranted.

Studies comparing full caloric early enteral feeding to lower targets in the critically ill have produced

inconclusive results. In four studies, there was no effect on mortality (432-435, one reported fewer

infectious complications (432) and others reported increased diarrhea and gastric residuals (434-435) and

increased incidence of infectious complications with full caloric feeding (433. In one study, mortality was

higher with higher feeding, but differences in feeding strategies were modest and sample size was small

(436). Therefore, there is insufficient evidence to support an early target of full caloric intake and, indeed,

some possibility of harm. Underfeeding (60-70% of target) or trophic feeding (upper limit of 500 kcal) are

probably better nutritional strategies in the first week of severe sepsis/septic shock. This upper limit for

trophic feeding is a somewhat arbitrary number, but based in part on the fact that the 2 recent studies

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used a range of 240-480 (434,435). Of note, underfeeding/trophic feeding strategies did not exclude

advancing diet as tolerated in those who improved quickly.

Some form of parenteral nutrition has been compared to alternative feeding strategies (eg, fasting or

enteral nutrition) in well over 50 studies (although only one exclusively studied sepsis) (437), and there

are currently 8 meta-analyses (430,438-444) . Two of the meta-analyses summarize parenteral nutrition

vs fasting or intravenous glucose (438,439) and 6 summarize parenteral versus enteral nutrition

(430,440,441,444), 2 of which attempt to explore the effect of early enteral nutrition (442,443). Recently, a

study much larger than most prior nutrition trials compared ICU patients randomized to early use of

parenteral nutrition to augment enteral feeding versus enteral feeding with only late initiation of parenteral

nutrition if necessary (445).

There is no direct evidence regarding the benefits or harm of parenteral nutrition in the first 48 hours in

sepsis. Rather, the evidence is generated predominantly from surgical, burns, and trauma patients. None

of the meta-analyses reports a mortality benefit with parenteral nutrition, except one suggesting

parenteral nutrition may be better than late introduction of enteral nutrition (443). Several suggested

parenteral nutrition had higher infectious complications compared both to fasting or intravenous glucose

and to enteral nutrition (430,439,440,432,443). Enteral feeding was associated with a higher rate of

enteral complications (eg, diarrhea) than parenteral nutrition (439). Of note, the use of parenteral nutrition

to supplement enteral feeding was also summarized by Dhaliwal et al, who also reported no benefit (441).

The Casaer et al trial reported that early initiation of parenteral nutrition led to longer hospital and ICU

length of stay, longer duration of organ support, and higher incidence of ICU-acquired infection. One-fifth

of patients had sepsis and there was no evidence of heterogeneity in treatment effects across subgroups,

including sepsis (445).

Therefore, there are no studies suggesting any superiority of TPN over enteral alone in the first 24 hours.

In fact, there is a suggestion that enteral nutrition (EN) may in fact be superior to TPN regarding infectious

complications and possibly requirement for intensive care and organ support.

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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. However, few specifically

addressed the early use of such supplements in sepsis.

Four meta-analyses evaluated immune-enhancing nutrition and found no difference in mortality, neither in

surgical nor medical patients (446-449). However, they analyzed all studies together, regardless of the

immunocomponent used, which could have compromised their conclusions. There are also other

individual studies analyzing diets with a mix of arginine, glutamine, antioxidants and/or omega-3 with

negative results (450,459) including a small study in septic patients showing a non-significant increase in

ICU mortality (453).

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 (453,454). To date, human trials of

L-arginine supplementation have generally been small and reported variable effects on mortality (455-

459). The only study in septic patients showed improved survival, but there are limitations in study design

(456). Other studies suggested no benefit (457-459) 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 (455,456) and length of stay (455). However, the relevance of these findings in

the face of potential harm is unclear.

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 (454,454). However, the clinical significance of these

findings is not clearly established.

Although a previous meta-analysis showed mortality reduction (430), 4 other meta-analyses did not (460-

463). Previous small studies not included in those meta-analyses have similar results (464,465). Three

66
recent well-designed studies also failed to show a mortality benefit in the primary analyses (228,466,467).

Again, however, none focused specifically on septic patients. Two small studies on septic patients

showed no benefit in mortality, (468,469) with significant reduction in infectious complications (468) and a

faster recovery of organ dysfunction (469). Some previous individual studies and meta-analyses showed

positive secondary outcomes, such as reduction in infectious morbidity (462,463,466) and organ

dysfunction (463). 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 (228) or organ dysfunction (466,467), even with parenteral glutamine. An ongoing trial

(REDOXS, www.clinicaltrials.gov/ NCT00133978) of 1200 patients will test both enteral and parenteral

glutamine and antioxidant supplementation in critically ill mechanically ventilated patients (470). 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 linolenic acid (GLA) are eicosanoid

precursors. The prostaglandins, leukotrienes, and thrombaxanes produced from EPA/GLA are less potent

than their arachidonic acid-derived equivalents, reducing the pro-inflammatory impact on the immune

response (453,454). 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 (471).

However, only one study was in septic patients (472), none was individually powered for mortality

(473,474), and all 3 used a diet with high omega-6 lipid content in the control group, which is not usual

standard of care in the critically ill. Recently, the authors who first reported reduced mortality in sepsis

(472) reported a follow-up multicenter study again finding improvement in non-mortality outcomes, though

notably with no demonstrable effect on mortality (475). Other studies using enteral (476-478) or

parenteral (479-481) fish oil failed to confirm these findings in general critical illness or acute lung injury.

Thus, at this point, there are no large, reproducible findings suggesting a clear benefit to the use of

immunomodulating nutritional supplements in sepsis, though larger trials are on-going.

W. Setting Goals of Care

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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 hours 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 patient’s best interest and may be what patients and

their family’s desire (482). Physicians have different end-of-life practices based on their region of practice,

culture, and religion (483). 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 (484). Models for structuring initiatives to enhance care in the ICU

highlight the importance of incorporating goals of care along with prognosis into treatment plans (485).

Additionally, discussing prognosis for achieving the goals of care and level of certainty of prognosis has

been identified as an important component of surrogate decision-making in the ICU (486,487). However,

variations exist in the use of advanced care planning and integration of palliative and end-of-life care in

the ICU, which can lead to conflicts that may threaten quality of care (488,489). The use of proactive

family care conferences to identify advanced directives and treatment goals within 72 hours of ICU

admission has been demonstrated to promote communication and understanding between the patient’s

family and the treating team; improve family satisfaction; decrease stress, anxiety, and depression in

surviving relatives; facilitate end-of-life decision making; and shorten length of stay in the ICU for patients

who die in the ICU (490-495). Clinical practice guidelines for support of the ICU patient and family

promote early and repeated care conferencing to reduce family stress and improve consistency in

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communication; open flexible visitation; family presence during clinical rounds and resuscitation; and

attention to cultural and spiritual support (496). Additionally, the integration of advanced care planning

and palliative care in the ICU focused on pain management, symptom control, and family support has

been shown to improve symptom management and patient comfort, and improve family communication

(485,491,497).

PEDIATRIC CONSIDERATIONS IN SEVERE SEPSIS

While sepsis in children is a major cause of mortality in industrialized countries with state of the art

intensive care units, the overall mortality from severe sepsis is much lower than that in adults, estimated

at about 2-10% (498-500). Severe sepsis hospital mortality is 2% in previously healthy children and 8%

in chronically ill children in the US (498). Definitions of sepsis, severe sepsis, septic shock and multiple

organ dysfunction/failure syndromes are similar to adult definitions but depend on age-specific heart rate,

respiratory rate, and white blood cell count cut-offs (501,502). This SSC document provides

recommendations only for term newborns and children in the industrialized resource-rich setting with full

access to mechanical ventilation and intensive care units. .

A. Initial Resuscitation

1. We suggest starting with face mask oxygen, or if needed and available, high flow nasal cannula

oxygen or nasopharyngeal CPAP (NP CPAP) for respiratory distress and hypoxemia. 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 resuscitation (grade 2C).

Rationale. Due to low functional residual capacity, young infants and neonates with severe sepsis may

require early intubation; however, during intubation and mechanical ventilation, increased intrathoracic

pressure can reduce venous return and lead to worsening shock if a patient is not volume loaded. In

69
patients who desaturate despite face mask oxygen, high flow nasal cannula oxygen or NP CPAP can be

used to increase functional residual capacity and reduce work of breathing allowing for establishment of

intravenous or intra-osseous access for fluid resuscitation and peripheral inotrope delivery (503, 504).

Drugs used for sedation have important side effects in these patients. For example, etomidate is

associated with increased mortality in children with meningococcal sepsis because of adrenal

suppression effect (505,506). Because attainment of central access is more difficult in children than

adults, reliance on peripheral or intra-osseus access can be substituted until and unless central access is

available.

2. We suggest that the initial therapeutic end points of resuscitation of septic shock be 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 mL·kg-1·hr-1, and normal mental status.SCVO2 saturation ≥ 70%

and cardiac index (CI) between 3.3 and 6.0 L/min/m2 should be targeted thereafter (grade 2C).

Rationale. Adult guidelines recommend lactate clearance as well, but children commonly have normal

lactate levels with septic shock. Regarding the many modalities used to measure SCVO2 and CI, the

specific use of one over the other is left to the practitoner’s discretion (507-513).

3. We recommend following ACCM-PALS guidelines for the management of septic shock (grade 1C).

Rationale. The ACCM-PALS guidelines are summarized in Figure 2. (511-513)

4. We recommend evaluating for and reversing pneumothorax, pericardial tamponade, intra-abdominal

hypertension, or endocrine emergencies in patients with refractory shock (grade 1C).

Rationale. Intra-abdominal hypertension is diagnosed by a bladder pressure >12 mm Hg (514).

Peritoneal paracentesis should be considered when the bladder pressure is >15 mmHg and surgical

decompression is warranted if the intra-abdominal pressure is > 0 mm Hg (515-516). Endocrine

emergencies include hypoadrenalism and hypothyroidism.

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 administration of antibiotics.

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. 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).

Rationale. Vascular access and blood drawing is more difficult in newborns and children. Antimicrobials

can be given intra-muscularly or orally (if tolerated) when access is not attainable until intravenous line

access is available (517-520).

2. We suggest clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension

(grade 2D).

Rationale. Children are more prone to toxic shock than adults because of 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 is unclear but it may be

considered in refractory toxic shock syndrome (521-528).

3. We recommend early and aggressive source control (grade 1D).

Rationale. Debridement and source control is paramount in severe sepsis and septic shock. Among

others necrotizing pneumonia, necrotizing fasciitis, gangrenous myonecrosis, empyema, and abcesses

can all require debridement or drainage. Perforated viscus requires repair and peritoneal wash out.

Delay in use of appropriate antibiotic, inadequate source control, and removal of infected devices are

associated with increased mortality in a synergistic manner (529-539).

4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is

preferred for severe disease (grade 1A).

Rationale. In adults, metronidazole is a first choice; however, response to treatment with C. difficile can

be best with enteral vancomycin. In very severe cases where diverting ileostomy or colectomy is

perfomed, enteral treatment should be considered until clinical improvement is ascertained (540-542).

C. Fluid Resuscitation

1. In the industrialized world with access to inotropes and mechanical ventilation, we suggest that initial

resuscitation of hypovolemic shock begin with infusion of isotonic crystalloids or albumin with boluses of

up to 20 mL/kg crystalloids (or albumin equivalent) over 5–10 minutes, titrated to reversing hypotension,

increasing urine output, and attaining normal capillary refill, peripheral pulses and level of consciousness

71
without inducing hepatomegaly or rales. If hepatomegly 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).

Rationale. Three RCTs compared the use of colloid to crystalloid resuscitation in children with

hypovolemic dengue shock with near 100% survival in all treatment arms (543-545). In the industrialized

world, 2 before-and-after studies observed 10-fold reductions in mortality when children with purpura /

meningococcal septic shock were treated in the community emergency department with fluid boluses,

inotropes, and mechanical ventilation (546,547). One randomized trial showed a reduction in septic

shock mortality from 40% to 12 % when increased fluid boluses, blood, and inotropes were given to attain

a SCVO2 monitor goal > 70% (512). A before-and-after quality improvement study showed reduction in

severe sepsis mortality from 4.0% to 2.4% with earlier delivery of fluid boluses and antibiotics in the first

hour in a pediatric emergencv department directed to reversing clinical signs of shock noted above (548).

By contrast, in a randomized controlled trial of children with severe infection in the sub-Saharan severe

malarial anemia belt where there was no accces to inotropes, mechanical ventilation, or intensive care,

there was an increased mortality when fluid boluses were given (without regard to the presence of

hepatomegaly or rales, or clinical goals) compared to provision of intravenous fluid at maintenance rate

and 20 mL/kg blood transfusion over 2 hours for children with a Hgb < 5 g/dL (549).

Children normally have a lower blood pressure than adults, and fall in blood pressure can be

prevented by vasoconstriction and increasing heart rate. Therefore, blood pressure by itself is not a

reliable end point for assessing the adequacy of resuscitation. However, once hypotension occurs,

cardiovascular collapse may soon follow. Thus fluid resuscitation is recommended even for both

normotensive and hypotensive children in hypovolemic shock (543-556). Because hepatomegaly and/or

rales occur in children who are fluid overloaded, these findings can be helpful signs of hypervolemia. In

the absence of these signs, large fluid deficits can exist, and initial volume resuscitation can require 40–

60 mL/kg or more; however, if these signs are present, then fluid administration should be ceased and

diuretics should be given. Inotrope infusions and mechnical ventilation are commonly required for

children with fluid refractory shock.

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D. Inotropes/Vasopressors/Vasodilators

1. We suggest beginning peripheral inotropic support until central venous access can be attained in

children who are not responsive to fluid resuscitation (grade 2C).

Rationale. Cohort studies show that delay in the use of inotropic therapies is associated with major

increases in mortality risk (555, 556). This delay is often related to difficulty in attaining central access. In

the initial resuscitation phase, inotrope/vasopressor therapy may be required to sustain perfusion

pressure, even when hypovolemia has not yet been resolved. Children with severe sepsis can present

with low cardiac output and high systemic vascular resistance, high cardiac output and low systemic

vascular resistance, or low cardiac output and low systemic vascular resistance shock (557). A child may

move from one hemodynamic state to another. Vasopressor or inotrope therapy should be used

according to the hemodynamic state (557). Dopamine-refractory shock may reverse with epinephrine or

norepinephrine infusion. In the case of extremely low systemic vascular resistance despite the use of

norepinephrine, vasopressin and terlipressin have been described in a number of case reports. Yet

evidence for the use of vasopressin or terlipressin in pediatric sepsis, as well as safety data, are still

lacking. Indeed, 2 RCTs showed no benefit in outcome with use of vasopressin or terlipressin in children

(558-561). Interestingly, while vasopressin levels are reduced in adults with septic shock, such levels

seem to vary quite extensively in children. When vasopressors are used for refractory hypotension, the

addition of inotropes is commonly needed to maintain adequate cardiac output (511, 512, 557).

2. We suggest that 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).

Rationale. The choice of vasoactive agent is initially determined by the clinical examination; however for

the child with invasive monitoring in place and demonstration of a persistent low cardiac output state with

high systemic vascular resistance and normal blood pressure despite fluid resuscitation and inotropic

support, vasodilator therapy can reverse shock. The use of Type III phosphodiesterase inhibitors

(amrinone, milrinone, enoximone), and the calcium sensitizer levosimendan, can be helpful because they

overcome receptor desensitization. Other important vasodilators include nitrosovasodilators, prostacyclin,

and fenoldopam. In 2 RCTs, pentoxyfilline reduced mortality from severe sepsis in newborns (511, 562-

571).

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E. Extracorporeal Membrane Oxygenation (ECMO) and Inhaled Nitric Oxide

1. We suggest consideration of ECMO for pediatric septic shock in the presence of refractory respiratory

failure (grade 2C).

Rationale. Survival from refractory shock or respiratory failure with sepsis and use of ECMO is 80% in

neonates and 50% in children. Best outcomes of 78% survival have been reported in children with septic

shock who underwent open chest cannulation rather than peripheral cannulation (similar to outcomes in

neonates with neck cannulation). Use of venovenous ECMO as part of the strategy for H1N1 mediated

ARDS in older children resulted in an 80% survival (511,572-578).

F. Corticosteroids

1. We suggest timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant

shock and suspected or proven absolute (classic) adrenal insufficiency.

Rationale. Approximately 25% of children with septic shock have absolute adrenal insufficiency defined

by a peak cortisol <18 μg/dL after the corticotropin stimulation test, or a basal cortisol level <4 μg/dL.

Patients at risk for absolute adrenal insufficiency include children with severe septic shock and purpura,

children who have previously received steroid therapies for chronic illness, and children with pituitary or

adrenal abnormalities. Initial treatment is hydrocortisone infusion at stress-dose (50 mg/m2/24 hrs);

however, infusions up to 50 mg/kg/d may be required to reverse shock in the short term. Death from

absolute adrenal insufficiency and septic shock occurs within 8 hours of presentation, Obtaining a serum

cortisol level at the time of empiric hydrocortisone may be helpful. (579-584).

G. Protein C and Activated Protein Concentrate

See section in Adjuvant Therapy related to the history of rhAPC.

H. Blood Products and Plasma Therapies

1. We suggest similar hemoglobin targets in children as in adults. During resuscitation of low superior

vena cava oxygen saturation shock (<70%), hemoglobin levels of 10 g/dL are targeted. After stabilization

74
and recovery from shock and hypoxemia then a lower target >7.0 g/dL can be considered reasonable

(grade 1B).

Rationale. The optimal hemoglobin for a critically ill child with severe sepsis is not known. A recent

multicenter trial reported no difference in mortality in hemodynamically stable critically ill children

managed with a transfusion threshold of 7 g/dL compared with those managed with a transfusion

threshold of 9.5 g/dL; however, the severe sepsis subgroup had an increase in nosocomial sepsis and

lack of clear evidence of equivalence in outcomes with the restrictive strategy (585, 586). Blood

transfusion is recommended by the World Health Organization (WHO) for severe anemia, Hgb <5 g/dL,

and acidosis. A RCT of early goal-directed therapy for pediatric septic shock using the threshold

hemoglobin of 10 g/dL Hgb for patients with a SVCO2 saturation <70% in the first 72 hours of pediatric

intensive care unit (PICU) admission showed improved survival in the multimodal intervention arm (512).

2. We suggest similar platelet transfusion targets in children as in adults (grade 2C).

3. We suggest the use of 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).

Rationale. We give plasma to reverse thrombotic microangiopathies in children with thrombocytopenia-

associated multiple organ failure and progressive purpura because FFP contains protein C, anti-thrombin

III, and other anticoagulant proteins. Rapid resuscitation of shock reverses most disseminated

intravascular coagulation; however, in some children purpura progresses in part due to critical

consumption of anti-thrombotic proteins (eg, protein C, antithrombin III, ADAMTS 13). Plasma is infused

with the goal of correcting prolonged PT/PTT times and halting purpura. Large volumes of plasma require

concomitant use of diuretics, CRRT, or plasma exchange to prevent >10% fluid overload (587-612).

I. Mechanical Ventilation

1. We suggest providing lung-protective strategies during mechanical ventilation (grade 2C).

Rationale. Some patients with ARDS will require increased PEEP to attain FRC and maintain

oxygenation, and peak pressures >30-35cm H2O to attain effective tidal volumes of 6-8 mL/kg with

adequate CO2 removal. In these patients, physicians generally transition from conventional pressure

control ventilation to pressure release ventilation (APRV) or to high frequency oscillatory ventilation

75
(HFOV). These modes maintain oxygenation with higher mean airway pressures using an “'open” lung

ventilation strategy. To be effective, these modes can require a mean airway pressure 5cm H2O higher

than that used with conventional ventilation. This can reduce venous return leading to greater need for

fluid resuscitation and vasopressor requirements (613-617)

J. Sedation/Analgesia/DrugToxicities

1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with

sepsis (grade 1D).

Rationale. Although there are no data supporting any particular drugs or regimens, it should be noted that

propofol should not be used for long-term sedation in children <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

(618-621).

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).

Rationale. Children with severe sepsis have reduced drug metabolism (622).

K. Glycemic Control

1. We suggest controlling hyperglycemia using a similar target as in adults <180 mg/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).

Rationale. In general, infants are at risk for developing hypoglycemia when they depend on intravenous

fluids. This means that a glucose intake of 4–6 mg·kg-1·min-1 or maintenance fluid intake with dextrose

10% normal saline containing solution is advised (6-8 mg/kg/min in newborns). Associations have been

reported between hyperglycemia and an increased risk of death and longer length of stay. A retrospective

pediatric ICU study reported associations of hyperglycemia, hypoglycemia, and glucose variability with

increased length of stay and mortality rates. A recent RCT of strict glycemic control compared to

moderate control using insulin in a PICU population found a reduction in mortality with an increase in

hypoglycemia. The authors plan to report neurologic outcomes in a 1-year follow-up cohort. Insulin

76
therapy should only be conducted with frequent glucose monitoring in view of the risks for hypoglycemia

which can be greater in newborns and children due to 1) relative lack of glycogen stores and muscle

mass for gluconeogenesis, and 2) the heterogeneity of the population with some excreting no

endogenous insulin and others demonstrating high insulin levels and insulin resistance (623-629).

L.. Diuretics and Renal Replacement Therapy

1. We suggest use of diuretics to reverse fluid overload, and if unsuccessful then continuous venovenous

hemofiltration (CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload (grade

2C).

Rationale. A retrospective study of children with meningococcemia showed an associated mortality risk

when children received too little or too much fluid resuscitation (550,554) A retrospective study of 113

critically ill children with MODS reported that patients with less fluid overload before CVVH had better

survival (630-632),

M. DVT Prophylaxis

1. We make no graded recommendations on the use of DVT prophylaxis in prepubertal children with

severe sepsis.

Rationale. Most DVTs in young children are associated with central venous catheters. Heparin-bonded

catheters may decrease the risk of catheter-associated DVT. No data on the efficacy of Ultra Fractionated

Heparin or Low Molecular Weight Heparin prophylaxis to prevent catheter-related DVT in children in the

ICU exist (633,634).

N. Stress Ulcer Prophylaxis

We make no graded recommendations on stress ulcer prophylaxis.

Rationale. Studies have shown that clinically important gastrointestinal bleeding in children occurs at

rates similar to adults. Stress ulcer prophylaxis strategy is commonly used in mechanically ventilated

children, usually with H2 blockers or proton pump inhibitors. Its effect is not known (635,636.)

O. Nutrition

1. Enteral nutrition should be given to children who can be fed enterally, and parenteral feeding in those

who cannot (grade 2C).

77
Rationale. D10% (always with Na containing solution in children) at maintenance rate provides the

glucose delivery requirements for newborns and children (637). 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.

SUMMARY AND FUTURE DIRECTIONS

Although this document is static, the optimum treatment of severe sepsis and septic shock is a dynamic

and evolving process. Since publication of the 2008 guidelines, there has been some additional evidence

that allows more certainty with which we make severe sepsis recommendations; however, more

programmatic clinical research in sepsis is essential to optimize these evidence-based medicine

recommendations.

New interventions will be proven and, as stated in the current recommendations, established

interventions may need modification. This publication represents an ongoing process. The Surviving

Sepsis Campaign and the consensus committee members are committed to updating the guidelines

regularly as new interventions are tested and published.

ACKNOWLEDGMENTS

The revision process was funded through a grant from the Gordon and Betty Irene Moore Foundation.

OTHER ACKNOWLEDGMENTS

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APPENDIX A

2012 SSC Guidelines Committee

R. Phillip Dellinger, (Co-Chair); Rui Moreno (Co-Chair); Leanne Aitken,a Hussain Al

Rahma,b Derek C. Angus, Dijillali Annane, Richard J. Beale, Gordon R. Bernard, Paolo Biban,c
Julian F. Bion, Thierry Calandra, Joseph A. Carcillo, Terry P. Clemmer, Clifford S. Deutschman,
J.V. Divatia,d Ivor S. Douglas, Bin Du,e Seitaro Fujishima, Satoshi Gando,f Herwig Gerlach,
Caryl Goodyear-Bruch,g Gordon Guyatt, Jan A. Hazelzet, Hiroyuki Hirasawa,h Steven M.
Hollenberg, Judith Jacobi, Roman Jaeschke, Ian Jenkins,i Edgar Jimenez,j Alan E. Jones,k Robert
M. Kacmarek, Winfried Kern,l Ruth M. Kleinpell,a Shin Ok Koh,m Joji Kotani, Mitchell Levy,n
Flavia Machado,o John Marini, John C. Marshall, Henry Masur, Sangeeta Mehta, John
Muscedere,p Lena M. Napolitano,q Mark E. Nunnally, Steven M. Opal,r Tiffany M. Osborn,s
Margaret M. Parker, Joseph E. Parrrillo, Haibo Qiu,t Adrienne G. Randolph, Konrad Reinhart,u
Jordi Rello, Ederlon Resende,v Andrew Rhodes,w Emanuel P. Rivers, Gordon D. Rubenfeld,x
Christa A. Schorr, Jonathan E. Sevransky, Khalid Shukri,y Eliezer Silva, Mark D. Soth, Charles
L. Sprung, Ann E. Thompson,z Sean R. Townsend, Jeffery S. Vender,A Jean-Louis Vincent,
Steve A. Webb,B Tobias Welte,C Janice L. Zimmerman.
a
World Federation of Critical Care Nurses; bEmirates Intensive Care Society; cEuropean
Society of Pediatric and Neonatal Intensive Care; dIndian Society of Critical Care Medicine;
e
Chinese Society of Critical Care Medicine; fJapanese Association for Acute Medicine;
g
American Association of Critical-Care Nurses, hJapanese Society of Intensive Care Medicine;
i
Society of Hospital Medicine; j World Federation of Societies of Intensive and Critical Care
Medicine; kSociety of Academic Emergency Medicine; lEuropean Society of Clinical
Microbiology and Infectious Diseases; mAsia Pacific Association of Critical Care Medicine;
n
Society of Critical Care Medicine; oLatin American Sepsis Institute; pCanadian Critical Care
Society; qSurgical Infection Society; rInfectious Diseases Society of America; sAmerican College
of Emergency Physicians; tChinese Society of Critical Care-China Medical Association;
u
German Sepsis Society; vBrazilian Society of Critical Care (AMIB); wEuropean Society of
Intensive Care Medicine; xAmerican Thoracic Society; yInternational Pan Arab Critical Care
Medicine Society; zPediatric Acute Lung Injury and Sepsis Investigators; AAmerican College of
Chest Physicians; BAustralian and New Zealand Intensive Care Society; CEuropean Respiratory
Society; World Federation of Pediatric Intensive and Critical Care Societies

Pediatric Subgroup

Jan Hazelzet, Adrienne Randolph, Margaret Parker, Ann Thompson, Paolo Biban, Alan Duncan, Cris

Mangia, Niranjan Kissoon, and Joseph Carcillo

129
130
Appendix C. ARDSnet Ventilator Management
Appendix C. ARDSnet Ventilator Management
• Assist control mode—volume ventilation
• Reduce tidal volume to 6 mL/kg lean body weight
• Keep Pplat <30 cm H2O
—Reduce TV as low as 4 mL/kg predicted body weight to limit Pplat
• Maintain SaO2/SpO2 88%–95%
• Anticipated PEEP settings at various FIO2 requirements

FiO2 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
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20-24

*Predicted Body Weight Calculation

• Male— 50 + 2.3 [height (inches) – 60] or 50 + 0.91 [height (cm) – 152.4]

• Female—45.5 + 2.3 [height (inches) – 60] or 45.5 + 0.91 [height (cm) – 152.4]

TV, tidal volume; SaO2, arterial oxygen saturation; PEEP, positive end-expiratory pressure.

1- The 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; 342:1301-1308

131
132
Appendix D. Summary of Ventilator Procedures in the Higher-PEEP Groups of the ALVEOLI Trial

Procedure Value
Ventilator mode Volume assist/control
Tidal-volume goal 6 ml/kg of predicted body weight
Plateau-pressure goal < 30 cm of water
Ventilator rate and pH goal 6-35, adjusted to achieve arterial pH > 7.30 if possible
Inspiration:expiration time 1:1 - 1:3
Oxygenation goal
PaO2 55- 80 mm Hg
SpO2 88 - 95%
Weaning attempted by means of pressure support when level of arterial
Weaning oxygenation acceptable with PEEP < 8 cm of water and FiO2 < 0.40

Allowable combinations of PEEP and FiO2†

Higher-PEEP group (after protocol changed to use higher levels of PEEP)

FiO2 0.3 0.3 0.4 0.4 0.5 0.5 0.5–0.8 0.8 0.9 1
PEEP 12 14 14 16 16 18 20 22 22 22–24

* Complete ventilator procedures and eligibility criteria are listed in the Supplementary Appendix (available with the full text of this article at
www.nejm.org) and at www.ardsnet.org. PaO2 denotes partial pressure of arterial oxygen, SpO2 oxyhemoglobin saturation as measured by
pulse oximetry, FiO2 fraction of inspired oxygen, and PEEP positive end-expiratory pressure.
† In both study groups (lower and higher PEEP), additional increases in PEEP to 34 cm of water were allowed but not required after the FiO2
had been increased to 1.0 according to the protocol.

Adapted Brower RG, Lanken PN, MacIntyre N, Matthay MA, et al. Higher versus lower positive end-expiratory pressures in
from: patients with the acute respiratory distress syndrome.N Engl J Med. 2004 Jul 22;351(4):327-36.

133
Table 1. Diagnostic criteria for sepsis

Infection, documented or suspected, and some of the following:

General variables
Fever (>38.3°C)
Hypothermia (core temperature <36°C)
Heart rate >90 min–1 or >2 SD above the normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over 24 hrs)
Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes
Inflammatory variables
Leukocytosis (WBC count >12,000 µL–1)
Leukopenia (WBC count <4000 µL–1)
Normal WBC count with >10% immature forms
Plasma C-reactive protein >2 SD above the normal value
Plasma procalcitonin >2 SD above the normal value
Hemodynamic variables
Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or an SBP decrease >40 mm
Hg in adults or <2 SD below normal for age)
Organ dysfunction variables
Arterial hypoxemia (PaO2/FIO2 <300)
Acute oliguria (urine output <0.5 mL/kg hr for at least 2 hrs despite adequate fluid
resuscitation)
Creatinine increase >0.5 mg/dL or 44.2 micromol/L
Coagulation abnormalities (INR >1.5 or a PTT >60 secs)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 µL–1)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L)
Tissue perfusion variables
Hyperlactatemia (>1 mmol/L)
Decreased capillary refill or mottling

WBC, white blood cell; SBP, systolic blood pressure; MAP, mean arterial blood pressure
INR, international normalized ration; a PTT, activated partial thromboplastin time.
Diagnostic criteria for sepsis in the pediatric population are signs and symptoms of
inflammation plus infection with hyper- or hypothermia (rectal temperature >38.5 or <35°C),
tachycardia (may be absent in hypothermic patients), and at least one of the following indications
of altered organ function: altered mental status, hypoxemia, increased serum lactate level or
bounding pulses.

Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis
Definitions Conference. Crit Care Med 2003; 31:1250-1256

134
Table 2

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 >upper limits lab normal
• Urine output <0.5 ml/kg hr for >2 hr despite adequate fluid resuscitation
• ALI with PaO2/FIO2 <250 in the absence of pneumonia as infection source
• ALI with PaO2/FIO2 <200 in the presence of pneumonia as infection source
• Creatinine >2.0 mg/dl (176.8 micromol/L)
• Bilirubin >2 mg/dl (34.2 micromol/L)
• Platelet count <100,000
• Coagulopathy (INR >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; 31:1250-1256

135
Table 3. Determination of the quality of evidence

• Underlying methodology
A (high) RCT
B (moderate) Downgraded RCT or upgraded observational studies
C (low) Well-done observationalstudies with controls
D (very low) Case series or expert opinion

• 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 (RR) >2 with no plausible
confounders]
2. Very large magnitude of effect with RR >5 and no threats to validity (by two levels)
3. Dose response gradient

*RCT= randomized controlled trial; RR=relative risk

136
Table 4. Factors Determining Strong vs. Weak Recommendation

What should be considered Recommended Process

High or moderate evidence The higher the quality of evidence, the more likely
(is there high or moderate quality evidence?) is a strong recommendation.

Certainty about the balance of benefits versus The larger the difference between the desirable
harms and burdens and undesirable consequences and the certainty
(is there 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 is a weak recommendation.

Certainty in or similar values The more certainty or similarity in values and

(is there certainty or similarity?) preferences, the more likely a strong
recommendation.

Resource implications The lower the cost of an intervention compared to

(are resources worth expected benefits?) the alternative that is considered and other costs
related to the decision – that is, fewer resources
consumed – the more likely is a strong
recommendation.

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Table 5 – Recommendations: Initial Resuscitation and Infection Issues

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 8–12 mm Hg
(b) Mean arterial pressure (MAP) ≥65 mm Hg
(c) Urine output ≥ 0.5 mL·kg-1·hr-1
(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 as rapidly as
possible (grade 2C).

B. Screening for Sepsis and Performance Improvement

1. Routine screening of seriously ill patients for severe sepsis to allow earlier implementation of therapy
(grade 1C).

2. Hospital based performance improvement efforts in severe sepsis (UG).

C. Diagnosis
1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (>45 minutes) 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 hr.) 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 (grade1C).

D. Antimicrobial Therapy
1. Intravenous antimicrobial therapy started as early as possible and within the first hour of recognition of
septic shock (grade 1B) and severe sepsis without septic shock (grade 1C).

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 de-escalation (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, multidrug- resistant 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).

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4b. Empiric combination therapy should not be administered for >3–5 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 7–10 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 not be used in patients with severe inflammatory states determined to be of
noninfectious cause (grade 1C).

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 intevention be
undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).

2. When infected peri-pancreatic 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 (SOD) and selective digestive decontamination (SDD) 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. Oral chlorhexidine gluconate (CHG) be used as a form of oropharyngeal decontamination to reduce
the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B).

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Table 6: Norepinephrine Compared to Dopamine in Severe Sepsis Summary of Evidence Table

Norepinephrine compared to dopamine in severe sepsis

Patient or population: Patients with severe sepsis
Settings: Intensive care unit
Intervention: Norepinephrine
Comparison: Dopamine
Sources: Analysis performed by Djillali Annane for Surviving Sepsis Campaign, using following publications: De Backer D. NEJM
2010;362:779-89; Marik PE. JAMA 1994;272:1354-7; Mathur RDAC. Indian Journal of Critical Care Medicine 2007;11:186-91; Martin
C. Chest 1993;103:1826-31; Patel GP. Shock 2010;33:375-80; Ruokonen E. Crit Care Med1993;21:1296-303.
Outcomes Illustrative comparative risks* (95% Relative No of Quality of the Comments
CI) effect Participants evidence
Assumed risk Corresponding risk (95% CI) (studies) (GRADE)
Dopamine Norepinephrine
Short-term mortality Study population RR 0.91 2043 ⊕⊕⊕⊝
530 per 1000 482 per 1000 (0.83 to (6 studies) moderate1,2
(440 to 524) 0.99)

Serious adverse events - Study population RR 0.47 1931 ⊕⊕⊕⊝

Supraventricular arrhythmias 229 per 1000 82 per 1000 (0.38 to (2 studies) moderate1,2
(34 to 195) 0.58)

Serious adverse events - Study population RR 0.35 1931 ⊕⊕⊕⊝

Ventricular arrhythmias 39 per 1000 15 per 1000 (0.19 to (2 studies) moderate1,2
(8 to 27) 0.66)

*The assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) 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
1
Strong heterogeneity in the results (I squared = 85%), however this reflects degree of effect, not direction of effect. We have
decided not to lower the evidence quality.
2
Effect results in part from hypovolemic and cardiogenic shock patients in De Backer, NEJM 2010. We have lowered the quality of
evidence one level for indirectness.

140
coronary artery due to ARDS Table 7. Recommendations: Hemodynamic Support and Adjunctive

Support

G. Fluid Therapy of Severe Sepsis

1. We recommend crystalloids be used in the initial fluid resuscitation of severe sepsis and septic shock.
(grade 1A).

2. We suggest adding albumin in the initial fluid resuscitation of severe sepsis and septic shock in
patients who require repeated boluses of crystalloids (grade 2B).

3. We recommend against the use of hydroxyethyl ethyl starches (grade 1B).

4, We recommend an initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with
suspicion of hypovolemia to achieve a minimum of 30 ml/kg of crystalloids (a portion of this may be
albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some
patients (see Initial Resuscitation recommendations) (grade 1C).

5.. We recommend that a fluid challenge technique be applied wherein fluid administration is continued as
long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure,
stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG).

H. Vasopressors
1. We recommend that vasopressor therapy initially target a mean arterial pressure (MAP) of 65 mm Hg
(grade 1C).

2. Norepinephrine as the first choice vasopressor (grade 1B).

3. Epinephrine when an additional agent is needed to maintain adequate blood pressure and to wean off
norepinephrine as MAP allows (grade1C).

4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or
decreasing NE dosage (UG)

5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-
induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for
salvage therapy (failure to achieve adequate MAP with other vasopressor agents). (UG).

6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg,
patients with low risk of arrhythmias and low heart rate). (grade 2C).

7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a)
norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood
pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low
dose vasopressin have failed to achieve MAP target (grade 1C).

8. Low-dose dopamine should not be used for renal protection (grade 1A).

9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources
are available (UG).

I. Inotropic Therapy
1. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if
in use) 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 (grade 1C).

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2. Not using a strategy to increase cardiac index to predetermined supranormal levels (grade 1B).

J. Corticosteroids
1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation
and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In
case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day
(grade 2C).

2. Not using the ACTH stimulation test to identify adults with septic shock who should receive
hydrocortisone (grade 2B).

3. We suggest treated patients have the hydrocortisone tapered when vasopressors are no longer
required (grade 2D).

4. We recommend that corticosteroids not be administered for the treatment of sepsis in the absence of
shock (grade 1D).

5. When hydrocortisone is given to treat septic shock, we suggest using continuous infusion rather than
repetitive bolus injections (2C).

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Table 8 – Recommendations: Other Supportive Therapy of Severe Sepsis

K. Blood Product Administration

1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as
myocardial ischemia, severe hypoxemia, acute hemorrhage or ischemic heart disease we recommend
that red blood cell transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to target
a hemoglobin concentration of 7.0 –9.0 g/dL in adults (grade 1B).

2. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis (grade 1B).

3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding
or planned invasive procedures (grade 2D).

4. Not using antithrombin for the treatment of severe sepsis and septic shock (grade 1B).

5. In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10
x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts
are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts
(≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures (grade 2D).

L. Immunoglobulins
1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock (grade 2B)

M. Selenium
1. Not using intravenous selenium for the treatment of severe sepsis (grade 2C).

N. History of Recommendations Regarding Use of Recombinant Activated Protein C (rhAPC)

A history of the evolution of SSC recommendations as to rhAPC(no longer available) is provided

O. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

1. Target a tidal volume of 6 mL/kg rather than 12 ml/kg predicted body weight in patients with sepsis-
induced ARDS (grade 1A).

2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures
in a passively inflated lung be ≤30 cm H2O (grade 1B).

3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration
(atelectotrauma) (grade 1B).

4. Strategies based on higher rather than lower levels of PEEP be used for patients with severe sepsis
induced ARDS (grade 2C).

5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia (grade 2C).

6. Prone positioning be used in sepsis-induced ARDS patients with a PaO2/FiO2 ratio ≤ 100 mm HG in
facilities that have experience with such practices (grade 2B).

7, That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30-45
degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (grade
1B)..

8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ALI/ARDS patients
in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks (grade
2B).

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9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis
undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical
ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without
vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory
pressure requirements; and e) low FIO2 requirements which can be met safely delivered with a face mask
or nasal cannula If the spontaneous breathing trial is successful, consideration should be given for
extubation (grade 1A).

10. Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS
(grade 1A).

11. A conservative rather than liberal fluid strategy for patients with established sepsis-induced acute lung
injury who do not have evidence of tissue hypoperfusion (grade 1C).

12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment
of sepsis- induced ARDS. (Grade 1B).

P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis

1. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting
specific titration endpoints (grade 1B).

2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ALI/ARDS
due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be
maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the
depth of blockade should be used (grade 1C).

3. A short course of NMBA of not greater than 48 hours for patients with early, severe sepsis-induced
ARDS (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 >180 mg/dL. This protocolized
approach should target an upper blood glucose < 180 mg/dL rather than an upper target blood glucose <
110 mg/dL (grade 1A).

2. We recommend that blood glucose values be monitored every 1–2 hrs until glucose values and insulin
infusion rates are stable and then every 4 hrs thereafter (grade 1C).

3. We recommend that 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). We recommend that this be accomplished with daily subcutaneous low-molecular

144
weight heparin (LMWH) (1B versus twice daily UFH and 2C versus three times daily UFH). If creatinine
clearance is <30 ml/min and LMWH is used, we recommend use of 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 1A).

2. When stress ulcer prophylaxis is used, we suggest the use of proton pump inhibitors rather than H2RA
(grade 2C)

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 cal 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. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles
where appropriate (grade 1B).

3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission (grade
2C).

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Table 9 – Recommendations: Special Considerations in Pediatrics

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 be 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 mL·kg-1·hr-1, and normal mental status. Superior vena cava O2 saturation >=
70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter (grade 2C).

3. Follow American College Critical Care Medicine-Pediatric Life Support ( ACCM-PALS) guidelines for
the management of septic shock (grade 1C).
The ACCM-PALS guidelines are summarized in Figure 2. (502-504)

4. Evaluate for and reverse pneumothorax, pericardial tamponade, intra-abdominal hypertension, or

endocrine emergencies in patients with refractory shock (grade 1C).

B. Antibiotics and Source Control

1. Empiric antibiotics 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 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 20 mL/kg
crystalloids (or albumin equivalent ) over 5–10 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) and Inhaled Nitric Oxide

1. Consider ECMO for refractory pediatric septic shock and respiratory failure (grade 2C).

F. Corticosteroids

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1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and
suspected or proven absolute (classic) adrenal insufficiency (grade 1 A) .

G. Protein C and Activated Protein Concentrate

No recommendation as no longer available

I. 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 10 g/dL are targeted. After stabilization and
recovery from shock and hypoxemia then a lower target > 7.0 g/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).

J. Mechanical Ventilation
1. Llung-protective strategies during mechanical ventilation (grade 2C).

K Sedation/Analgesia/DrugToxicities
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).

L. Glycemic Control
1. Control hyperglycemia using a similar target as in adults < 180 mg/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).

M Diuretics and Renal Replacement Therapy

1. Use diuretics to reverse fluid overload, and if unsuccessful then continuous venovenous hemofiltration
(CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload (grade 2C).

O. Deep Vein Thrombosis (DVT) Prophylaxis

No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.

P. Stress Ulcer(SU) Prophylaxis

No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis

Q. Nutrition
1. Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot
(grade 2C).

147
148
Figure 2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic

support in infants and children.

149
Figure 1. Surviving Sepsis Campaign Care Bundles.
WITHIN 3 HOURS OF SEVERE SEPSIS:

1) Measure lactate level

2) Obtain blood cultures prior to adminiatration of antibiotics

3) Administer broad spectrum antibiotics

4) Administer 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L

WITHIN 6 HOURS OF INITIAL SYMPTOMS FOR SEPTIC SHOCK:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation to

maintain a mean arterial pressure (MAP)≥65mmHg)

6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or

initial lactate ≥4 mmol/L (36mg/dl):

- Achievecentral venous pressure (CVP) of ≥8 mm Hg

- Achieve central venous oxygen saturation (ScvO2) of ≥70%

7) Remeasure lactate if initial lactate was elevated

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Online Appendix A

SSC Conflict of Interest Policy:

The SSC Guidelines Committee developed and adopted a comprehensive conflict of interest

(COI) policy at the commencement of the current update process. This policy was established to

ensure that SSC managed real and potential COI (both financial land non-financial) in an open and

effective manner in order to secure and preserve transparency and public trust in the integrity of SSC

processes and products. The comprehensive policies and standards for the management of COI

applied to all subcommittees, work groups, task forces, evidence process panels, and writing panels

as well as individual volunteers, liaisons, staff, and others involved in SSC Guidelines Committee

work.

The goals of the COI policy were (a) to enhance the objectivity, scientific rigor and transparency of

official SSC statements, guidelines and documents by providing an explicit methodology for

individuals and participating organizations to identify and disclose all personal or institutional

“competing interests” that may cause or be perceived as causing a COI affecting the individual’s

participation in the activity, and resolve all conflicts of interest and (b) to provide for disclosure and

resolution of conflicts of interest in a manner respectful of the SSC participating organizations and

other individuals essential to SSC activities, and respectful of confidentiality to the extent appropriate.

Individual participants were required to provide a written disclosure of all potential conflicts of

interest (both financial and non-financial) by completing the International Committee of Medical

Journal Editors (ICMJE) Uniform Disclosure Form for Potential Conflicts of Interest. While

committee members were encouraged to specify remuneration of any dollar amounts, this was

not mandatary. A separate questionnaire was developed to record non-financial COI including an

151
assessment of each participants approach to the use of guidelines and incorporation of evidence into

clinical decision making in sepsis.

Updates were required whenever material changes occurred in the individual’s status. Processes

were established for review and adjudication of COI (Appendix B of primary document). Individuals

with COI in a particular area or topic who were selected for a leadership role with oversight or

responsibility for that area or topic were subject to heightened adjudication by the executive

committee. The executive reviewed initial disclosures before deciding on participants, and excluded

participants if there was a non‐resolvable conflict of interest. The chair of each subgroup and more

than 50% of the members of each group were required to be free of any relevant relationship with

industry and of any significant nonfinancial COI or competing organizational relationship. Any chair

of a writing group with any relevant COI was asked to step down as a chair.

During in-person meetings and telephone conference calls, each individual was required to make a

verbal statement each time they spoke regarding their potential COI. Any individuals with a financial

conflict relative to the subject matter about to be discussed were asked to recuse themselves from the

deliberation, unless they had special information of a technical nature. Formal abstention from all

votes and actions was required for any individual with a potential recorded COI.

152
Authors’ Disclosure Information:

Dr. Aitken disclosed that she has no potential conflicts of interest. Her non-financial disclosures
include publications on protocol directed sedation and nursing considerations to complement the
Surviving Sepsis Campaign guidelines.

Dr. Al Rahma disclosed that he has no potential conflicts of interest.

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) and received a consulting income (anti-
TRL4 therapy for severe sepsis) from Eisai, Inc. Travel/accommodation expenses were
reimbursed by Eisai, Inc. Additionally, he is the primary investigator for an ongoing National
Institutes of Health-funded study comparing early resuscitation strategies for sepsis induced
tissue hypoperfusion.

Dr. Annane participated on the Fresenius Kabi International Advisory Board (honorarium 2000€).
His non-financial 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 versus norepinephrine (CATS study) – Lancet 2007.
He also is the principle investigator of an ongoing investigator-led multinational randomized
controlled trial of crystalloids versus colloids (Crystal Study).

Dr. Beale received compensation for his participation as board member for Eisai, Inc, Applied
Physiology, bioMérieux, Covidien, SIRS-Lab, and Novartis. Consulting income 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). He received honoraria (paid to his
institution) from Applied Physiology (Applied Physiology PL SAB, Applied Physiology SAB,
Brussels, Satellite Symposium at the ISICEM, Brussels); bioMérieux (GeneXpert Focus Group,
France); SIRS-Lab (SIRS-LAB 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); Eli Lilly and Company (development of
educational presentations including service on speaker’ bureaus (intensive care school hosted in
department). Travel/accommodations were reimbursed from bioMerieux (GeneXpert Focus
Group, France) and LiDCO (Winter Anaesthetic and Critical Care Review Conference);
Surviving Sepsis Campaign (Publications Meeting, New York; Care Bundles Conference,
Manchester); SSC Publication Committee Meeting and SSC Executive Committee Meeting,
Nashville; SSC Meeting, Manchester); Novartis (Advisory Board Meeting, Zurich); Institute of
Biomedical Engineering (Hospital of the Future Grand Challenge Kick-Off Meeting; Hospital of
the Future Grand Challenge Interviews EPSRC Headquarters, Swindon; Philips (Kick-Off
Meeting, Boeblingen, Germany; MET Conference, Cohenhagen); Covidien (Adult Monitoring

153
Advisory Board Meeting, Frankfurt); Eisai (ACCESS Investigators Meeting, Barcelona).His
non-financial disclosures include authorship of the position statement on fluid resuscitation from
the ESICM task force on colloids (yet to be finalized).

Dr. Bernard received compensation for his participation as a board member of Cumberland
Pharmaceuticals, Nashville, TN ($50,000-$100,000- no known conflict with any topic area); and
AstraZeneca ($1,000-$5,000 - paid consultancy ended in 2009). He received grant support from
AstraZeneca ($100,000 - grant is in support of the study on statins in the treatment of H1N1
influenza). He has stock/stock options in Cumberland Pharmaceuticals (no known conflict with
topic area). Vanderbilt University was the coordinating center for the PROWESS Shock trial (Eli
Lilly-income support commensurate with 1% to 5% effort on the project. His non-financial
disclosures include initial authorship of the PROWESS trial of aPC in sepsis.

Dr. Biban disclosed that he has no potential conflicts of interest.

Dr. Bion received grant support for being the senior clinical leader of the National Patient Safety
Agency’s ‘Matching Michigan’ project.

Dr. Calandra reports grant support from Baxter (research grant on testing of anti-MIF
monoclonal antibodies for treatment of sepsis); bioMérieux (development of diagnostic tests for
fungal infections—money to research foundation); Merck Sharp & Dohme-Chibret AG (grant
for medical mycology); and Roche Diagnostics (research grant for SeptiFast). He consulted for
Astellas (speaker and chairperson at company sponsored symposium [ESICM 2009 and ISICEM
2010- antifungal therapy]); Baxter (anti-MIF monoclonal antibodies for treatment of sepsis);
bioMérieux (diagnostic tests for infectious diseases); Essex Chemie AG (advisory board);
Evolva (advisory board); Merck Sharp & Dohme-Chibret AG (antifungal agents, and was on the
advisory board of a chairperson meeting); and Pfizer (speaker at meeting). He also reports
monetary compensation for his participation in review activities (data monitoring boards,
statistical analysis, end point committees [Eisai - steering committee; Eritoran Clinical Trial;
PPD; Novartis]). His institution received grant support from the Swiss National Science
Foundation. Furthermore, he is a member of the Research Council of the Swiss National Science
Foundation. His non-financial disclosures include authorship of review articles on the use of
mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis.

Dr. Carcillo received grant support from the National Institutes of Health and holds a patent from
the University of Pittsburgh. His non-financial disclosures include authorship of the ACCM-
PALS guideline and publications on the management of sepsis and shock in children.

Dr. Clemmer has non-financial conflicts as a member of ARDSNet since its inception and is a
contributor to many of its publications. He developed a protocol for the standard use of APRV
for local use. Additionally, he has published and lectured on the removal of sedation and early
ambulation of mechanically ventilated patients.

Dr. Dellinger consulted for Biotest (immunoglobin concentrate available in Europe for potential
use in sepsis); and AstraZeneca (anti-TNF compound in sepsis clinical trial). His institution
received consulting income from IKARIA (inhaled nitric oxide available for off label use in

154
ARDS) and grant support from Spectral Diagnostics Inc. (endotoxin removal clinical trial);
Ferring (vasopressin analog clinical trial-ongoing); and AstraZeneca (anti-TNF clinical trial-
ongoing). He received payment for educational presentations, including service on the speakers
bureau from Eisai (anti-endotoxin compound in clinical trial).

Dr. Deutschman has non-financial involvement as a coauthor of the Society of Critical Care
Medicine’s Glycemic Control guidelines.

Dr. Divatia received unrestricted education grants to his institution (Edwards India, USD $8,000).
He also received income from Asia Ventilation Forum (workshop/symposium speaker -
Covidien paid honoraria). Travel/accommodations were reimbursed by Edwards India;
AstraZeneca India and MSD India. His non-financial involvement includes being a board
member of the Asia Ventilation Forum (AVF is a working group to enhance ventilatory
management in Asian countries).

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 2009-2011). 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). In addition, he has a pending patent for
a bed backrest elevation monitor.

Dr. Fujishima disclosed any potential conflicts of interest.

Dr. Gando received grant support for Grants-in-Aid for Science Research from the Ministry of
Education, Science, Sports, and Culture in Japan (Grant # 2007-19390456). 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. Gerlach 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).Gerlach disclosed that he has no
potential conflicts of interest.

Dr. Goodyear-Bruch disclosed that she has no potential conflicts of interest.

Dr. Guyatt disclosed that he has no potential conflicts of interest.

Dr. Hazelzet received travel/accommodations reimbursement from ESPNIC and EMEA (EC or
expert meeting). He is the Medical President of ESPNIC, and is a member of the European
Pediatric Genetic Study consortium.

155
Dr. Hirasawa reports income to his institution from the Surviving Sepsis Campaign Guideline
Committee ($10,000-$25,000). He received honoraria from the Surviving Sepsis Campaign
Guideline Committee ($1,000-$5,000). He is the senior author of a manuscript describing the
efficacy of continuous hemodiafiltration with cytokine-absorbing hemofilter on sepsis mediator
removal.

Dr.Hollenberg consulted for Eisai (Eritoran).

Dr. Jacobi reports grant support to her institution from Eli Lilly (Project Mercury-experience
with DAA and an unrestricted educational grant 2009: $1,000-$5,000). She reports income to her
institution for the development of educational presentations including service on speakers’
bureaus (Eli Lilly 2001-2006; CareFusion Center for Clinical Safety (2007)).
Travel/accommodations reimbursed to her institution from Eli Lilly’s Speaker’s Bureau (SCCM
travel-until 2006). She and her husband own stock in healthcare companies, (managed by a
broker): Abbott Labs (No sepsis-specific related products); Cardinal Health (distributor of
products only - no sepsis therapies of their own); Baxter International (150 shares ~ $8,000-
fluids used for resuscitation- may be used in sepsis patients); Edwards Life Sciences (30 shares ~
$2,500 - monitoring devices used in sepsis patients); Merck Medco (no sepsis related products);
Pfizer (179 shares ~ $3,400 - antimicrobial products used in sepsis patients- no sepsis-specific
therapies). She is the past president of the Society of Critical Care Medicine, and chairs the
Society of Critical Care Medicine’s task force completing the Glycemic Control guidelines. She
is a coauthor of the ‘Project Mercury’ paper (retrospective evaluation of drotrecogin alfa
activated that demonstrated a higher risk of bleeding compared with the prior research
populations in RCTs).

Dr. Jaeschke disclosed that he has no potential conflicts of interest.

Dr. Jenkins received income for speakers’ bureau activities related to DVT prevention from
Medavera and Haymarket Medical Education and Quintiles. He is an author of a sepsis review
article (published in the Journal of Hospital Medicine, 2006).

Dr. Jimenez received grants paid to his institution from CareFusion (mechanical ventilation
research); KCI (abdominal compartment syndrome device research); and Hamilton (mechanical
ventilation research). He received income from CareFusion (mechanical ventilation talks related
to ongoing research); and KCI (moderator of kinetic therapy symposium).
Travel/accommodations reimbursement from CareFusion (travel expenses while giving
talks/workshops overseas).

Dr. Jones received grant support from HTI. He is an elected board member of SAEM and EMF.
In addition he is the primary author on a manuscript comparing lactate clearance with central
venous oxygen saturation.

Dr. Kacmarek is the author of original research papers, editorials and chapters showing the
benefit of lung protective ventilation.

156
Dr. Kern consulted for Pfizer and received grant support paid to his institution from Pfizer. He
received honoraria from Pfizer; Janssen-Cilag; Astrellas; and Novartis. Travel/accommodations
reimbursed by Bayer.

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-yr R01 grant, PI and 3-yr 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; American
Association of Critical Care Nurses (one night hotel coverage at national conference).

Dr. Koh disclosed that he has no potential conflicts of interest.

Dr. Kotani reports grant support paid to his institution from AstraZeneca, Asahi Kasei Pharma;
EBMs; Kaken Pharmaceutical; Nihon Pharmaceutical; Teijin Pharma Limited; CSL Behring;
Torii Pharmaceutical; Mitsubishi Tanabe Pharma; Pfizer Japan Inc.; Daiichi Sankyo, Benesis,
Mochida Pharmaceutical, Terumo, Abbott Japan, Otsuka Pharmaceutical Inc; Ono
Pharmaceutical; Shionogi; and Toray Medical.

Dr. Levy reports 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). He has
been involved with the Surviving Sepsis Campaign guideline from its beginning.

Dr. Machado reports unrestricted grant support paid to his institution for Surviving Sepsis
Campaign implementation in Brazil (Eli Lilly do Brasil). He is the primary investigator for an
ongoing study involving vasopressin.

Dr. Marini consulted for GE Healthcare (Scientific Advisory Committee). He reports research
grant support was paid to institution from GE Healthcare. In addition, he is the investigator for
research studies in pandemic influenza (PI for ongoing study of statins as adjuvant therapy); and
antibiotics in acquired infection (PI of RCT of empiric antibiotics vs. placebo for suspected ICU-
acquired infection).

Dr. Marshall reports consulting income deposited to university division group practice for work
as a Steering Committee member for the PROWESS Shock Study; (Eli Lilly); Steering
Committee and Clinical Evaluation Committee; ACCESS Study; (Eisai); Steering Committee
member for EUPHRATES study; (Spectral Diagnostics; DMC; Artisan Therapeutics; DMC Leo
Pharma). He consulted for Idaho Technologies; Bayer; Roche Diagnostics; Pfizer; Daiichi
Sankyo; and Vertex Pharmaceuticals. Travel/accommodations reimbursed by Spectral
Diagnostics for travel as a speaker to a meeting in Moscow (bioMerieux meeting in Paris). is the
Chair of the Canadian Critical Care Trials Group that has undertaken some of the primary
research underlying the SSC guidelines; Chair of the International Forum of Acute Care Trialists,
an umbrella organization whose members include a number of investigator-led and run consortia
that have published work that has formed the basis for the SSC guidelines. He is also a member
and past chair of the International Sepsis Forum (received a stipend while chair). He is the
157
primary investigator for an ongoing study of statins as adjuvant therapy and is the primary
investigator of RCT of empiric antibiotics vs. placebo for suspected ICU- acquired infection.

Dr. Masur disclosed that he has no potential conflicts of interest.

Dr. Mehta reports grant support paid to his institution for a sedation related research grant from
Canadian Institutes of Health Research. He received honoraria from Hospira (Advisory Board
member, $1,500).

Dr. Moreno consulted for bioMerieux (expert meeting). He is a coauthor of a paper on

corticosteroids in patients with septic shock. He is the author of several manuscripts defining
sepsis and stratification of the patient with sepsis. He is also the author of several manuscripts
contesting the utility of sepsis bundles.

Dr. Muscedere reports grant support to his institution for the VAP knowledge translation study
($10,000-$25,000). He received honoraria from Astellas (advisory board for Doripenem $1,000-
$5,000). He was the site investigator for a multicenter study on surfactant for ARDS ($10,000-
$25,000) from Pneuma Pharma and was the site investigator for a multicenter study on the
treatment of VAP with Tygecycline (ongoing study - no funds received) from Wyeth. He is a
contributing author on a systemic review and meta-analysis of PCT use. He as also is the lead
author for a systematic review and meta-analysis of subglottic secretion drainage for the
prevention of VAP.

Dr. Napolitano consulted as an advisory board member for Wyeth, Pfizer, and Ortho McNeil.
She received honoraria from medical educational companies (CME lectures and national
meetings). Travel/accommodations were reimbursed by Pfizer, Wyeth, and Ortho McNeil.

Dr. Nunnally received a stipend for a chapter on diabetes mellitus. Additionally, he is an author
of editorials contesting classic tight glucose control.

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 immunoglobin 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 yrs); Eisai ($30,000 for 3 yrs);
Astra Zeneca ($30,000 for 1 yr); Aggenix ($30,000 for 1 yr); 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). 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). Additionally, he
is also on the Data Safety Monitoring Board for Tetraphase (received US $600 in 2012).

Dr. Osborn consulted for Sui Generis Health ($200). Her institution receives grant support from

158
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
[non-industry] grant. Grant awarded to chief investigator from ICNARC). She is a trial clinician
for ProMISe.

Dr. Parker provides expert testimony for Amer Cunningham Co (June 2010).

Dr. Parrillo consulted for Artisan, Philips, and Cytosorbents Inc and Sangart DSMB. His
institution received grants from the Robert Wood Johnson Foundation (New Jersey Health
Initiative: Heart Failure) and the Salem Health and Wellness Foundation. He is board member of
the National Heart, Blood and Lung Institute’s Heart Failure Network.

Dr. Qiu’s institution received grants from Pfizer (US $30,000 for MRSA survey); MSD China
(US $10,000 for Candidemia survey in China); and Xian-Janssen Pharmaceutical Ltd (US $8,000
for PK/PD of Itraconazole in severe fungal infection). He received honoraria from Pfizer; MSD
China; Eli Lilly; AstraZeneca; and Drager(money paid to his institution). He received travel
reimbursement from Pfizer (to attend annual ESICM meeting in 2011) and MSD China (to attend
SCCM’s 41st Congress).

Dr. Randolph consulted for Eisai Pharmaceuticals and Discovery Labs.

Dr. Reinhart consulted for EISAI (Steering Committee member - less then US $10,000);
BRAHMS Diagnostics (Less than US $10,000); and SIRS-Lab Jena (founding member, less than
US $10,000). He received honararia 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 (~ US
$100,000).

Dr. Rello consulted for Intercell (board member); Pasteur-Sanofi, Polyphor and Roche.. He has
received grant support from Intercell and Jansen -Cilag. He also received income from Pfizer
(lectures) and Wyeth and Pfizer (development of educational presentations).

Dr. Resende received monetary support from Edwards Life Sciences Brazil (development of
educational presentation). He is the primary author of a scientific paper about epidemiology of
severe sepsis in the emergency department.

Dr. Rhodes consulted for Eli Lilly- monetary compensation paid to himself as well as his
instritution (Steering Committee for the PROWESS Shock trial) and LiDCO.
Travel/accommodation reimbursement 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,
andbelieves in the concept of minimally invasive hemodynamic monitoring.

Dr. Rivers consulted for AstraZeneca ($2,000); bioMerieux ($1,000); Aggenix ($1,500); Idaho
Technologies ($1000), Massimo ($1000), Phillips Electronics ($500), Edwards Life Sciences (no
money was received); Institute of Medicine, National Academies of Sciences (consulted to the

159
U.S. Government on health affairs); Eisai Pharma ($1,500). His institution received grant support
from Biosite, Inc (biomarkers in sepsis $120,000); Edwards Life Sciences (Inflammation of
sepsis $150,000); National Institutes of Health (community-acquired sepsis $500,000);
Aggennix-telactoferin in sepsis $50,000); Hutchinsons Technologies (NIRS in the triage of ED
patients [co-investigator] $150,000); Innverness (biomarker for renal failure-$90,000 for one
year). He received honoraria from Edwards Lifesciences, Elan Pharmaceuticals ($1,500); Merck
($4,000); and Eli Lilly. He owns the rights to a patent for venous oximetry (never received re-
numeration or royalties). He is the co-investigator on the following studies: cortisol levels in
sepsis; telactoferrin in sepsis; observational study of SSC implementation; procalcitonin in
sepsis; and markers of renal failure. Additionally, he is on the Quality and Safety Board for
Catholic Health Partners East.

Dr. Rubenfeld received grant support from non-profit 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); Simens ($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, 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.

Ms. Schorr reports travel support from the Society of Critical Care Medicine (Faculty member of
SSC Phase III). is a coauthor of a prospective cohort study of 15,022 patients studying an
intervention to facilitate compliance with the SSC guidelines (specifically SSC bundle
performance improvement). She is the coauthor of a multicenter study of early lactate clearance
as a determinant of survival in patients with presumed sepsis.

Dr. Sevransky reports 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. Shukri disclosed that he has no potential conflicts of interest.

Dr. Silva consulted for MSD ($3,000).

Dr. Soth received honoraria from Wyeth ($2,000 resident review).

Dr. Sprung reports 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 (<$1,000). His institution receives

160
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 also 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 NICE SUGAR 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.

Dr. Thompson disclosed that she has no potential conflicts of interest.

Dr. Townsend is an advocate for Healthcare Quality Improvement.

Dr. Vender receives honoraria and consulting income from Edwards Lifesciences and Hospira
(lectures on hemodynamic monitoring and for consulting on new technologies).

Dr. Vincent reports consulting income paid to his institution from Astellas; AstraZeneca;
Curacyte; Eli Lilly; Eisai; Ferring; GlaxoSmithKline; Merck; and Pfizer. His institution received
honoraria on his behalf from Astellas; AstraZeneca; Curacyte; Eli Lilly; Eisai; Ferring; Merck;
and Pfizer. His institution received grant support from Astellas; Curacyte; Eli Lilly; Eisai;
Ferring; and Pfizer. His institution received payment for educational presentations from Astellas;
AstraZeneca; Curacyte; Eli Lilly; Eisai; Ferring; Merck; and Pfizer.

Dr. Webb consulted for AstraZeneca (anti-infectives $1,000-$5,000) and Jansen-Cilag (ani-
infectives $1,000-$5,000). He received grant support 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 versus 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 betalactam 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). Received travel/accommodations reimbursed from
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. Welte consulted for Novartis; MSD; Bayer; AstraZeneca; Astellas; and Pfizer. His institution
received grant support from Novartis and Bayer. He received honoraria from Intercell, Pari (Data
Monitoring Board), GlaxoSmithKline, Nycomed, Novartis (COPD) and MED Update (Pneumo
and ICU Update development).

Dr. Zimmerman disclosed that she has no potential conflicts of interest.

161
162
Online Appendix B

Supplemental Bibliography

Observational studies showing improved outcomes with early quantitative

resuscitation between 2001-2011

1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of

severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
2. Gao F, Melody T, Daniels DF, Giles S, Fox S. 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:R764-70.
3. Sebat F, Johnson D, Musthafa AA, et al. A multidisciplinary community hospital program
for early and rapid resuscitation of shock in nontrauma patients. Chest 2005;127:1729-43.
4. Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based "standard
operating procedure" and outcome in septic shock. Crit Care Med 2006;34:943-9.
5. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple
Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34:1025-32.
6. Trzeciak S, Dellinger RP, Abate NL, et al. Translating research to clinical practice: a 1-year
experience with implementing early goal-directed therapy for septic shock in the emergency
department. Chest 2006;129:225-32.
7. Micek ST, Roubinian N, Heuring T, et al. Before-after study of a standardized hospital
order set for the management of septic shock. Crit Care Med 2006;34:2707-13.
8. Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP. A modified goal-directed protocol
improves clinical outcomes in intensive care unit patients with septic shock: a randomized
controlled trial. Shock 2006;26:551-7.
9. Nguyen HB, Corbett SW, Steele R, et al. Implementation of a bundle of quality indicators
for the early management of severe sepsis and septic shock is associated with decreased
mortality. Crit Care Med 2007;35:1105-12.
10. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical
effectiveness of an emergency department-based early goal-directed therapy protocol for
severe sepsis and septic shock. Chest 2007;132:425-32.
11. El Solh AA, Akinnusi ME, Alsawalha LN, Pineda LA. Outcome of septic shock in older
adults after implementation of the sepsis "bundle". J Am Geriatr Soc 2008;56:272-8.
12. Castro R, Regueira T, Aguirre ML, et al. An evidence-based resuscitation algorithm
applied from the emergency room to the ICU improves survival of severe septic shock. Minerva
Anestesiol 2008;74:223-31.
13. Zambon M, Ceola M, Almeida-de-Castro R, Gullo A, Vincent JL. Implementation of the
Surviving Sepsis Campaign guidelines for severe sepsis and septic shock: we could go faster. J
Crit Care 2008;23:455-60.
14. Zubrow MT, Sweeney TA, Fulda GJ, et al. Improving care of the sepsis patient. Jt Comm J
Qual Patient Saf 2008;34:187-91.

163
15. Focht A, Jones AE, Lowe TJ. Early goal-directed therapy: improving mortality and
morbidity of sepsis in the emergency department. Jt Comm J Qual Patient Saf 2009;35:186-91.
16. Puskarich MA, Marchick MR, Kline JA, Steuerwald MT, Jones AE. One year mortality of
patients treated with an emergency department based early goal directed therapy protocol for
severe sepsis and septic shock: a before and after study. Crit Care 2009;13:R167.
17. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a
multicenter severe sepsis educational program in Spain. Jama 2008;299:2294-303.
18. Girardis M, Rinaldi L, Donno L, et al. 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.
19. Wang JL, Chin CS, Chang MC, et al. Key process indicators of mortality in the
implementation of protocol-driven therapy for severe sepsis. J Formos Med Assoc
2009;108:778-87.
20. Pestana D, Espinosa E, Sanguesa-Molina JR, et al. Compliance with a sepsis bundle and
its effect on intensive care unit mortality in surgical septic shock patients. J Trauma 2010.
21. Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, et al. Impact of the Surviving
Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients:
results of a three-year follow-up quasi-experimental study. Crit Care Med 2010;38:1036-43.
22. Lefrant JY, Muller L, Raillard A, et al. Reduction of the severe sepsis or septic shock
associated mortality by reinforcement of the recommendations bundle: A multicenter study.
Ann Fr Anesth Reanim 2010.
23. Cardoso T, Carneiro AH, Ribeiro O, Teixeira-Pinto A, Costa-Pereira A. Reducing mortality
in severe sepsis with the implementation of a core 6-hour bundle: results from the Portuguese
community-acquired sepsis study (SACiUCI study). Crit Care 2010;14:R83.
24. Crowe CA, Mistry CD, Rzechula K, Kulstad CE. Evaluation of a modified early goal-
directed therapy protocol. Am J Emerg Med 2010;28:689-93.
25. Daniels R, Nutbeam T, McNamara G, Galvin C. The sepsis six and the severe sepsis
resuscitation bundle: a prospective observational cohort study. Emerg Med J 2011;28:507-12.
26. Gurnani PK, Patel GP, Crank CW, et al. Impact of the implementation of a sepsis protocol
for the management of fluid-refractory septic shock: a single-center, before-and-after study.
Clin Ther 2010;32:1285-93.
27. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an
international guideline-based performance improvement program targeting severe sepsis.
Critical Care Medicine 2010;38:367-74.
28. Macredmond R, Hollohan K, Stenstrom R, Nebre R, Jaswal D, Dodek P. Introduction of a
comprehensive management protocol for severe sepsis is associated with sustained
improvements in timeliness of care and survival. Qual Saf Health Care 2010.
29. Coba V, Whitmill M, Mooney R, et al. Resuscitation bundle compliance in severe sepsis
and septic shock: improves survival, is better late than never. J Intensive Care Med 2011.
30. Sivayoham N, Rhodes A, Jaiganesh T, van Zyl Smit N, Elkhodhair S, Krishnanandan S.
Outcomes from implementing early goal-directed therapy for severe sepsis and septic shock : a
4-year observational cohort study. Eur J Emerg Med 2011.

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31. Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Ortiz F, Llorca J, Delgado-
Rodriguez M. Late compliance with the sepsis resuscitation bundle: impact on mortality. Shock
2011;36:542-7.
32. Schramm GE, Kashyap R, Mullon JJ, Gajic O, Afessa B. Septic shock: A multidisciplinary
response team and weekly feedback to clinicians improve the process of care and mortality. Crit
Care Med 2011;39:252-8.
33. Nguyen HB, Kuan WS, Batech M, et al. Outcome effectiveness of the severe sepsis
resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national
evaluation. Crit Care 2011;15:R229.
34. Shiramizo SC, Marra AR, Durao MS, Paes AT, Edmond MB, Pavao dos Santos OF.
Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle
in a hospital setting. PLoS ONE 2011;6:e26790.
35. Tromp M, Tjan DH, van Zanten AR, et al. The effects of implementation of the Surviving
Sepsis Campaign in the Netherlands. Neth J Med 2011;69:292-8.

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Online Appendix C

Combined topical digestive tract antibiotics (includes chlorhexidine) versus no prophylaxis for mechanical
ventilation > 48 hours
Patients: Adults intubated > 48 hours
Settings: Intensive care unit
Intervention: Topical digestive tract antimicrobials, including chlorhexidine
Comparison: No prophylaxis
Sources: Analysis performed by Mark Nunnally and Steve Opal for Surviving Sepsis Campaign, using following publications:
Liberati A. Cochrane Database of Systematic Reviews 2010 Issue 9; de Smet AMGA. NEJM 2009;360(1):20-3; Chan E. BMJ
2007;334:889-900; Bellisimo-Rodrigues F. Infect Control Hosp Epidemiol 2009;30(10):952-58; Cabov T. Wien Klin Wochenschr
2010;122:397-404; Panchabhai TS. Chest 2009;135:1150-56; Scannapieco FA. Crit Care 2009;13(4):R117;Tantipong H. Infect
Control Hosp Epidemiol 2008;29(2):131-6.
Outcomes Illustrative comparative risks Relative No of Quality of the Comments
(95% CI) effect Participants evidence
Assumed Corresponding risk (95% CI) (studies) (GRADE)
risk
Control Topical
antimicrobials
Overall mortality, all studies 269 per 266 per 1000 RR 0.99 8530 ⊕⊕⊕⊝
1000 (250 to 285) (0.93 to (25 studies) moderate1,2,3
1.06)
Overall mortality - 178 per 188 per 1000 RR 1.06 2853 ⊕⊕⊕⊝
chlorhexidine v no 1000 (164 to 215) (0.92 to (11 studies) moderate2,3,4
prophylaxis 1.21)
Overall mortality - topical 313 per 303 per 1000 RR 0.97 5677 ⊕⊕⊕⊝
antibiotics v no prophylaxis 1000 (281 to 328) (0.9 to 1.05) (14 studies) moderate2,3,5
Respiratory tract infection 221 per 124 per 1000 RR 0.56 4588 ⊕⊕⊕⊝
all studies 1000 (99 to 152) (0.45 to (23 studies) moderate2,6
0.69)
Respiratory tract infection - 156 per 100 per 1000 RR 0.64 2853 ⊕⊕⊕⊝
Chlorhexidine v no prophylaxis 1000 (80 to 127) (0.51 to (11 studies) moderate2,7
0.81)
Respiratory tract infection - 321 per 154 per 1000 RR 0.48 1735 ⊕⊕⊕⊝
Topical antibiotic v no 1000 (106 to 218) (0.33 to (12 studies) moderate2,8
prophylaxis 0.68)
*The assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) 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
1
I squared = 0%; test for subgroup differences, I squared = 15%.
2
Patient population includes all critically ill patients, not just septic patients.
3
Several studies suggest harm, but we did not lower the quality of evidence for imprecision.
4
I squared = 11% (p = 0.34).
5
I squared = 0%.
6
I squared = 52% (p = 0.002). Test for subgroup differences, I squared = 46.6% (p = 0.17). We did not lower for heterogeneity,
because the issue is only the degree of benefit.
7
I squared = 20% (p = 0.26).
8
I squared = 68% (p = 0.0003). We did not lower for heterogeneity, because the issue is only the degree of benefit.

166
Online Appendix D

Low dose long term glucocorticosteroids for severe sepsis and septic shock
Patient or population: Patients with severe sepsis and septic shock
Settings: Intensive care unit
Intervention: Low dose long term glucocorticosteroids
Comparison: No corticosteroid
Sources: Analysis performed by Herwig Gerlach for the Surviving Sepsis Campaign, using following publication: Patel GP. Am J
Respir Crit Care Med 2012;185:133-9.
Outcomes Illustrative comparative risks Relative No of Quality of the Comments
(95% CI) effect Participants evidence
Assumed Corresponding risk (95% CI) (studies) (GRADE)
risk
Placebo Low dose long term
glucocorticosteroids
Mortality 432 per 394 per 1000 RR 0.91 968 ⊕⊕⊝⊝
Follow-up: mean 28 days 1000 (329 to 467) (0.76 to (6 studies) low1,2
1.08)
Mortality in higher baseline 612 per 471 per 1000 RR 0.77 381 ⊕⊕⊕⊝
mortality studies 1000 (343 to 642) (0.56 to (3 studies) moderate3,4
Follow-up: mean 28 days 1.05)
Mortality in lower baseline 317 per 336 per 1000 RR 1.06 587 ⊕⊕⊕⊝
mortality studies 1000 (270 to 425) (0.85 to (3 studies) moderate5
Follow-up: mean 28 days 1.34)
*The assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) 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
1
Some suggestion of heterogeneity between 3 studies with higher baseline mortality and 3 with lower.
2
Results are not statistically significant and include large benefit and small harm.
3
I squared 31%, but concerns size of benefit and not direction.
4
Imprecision. With the use of fixed effect model RR 0.82 (0.69-0.99).
5
Imprecision as confidence intervals include harm.

167
Online Appendix E
Neuromuscular blocking agents (NMBA) compared to Placebo in patients with Acute Respiratory Distress
Syndrome (ARDS).
Patient or population: Patients with ARDS
Settings: Intensive care unit (ICU)
Intervention: NMBA
Comparison: Placebo
Sources: Analysis performed by Alhazzani, W and Sevransky, J for the Surviving Sepsis Campaign, using following publications:
Papazian L. NEJM 2010;363:1107-16; Gainnier M. Crit Care Med 2004;32:113-9; and Forel JM. Crit Care Med 2006;34:2749-57.
Outcomes Illustrative comparative risks (95% CI) Relative No of Quality of the Comments
Assumed Corresponding risk effect Participants evidence
risk (95% CI) (studies) (GRADE)
Placebo NMBA
Mortality at 28 Study population RR 0.66 431 ⊕⊕⊕⊝
days 389 per 257 per 1000 (0.50 to (3 studies) moderate1,2
1000 (195 to 339) 0.87)

Mortality in the 447 per 313 per 1000 RR 0.70 431 ⊕⊕⊕⊝
ICU 1000 (246 to 398) (0.55 to (3 studies) moderate1,2
0.89)
Ventilator Free The mean ventilator free days in 431 ⊕⊕⊕⊕
Days the intervention groups was (3 studies) high3
Follow-up: 28 days 1.91 higher
(0.28 to 3.55 higher)
ICU acquired 298 per 322 per 1000 RR 1.08 431 ⊕⊕⊝⊝
weakness 1000 (247 to 420) (0.83 to (3 studies) low1,2,4
1.41)
Barotrauma 96 per 41 per 1000 RR 0.43 431 ⊕⊕⊕⊝
1000 (19 to 87) (0.20 to (3 studies) moderate1,2
0.90)
*The assumed risk is the control group risk across studies. The corresponding risk (and its 95% confidence interval) 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
1
Two trials lacked appropriate blinding.
2
Due to small number of available trials we could not assess for publication bias.
3
Ventilator Free Days correlate with survival.
4
Wide confidence interval crossing equivalence and including significant harm.

168
 Online Appendix F
Histamine-2 receptor antagonists (H2RA) compared to placebo or no treatment for prevention of GI bleeding
Patient or population: Critically ill patients
Settings: Intentsive care units
Intervention: H2RA
Comparison: Placebo or no treatment
Source: Prepared by Alhazzani, W and Sprung, C for the Surviving Sepsis Campaign using the following
studies: Marik PE. Crit Care Med 2010;38:2222-8; Leonard J . Am J Gastroenterol 2007;102:2047-56.
Outcomes Illustrative comparative Relative effect No of Quality of the Comments
risks (95% CI) (95% CI) Participants evidence
Assumed Corresponding (studies) (GRADE)
risk risk
Control H2RA
Clinically important GI bleeding (CIB) Low1 Odds Ratio 1836 ⊕⊕⊕⊝
5 per 2 per 1000 (OR) 0.47 (17 studies) moderate2,3,4
1000 (1 to 4) (0.29 to 0.76)

High1
50 per 24 per 1000
1000 (15 to 38)
Overall mortality 164 per 168 per 1000 OR 1.03 1540 ⊕⊕⊕⊝
1000 (132 to 211) (0.78 to 1.37) (14 studies) moderate4,5
Nosocomial (hospital acquired) 114 per 165 per 1000 OR 1.53 1157 ⊕⊕⊕⊝
pneumonia 1000 (103 to 252) (0.89 to 2.61) (9 studies) moderate4,6
Clostridium difficile infection (in studies 50 per 93 per 1000 OR 1.95 18468 ⊕⊝⊝⊝
examining any antisecretory therapy7) 1000 (72 to 120) (1.48 to 2.58) (19 studies) very low7
1
Frequency of clinically important GI bleeding varies (1.5% (observational study, Cook NEJM 1994;330:377), 3.8% (group receiving
sucralfate in Cook NEJM 1998,338:791)). In the first study patients without need for mechanical ventilation for >48h and without
coagulopathy (platelet count <50,000 or INR>1.5 or APTT>2 times normal) had 0.1% risk of bleeding. Other authors list number of
other potential risk factors of less established significance including burn, brain or multiple trauma, hypotension, renal or liver failure,
steroid use, etc.
2
All studies used randomization, most used blinding. Quality of evidence not lowered.
3
Benefits not present in studies using enteral nutrition for all or most of the patients (OR for mortality 1.89 (1.04-3.44, total of 65
events)); for pneumonia OR 2.81 (1.2-6.56, 41 events) and for CIB 1.26 (0.43-3.7, 28 events). We consider this an exploratory finding
and, while lowering the quality of evidence, decided to provide one recommendation. We acknowledge the possibility of a different
interpretation.
4
Most studies are old, and may be of limited applicability today. Quality of Evidence not lowered.
5
Overall no difference, possible harm in studies using enteral nutrition.
6
Unable to exclude harm.
7
From Leonard J, et al. Am J Gastroenterol 2007;102: 2047. Observational studies with indirectness to critically ill patients. The
association was numerically greater for PPI (OR 2.05 (1.47-2.85)) than for H2RA (OR 1.48 (1.06-2.06)) without statistically significant
difference between those two classes of drugs (p=0.17). We did not consider this outcome critical, but we acknowledge the possibility
of a different interpretation.

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Online Appendix G

Proton Pump Inhibitors (PPI) compared to Histamine-2 receptor antagonists (H2RA) for prevention of GI
bleeding
Patient or population: Critically ill patients
Settings: Intensive care units
Intervention: PPI
Comparison: H2RA
Sources: Prepared by Alhazzani, W and Sprung, C for the Surviving Sepsis Campaign using the following studies: Al-Hazzani. Pol
Arch Int Med 2012. Leonard J. Am J Gastroent 2007102:2047-56.
Outcomes Illustrative comparative risks Relative effect No of Quality of the Comments
(95% CI) (95% CI) Participants evidence
Assumed Corresponding risk (studies) (GRADE)
risk
H2RA Proton Pump
Inhibitors (PPI)
Clinically important GI Low Relative Risk 1274 ⊕⊕⊝⊝
bleeding 10 per 4 per 1000 (RR) 0.36 (11 studies) low2,3,4
1000 (2 to 7) (0.19 to 0.67)1

High
50 per 18 per 1000
1000 (10 to 34)
Overall mortality 223 per 223 per 1000 RR 1.00 1007 ⊕⊕⊕⊝
1000 (181 to 275) (0.81 to 1.23) (7 studies) moderate5
Nosocomial pneumonia 105 per 112 per 1000 RR 1.06 1100 ⊕⊕⊕⊝
1000 (77 to 160) (0.73 to 1.52)6 (8 studies) moderate2,7
Clostridium difficile infection 50 per 93 per 1000 Odds Ratio 18468 ⊕⊝⊝⊝8
(in studies examining any 1000 (72 to 120) (OR) 1.95 (19 studies) very low
antisecretory therapy) (1.48 to 2.58)
1
In two recent meta-analyses (Pongprasobchai. J Med Assoc Thai 2009;92:632; Lin. Crit Care Med 2010;38:1197): OR 0.42 (95%
CI 0.2-0.91) and Risk Difference (RD) -4% (95% CI -9 to +1%).
2
Only 3 studies were in low bias risk category. For the remainder, the bias risk was mostly due to unclear blinding and unclear
concealment of randomization. This is less important for mortality (not downgraded for that outcome).
3
High or unknown risk of bias studies (lower quality) provided larger estimate of PPI efficacy than studies of higher quality (RR 0.16
(0.07-0.39)) versus 0.6 (0.27-1.35).
4
Some asymmetry noted; quality of evidence is not lowered.
5
A minority of the studies was in the low bias risk category. Most studies had unclear blinding and concealment of randomization.
6
Two recent meta-analyses (Pongprasobchai 2009; Lin 2010): RD +1% (-9 to +11%), OR 1.02 (0.59-1.75).
7
Imprecision: Wide confidence interval.
8
From Leonard J, et al. Am J Gastroenterol 2007;102: 2047. Observational studies with indirectness to critically ill patientsThe
association was numerically greater for PPI (OR 2.05 (1.47-2.85)) than for H2RA (OR 1.48 (1.06-2.06)) without statistically significant
difference between those two classes of drugs (p=0.17). We did not consider this outcome critical, but we acknowledge the
possibility of a different interpretation.

170
Online Appendix H

Figure 1: Mortality in Clinical Trials of Intensive Insulin Therapy by High or Moderate Control
Groups

171