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Surviving Sepsis Campaign
International Guidelines for Management of
Severe Sepsis and Septic Shock: 2012
Table of Contents
ABSTRACT ....................................................................................................... 580
INTRODUCTION ............................................................................................... 583
METHODOLOGY ............................................................................................... 583
DEFINITIONS ...................................................................................................... 583
HISTORY OF THE GUIDELINES ............................................................................. 583
SELECTION AND ORGANIZATION OF COMMITTEE MEMBERS ................................. 584
SEARCH TECHNIQUES ........................................................................................ 584
GRADING OF RECOMMENDATIONS ...................................................................... 584
CONFLICT OF INTEREST POLICY ......................................................................... 587
MANAGEMENT OF SEVERE SEPSIS................................................................. 587
INITIAL RESUSCITATION AND INFECTION ISSUES .......................................... 587
A. Initial Resuscitation ....................................................................................... 587
B. Screening for Sepsis and Performance Improvement ....................................... 590
C. Diagnosis ..................................................................................................... 590
D. Antimicrobial Therapy .................................................................................... 591
E. Source Control ............................................................................................. 594
F. Infection Prevention ....................................................................................... 594
HEMODYNAMIC SUPPORT AND ADJUNCTIVE THERAPY ................................ 595
G. Fluid Therapy of Severe Sepsis ...................................................................... 595
H. Vasopressors................................................................................................ 597
I. Inotropic Therapy .......................................................................................... 599
J. Corticosteroids ............................................................................................. 599
Surviving Sepsis Campaign
SUPPORTIVE THERAPY OF SEVERE SEPSIS ................................................... 600
K. Blood Production Administration ..................................................................... 600
L. Immunoglobulins ........................................................................................... 601
M. Selenium ...................................................................................................... 601
N. History of Recommendations Regarding Use of
Recombinant Activated Protein C .................................................................... 604
O. Mechanical Ventilation of Sepsis-Induced Respiratory Distress Syndrome ........... 604
P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis ............................ 607
Q. Glucose Control ............................................................................................ 608
R. Renal Replacement Therapy ........................................................................... 609
S. Bicarbonate Therapy ..................................................................................... 610
T. Deep Vein Thrombosis Prophylaxis ................................................................. 610
U. Stress Ulcer Prophylaxis ................................................................................ 611
V. Nutrition ...................................................................................................... 611
W. Setting Goals of Care .................................................................................... 613
PEDIATRIC CONSIDERATIONS IN SEVERE SEPSIS ......................................... 613
A. Initial Resuscitation ........................................................................................ 613
B. Antibiotics and Source Control ....................................................................... 615
C. Fluid Resuscitation ........................................................................................ 615
D. Inotropes/Vasopressors/Vasodilators ............................................................. 617
E. Extracorporeal Membrane Oxygenation (ECMO) ............................................... 618
F. Corticosteroids ............................................................................................. 618
G. Protein C and Activated Protein Concentrate ................................................... 618
H. Blood Products and Plasma Therapies ............................................................ 618
I. Mechanical Ventilation ................................................................................... 618
J. Sedation/Analgesia/Drug Toxicities ................................................................ 618
K. Glycemic Control........................................................................................... 619
L. Diuretics and Renal Replacement Therapy ....................................................... 619
M. Deep Vein Thrombosis (DVT) Prophylaxis ......................................................... 619
N. Stress Ulcer (SU) Prophylaxis ......................................................................... 619
O. Nutrition ....................................................................................................... 619
SUMMARY AND FUTURE DIRECTIONS ............................................................ 619
ACKNOWLEDGMENTS ..................................................................................... 619
REFERENCES................................................................................................... 620
Surviving Sepsis Campaign
International Guidelines for Management
of Severe Sepsis and Septic Shock:
2012 TABLES, FIGURES, and APPENDICES
TABLES
TABLE 1. DIAGNOSTIC CRITERIA FOR SEPSIS ....................................................... 585
TABLE 2. SEVERE SEPSIS .................................................................................. 586
TABLE 3. DETERMINATION OF THE QUALITY OF EVIDENCE ................................... 586
TABLE 4. FACTORS DETERMINING STRONG VS WEAK RECOMMENDATION ............. 587
TABLE 5. RECOMMENDATIONS: INITIAL RESUSCITATION AND
INFECTION ISSUES .............................................................................. 588
TABLE 6. RECOMMENDATIONS: HEMODYNAMIC SUPPORT AND
ADJUNCTIVE THERAPY ......................................................................... 596
TABLE 7. NOREPINEPHRINE COMPARED WITH DOPAMINE IN
SEVERE SEPSIS SUMMARY OF EVIDENCE ............................................. 598
TABLE 8. RECOMMENDATIONS: OTHER SUPPORTIVE THERAPY OF
SEVERE SEPSIS .................................................................................. 602
TABLE 9. RECOMMENDATIONS: SPECIAL CONSIDERATIONS IN PEDIATRICS ........... 614
FIGURES
FIGURE 1. SURVIVING SEPSIS CAMPAIGN BUNDLES.............................................. 591
FIGURE 2. ALGORITHM FOR TIME SENSITIVE, GOAL-DIRECTED
STEPWISE MANAGEMENT OF HEMODYNAMIC SUPPORT
IN INFANTS AND CHILDREN ................................................................. 616
APPENDICES
APPENDIX A: 2012 SURVIVING SEPSIS CAMPAIGN GUIDELINES
COMMITTEE AND PEDIATRIC SUBGROUP.......................................... 635
APPENDIX B: CONFLICT OF INTEREST PROCESS .................................................. 636
APPENDIX C: ARDSNET VENTILATOR MANAGEMENT ............................................. 637
APPENDIX D. SUMMARY OF VENTILATOR PROCEDURES IN THE
HIGHER PEEP GROUPS OF THE ALVEOLI TRIAL ................................. 637
3PECIAL !RTICLES
Surviving Sepsis Campaign: International
Guidelines for Management of Severe Sepsis
and Septic Shock: 2012
R. Phillip Dellinger, MD1; Mitchell M. Levy, MD2; Andrew Rhodes, MB BS3; Djillali Annane, MD4;
Herwig Gerlach, MD, PhD5; Steven M. Opal, MD6; Jonathan E. Sevransky, MD7; Charles L. Sprung, MD8;
Ivor S. Douglas, MD9; Roman Jaeschke, MD10; Tiffany M. Osborn, MD, MPH11; Mark E. Nunnally, MD12;
Sean R. Townsend, MD13; Konrad Reinhart, MD14; Ruth M. Kleinpell, PhD, RN-CS15;
Derek C. Angus, MD, MPH16; Clifford S. Deutschman, MD, MS17; Flavia R. Machado, MD, PhD18;
Gordon D. Rubenfeld, MD19; Steven A. Webb, MB BS, PhD20; Richard J. Beale, MB BS21;
Jean-Louis Vincent, MD, PhD22; Rui Moreno, MD, PhD23; and the Surviving Sepsis Campaign
Guidelines Committee including the Pediatric Subgroup*
Objective: 4O PROVIDE AN UPDATE TO THE h3URVIVING 3EPSIS #AM- Methods: 4HE AUTHORS WERE ADVISED TO FOLLOW THE PRINCIPLES OF THE
PAIGN 'UIDELINES FOR -ANAGEMENT OF 3EVERE 3EPSIS AND 3EPTIC 'RADING OF 2ECOMMENDATIONS !SSESSMENT $EVELOPMENT AND
3HOCK v LAST PUBLISHED IN %VALUATION '2!$% SYSTEM TO GUIDE ASSESSMENT OF QUALITY OF EVI-
Design: ! CONSENSUS COMMITTEE OF INTERNATIONAL EXPERTS REP- DENCE FROM HIGH ! TO VERY LOW $ AND TO DETERMINE THE STRENGTH
RESENTING INTERNATIONAL ORGANIZATIONS WAS CONVENED .OMINAL OF RECOM MENDATIONS AS STRONG OR WEAK 4HE POTENTIAL DRAW-
GROUPS WERE ASSEMBLED AT KEY INTERNATIONAL MEETINGS FOR THOSE BACKS OF MAKING STRONG RECOMMENDATIONS IN THE PRESENCE OF LOW
COMMITTEE MEMBERS ATTENDING THE CONFERENCE ! FORMAL CON- QUALITY EVIDENCE WERE EMPHASIZED 3OME RECOMMENDATIONS WERE
mICT OF INTEREST POLICY WAS DEVELOPED AT THE ONSET OF THE PROCESS UNGRADED 5' 2ECOMMENDATIONS WERE CLASSIlED INTO THREE
AND ENFORCED THROUGHOUT 4HE ENTIRE GUIDELINES PROCESS WAS GROUPS THOSE DIRECTLY TARGETING SEVERE SEPSIS THOSE TARGETING
CONDUCTED INDEPENDENT OF ANY INDUSTRY FUNDING ! STAND
ALONE GENERAL CARE OF THE CRITICALLY ILL PATIENT AND CONSIDERED HIGH PRIORITY IN
MEETING WAS HELD FOR ALL SUBGROUP HEADS CO
AND VICE
CHAIRS SEVERE SEPSIS AND PEDIATRIC CONSIDERATIONS
AND SELECTED INDIVIDUALS 4ELECONFERENCES AND ELECTRONIC
BASED Results: +EY RECOMMENDATIONS AND SUGGESTIONS LISTED BY CAT-
DISCUSSION AMONG SUBGROUPS AND AMONG THE ENTIRE COMMITTEE EGORY INCLUDE EARLY QUANTITATIVE RESUSCITATION OF THE SEPTIC
SERVED AS AN INTEGRAL PART OF THE DEVELOPMENT PATIENT DURING THE lRST HRS AFTER RECOGNITION # BLOOD CULTURES
1
#OOPER 5NIVERSITY (OSPITAL #AMDEN .EW *ERSEY 20
2OYAL 0ERTH (OSPITAL 0ERTH 7ESTERN !USTRALIA
2
7ARREN !LPERT -EDICAL 3CHOOL OF "ROWN 5NIVERSITY 0ROVIDENCE 2HODE 21
'UYS AND 3T 4HOMAS (OSPITAL 4RUST ,ONDON 5NITED +INGDOM
)SLAND 22
%RASME 5NIVERSITY (OSPITAL "RUSSELS "ELGIUM
3
3T 'EORGES (OSPITAL ,ONDON 5NITED +INGDOM 23
5#).# (OSPITAL DE 3O *OS #ENTRO (OSPITALAR DE ,ISBOA #ENTRAL
(PITAL 2AYMOND 0OINCAR 'ARCHES &RANCE %0% ,ISBON 0ORTUGAL
5
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-EMBERS OF THE 33# 'UIDELINES #OMMITTEE AND 0EDIATRIC 3UB-
-EMORIAL (OSPITAL OF 2HODE )SLAND 0AWTUCKET 2HODE )SLAND GROUP ARE LISTED IN Appendix A AT THE END OF THIS ARTICLE
7
%MORY 5NIVERSITY (OSPITAL !TLANTA 'EORGIA
3UPPLEMENTAL DIGITAL CONTENT IS AVAILABLE FOR THIS ARTICLE $IRECT 52, CITA-
(ADASSAH (EBREW 5NIVERSITY -EDICAL #ENTER *ERUSALEM )SRAEL
TIONS APPEAR IN THE PRINTED TEXT AND ARE PROVIDED IN THE (4-, AND 0$& VER-
9
$ENVER (EALTH -EDICAL #ENTER $ENVER #OLORADO
SIONS OF THIS ON THE JOURNALS 7EB SITE HTTPJOURNALSLWWCOMCCMJOURNAL
10
-C-ASTER 5NIVERSITY (AMILTON /NTARIO #ANADA
11
"ARNES
*EWISH (OSPITAL 3T ,OUIS -ISSOURI #OMPLETE AUTHOR AND COMMITTEE DISCLOSURES ARE LISTED IN Supplemental
12
5NIVERSITY OF #HICAGO -EDICAL #ENTER #HICAGO )LLINOIS Digital Content 1 HTTPLINKSLWWCOM##-!
13
#ALIFORNIA 0ACIlC -EDICAL #ENTER 3AN &RANCISCO #ALIFORNIA 4HIS ARTICLE IS BEING SIMULTANEOUSLY PUBLISHED IN Critical Care Medicine
&RIEDRICH 3CHILLER 5NIVERSITY *ENA *ENA 'ERMANY AND Intensive Care Medicine
15
2USH 5NIVERSITY -EDICAL #ENTER #HICAGO )LLINOIS &OR ADDITIONAL INFORMATION REGARDING THIS ARTICLE CONTACT 20 $ELLINGER
5NIVERSITY OF 0ITTSBURGH 0ITTSBURGH 0ENNSYLVANIA $ELLINGER
0HIL #OOPER(EALTHEDU
17
0ERELMAN 3CHOOL OF -EDICINE AT THE 5NIVERSITY OF 0ENNSYLVANIA
0HILADELPHIA 0ENNSYLVANIA #OPYRIGHT BY THE 3OCIETY OF #RITICAL #ARE -EDICINE AND THE %URO-
&EDERAL 5NIVERSITY OF 3AO 0AULO 3AO 0AULO "RAZIL PEAN 3OCIETY OF )NTENSIVE #ARE -EDICINE
19
3UNNYBROOK (EALTH 3CIENCES #ENTER 4ORONTO /NTARIO #ANADA DOI: 10.1097/CCM.0b013e31827e83af
580 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
BEFORE ANTIBIOTIC THERAPY # IMAGING STUDIES PERFORMED UNLESS CONTRAINDICATED " A CONSERVATIVE mUID STRATEGY FOR
PROMPTLY TO CONlRM A POTENTIAL SOURCE OF INFECTION 5' ADMIN- PATIENTS WITH ESTABLISHED !2$3 WHO DO NOT HAVE EVIDENCE OF
ISTRATION OF BROAD
SPECTRUM ANTIMICROBIALS THERAPY WITHIN HR OF TISSUE HYPOPERFUSION # PROTOCOLS FOR WEANING AND SEDA-
RECOGNITION OF SEPTIC SHOCK " AND SEVERE SEPSIS WITHOUT SEP- TION ! MINIMIZING USE OF EITHER INTERMITTENT BOLUS SEDATION
TIC SHOCK # AS THE GOAL OF THERAPY REASSESSMENT OF ANTIMI- OR CONTINUOUS INFUSION SEDATION TARGETING SPECIlC TITRATION
CROBIAL THERAPY DAILY FOR DE
ESCALATION WHEN APPROPRIATE " ENDPOINTS " AVOIDANCE OF NEUROMUSCULAR BLOCKERS IF POS-
INFECTION SOURCE CONTROL WITH ATTENTION TO THE BALANCE OF RISKS AND SIBLE IN THE SEPTIC PATIENT without !2$3 # A SHORT COURSE
BENElTS OF THE CHOSEN METHOD WITHIN HRS OF DIAGNOSIS # OF NEUROMUSCULAR BLOCKER NO LONGER THAN HRS FOR PATIENTS
INITIAL mUID RESUSCITATION WITH CRYSTALLOID " AND CONSIDERATION with EARLY !2$3 AND A 0AO2&IO2 MM (G # A PROTO-
OF THE ADDITION OF ALBUMIN IN PATIENTS WHO CONTINUE TO REQUIRE COLIZED APPROACH TO BLOOD GLUCOSE MANAGEMENT COMMENCING
SUBSTANTIAL AMOUNTS OF CRYSTALLOID TO MAINTAIN ADEQUATE MEAN INSULIN DOSING WHEN TWO CONSECUTIVE BLOOD GLUCOSE LEVELS ARE
ARTERIAL PRESSURE # AND THE AVOIDANCE OF HETASTARCH FORMULA- MGD, TARGETING AN UPPER BLOOD GLUCOSE MGD,
TIONS # INITIAL mUID CHALLENGE IN PATIENTS WITH SEPSIS
INDUCED ! EQUIVALENCY OF CONTINUOUS VENO
VENOUS HEMOlLTRATION OR
TISSUE HYPOPERFUSION AND SUSPICION OF HYPOVOLEMIA TO ACHIEVE A INTERMITTENT HEMODIALYSIS " PROPHYLAXIS FOR DEEP VEIN THROM-
MINIMUM OF M,KG OF CRYSTALLOIDS MORE RAPID ADMINISTRATION BOSIS " USE OF STRESS ULCER PROPHYLAXIS TO PREVENT UPPER
AND GREATER AMOUNTS OF mUID MAY BE NEEDED IN SOME PATIENTS GASTROINTESTINAL BLEEDING IN PATIENTS WITH BLEEDING RISK FACTORS
# mUID CHALLENGE TECHNIQUE CONTINUED AS LONG AS HEMODY- " ORAL OR ENTERAL IF NECESSARY FEEDINGS AS TOLERATED RATHER
NAMIC IMPROVEMENT AS BASED ON EITHER DYNAMIC OR STATIC VARI- THAN EITHER COMPLETE FASTING OR PROVISION OF ONLY INTRAVENOUS
ABLES 5' NOREPINEPHRINE AS THE lRST
CHOICE VASOPRESSOR TO GLUCOSE WITHIN THE lRST HRS AFTER A DIAGNOSIS OF SEVERE SEP-
MAINTAIN MEAN ARTERIAL PRESSURE MM (G " EPINEPHRINE SISSEPTIC SHOCK # AND ADDRESSING GOALS OF CARE INCLUDING
WHEN AN ADDITIONAL AGENT IS NEEDED TO MAINTAIN ADEQUATE BLOOD TREATMENT PLANS AND END
OF
LIFE PLANNING AS APPROPRIATE "
PRESSURE " VASOPRESSIN 5MIN CAN BE ADDED TO NOR- AS EARLY AS FEASIBLE BUT WITHIN HRS OF INTENSIVE CARE UNIT
EPINEPHRINE TO EITHER RAISE MEAN ARTERIAL PRESSURE TO TARGET OR ADMISSION # 2ECOMMENDATIONS SPECIlC TO PEDIATRIC SEVERE
TO DECREASE NOREPINEPHRINE DOSE BUT SHOULD NOT BE USED AS SEPSIS INCLUDE THERAPY WITH FACE MASK OXYGEN HIGH mOW NASAL
THE INITIAL VASOPRESSOR 5' DOPAMINE IS NOT RECOMMENDED CANNULA OXYGEN OR NASOPHARYNGEAL CONTINUOUS 0%%0 IN THE
EXCEPT IN HIGHLY SELECTED CIRCUMSTANCES # DOBUTAMINE PRESENCE OF RESPIRATORY DISTRESS AND HYPOXEMIA # USE OF
INFUSION ADMINISTERED OR ADDED TO VASOPRESSOR IN THE PRESENCE PHYSICAL EXAMINATION THERAPEUTIC ENDPOINTS SUCH AS CAPILLARY
OF A MYOCARDIAL DYSFUNCTION AS SUGGESTED BY ELEVATED CARDIAC RElLL # FOR SEPTIC SHOCK ASSOCIATED WITH HYPOVOLEMIA THE
lLLING PRESSURES AND LOW CARDIAC OUTPUT OR B ONGOING SIGNS USE OF CRYSTALLOIDS OR ALBUMIN TO DELIVER A BOLUS OF M,KG
OF HYPOPERFUSION DESPITE ACHIEVING ADEQUATE INTRAVASCULAR VOL- OF CRYSTALLOIDS OR ALBUMIN EQUIVALENT OVER TO MINS #
UME AND ADEQUATE MEAN ARTERIAL PRESSURE # AVOIDING USE MORE COMMON USE OF INOTROPES AND VASODILATORS FOR LOW CARDIAC
OF INTRAVENOUS HYDROCORTISONE IN ADULT SEPTIC SHOCK PATIENTS IF OUTPUT SEPTIC SHOCK ASSOCIATED WITH ELEVATED SYSTEMIC VASCULAR
ADEQUATE mUID RESUSCITATION AND VASOPRESSOR THERAPY ARE ABLE RESISTANCE # AND USE OF HYDROCORTISONE ONLY IN CHILDREN WITH
TO RESTORE HEMODYNAMIC STABILITY # HEMOGLOBIN TARGET OF SUSPECTED OR PROVEN hABSOLUTEv@ ADRENAL INSUFlCIENCY #
n GD, IN THE ABSENCE OF TISSUE HYPOPERFUSION ISCHEMIC Conclusions: 3TRONG AGREEMENT EXISTED AMONG A LARGE COHORT
CORONARY ARTERY DISEASE OR ACUTE HEMORRHAGE " LOW TIDAL OF INTERNATIONAL EXPERTS REGARDING MANY LEVEL RECOMMENDA-
VOLUME ! AND LIMITATION OF INSPIRATORY PLATEAU PRESSURE " TIONS FOR THE BEST CARE OF PATIENTS WITH SEVERE SEPSIS !LTHOUGH
FOR ACUTE RESPIRATORY DISTRESS SYNDROME !2$3 APPLICATION OF A SIGNIFICANT NUMBER OF ASPECTS OF CARE HAVE RELATIVELY WEAK
AT LEAST A MINIMAL AMOUNT OF POSITIVE END
EXPIRATORY PRESSURE SUPPORT EVIDENCE
BASED RECOMMENDATIONS REGARDING THE
0%%0 IN !2$3 " HIGHER RATHER THAN LOWER LEVEL OF 0%%0 ACUTE MANAGEMENT OF SEPSIS AND SEPTIC SHOCK ARE THE FOUNDA-
FOR PATIENTS WITH SEPSIS
INDUCED MODERATE OR SEVERE !2$3 TION OF IMPROVED OUTCOMES FOR THIS IMPORTANT GROUP OF CRITICALLY
# RECRUITMENT MANEUVERS IN SEPSIS PATIENTS WITH SEVERE ILL PATIENTS Crit Care Med n
REFRACTORY HYPOXEMIA DUE TO !2$3 # PRONE POSITIONING IN Key Words: EVIDENCE
BASED MEDICINE 'RADING OF 2ECOMMENDATIONS
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INDUCED !2$3 PATIENTS WITH A 0A/2&I/2 RATIO OF 100 !SSESSMENT $EVELOPMENT AND %VALUATION CRITERIA GUIDELINES
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3PONSORING ORGANIZATIONS !MERICAN !SSOCIATION OF #RITICAL
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OF %MERGENCY 0HYSICIANS !MERICAN 4HORACIC 3OCIETY !SIA 0ACIlC -EDICINE *APANESE 3OCIETY OF )NTENSIVE #ARE -EDICINE 0EDIATRIC !CUTE
!SSOCIATION OF #RITICAL #ARE -EDICINE !USTRALIAN AND .EW :EALAND ,UNG )NJURY AND 3EPSIS )NVESTIGATORS 3OCIETY FOR !CADEMIC %MERGENCY
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S METHODOLOGY
epsis is a systemic, deleterious host response to infection
leading to severe sepsis (acute organ dysfunction second-
ary to documented or suspected infection) and septic Definitions
shock (severe sepsis plus hypotension not reversed with fluid Sepsis is defined as the presence (probable or documented) of
resuscitation). Severe sepsis and septic shock are major health- infection together with systemic manifestations of infection.
care problems, affecting millions of people around the world Severe sepsis is defined as sepsis plus sepsis-induced organ
each year, killing one in four (and often more), and increasing dysfunction or tissue hypoperfusion (Tables 1 and 2) (6).
in incidence (15). Similar to polytrauma, acute myocardial Throughout this manuscript and the performance improve-
infarction, or stroke, the speed and appropriateness of therapy ment bundles, which are included, a distinction is made
administered in the initial hours after severe sepsis develops between definitions and therapeutic targets or thresholds. Sep-
are likely to influence outcome. sis-induced hypotension is defined as a systolic blood pressure
The recommendations in this document are intended to (SBP) < 90 mm Hg or mean arterial pressure (MAP) < 70 mm
provide guidance for the clinician caring for a patient with Hg or a SBP decrease > 40 mm Hg or less than two standard
severe sepsis or septic shock. Recommendations from these deviations below normal for age in the absence of other causes
guidelines cannot replace the clinicians decision-making capa- of hypotension. An example of a therapeutic target or typical
bility when he or she is presented with a patients unique set of threshold for the reversal of hypotension is seen in the sepsis
clinical variables. Most of these recommendations are appro- bundles for the use of vasopressors. In the bundles, the MAP
priate for the severe sepsis patient in the ICU and non-ICU set- threshold is 65 mm Hg. The use of definition vs. threshold will
tings. In fact, the committee believes that the greatest outcome be evident throughout this article. Septic shock is defined as
improvement can be made through education and process sepsis-induced hypotension persisting despite adequate fluid
change for those caring for severe sepsis patients in the non- resuscitation. Sepsis-induced tissue hypoperfusion is defined
ICU setting and across the spectrum of acute care. Resource as infection-induced hypotension, elevated lactate, or oliguria.
limitations in some institutions and countries may prevent
physicians from accomplishing particular recommendations. History of the Guidelines
Thus, these recommendations are intended to be best practice These clinical practice guidelines are a revision of the 2008
(the committee considers this a goal for clinical practice) and SSC guidelines for the management of severe sepsis and septic
not created to represent standard of care. The Surviving Sepsis shock (7). The initial SSC guidelines were published in 2004
Campaign (SSC) Guidelines Committee hopes that over time, (8) and incorporated the evidence available through the end
particularly through education programs and formal audit of 2003. The 2008 publication analyzed evidence available
and feedback performance improvement initiatives, the guide- through the end of 2007. The most current iteration is based
lines will influence bedside healthcare practitioner behavior on updated literature search incorporated into the evolving
that will reduce the burden of sepsis worldwide. manuscript through fall 2012.
#RITICAL #ARE -EDICINE www.ccmjournal.org 583
Dellinger et al
Selection and Organization of Committee Members Grading of Recommendations
The selection of committee members was based on inter- We advised the authors to follow the principles of the Grading
est and expertise in specific aspects of sepsis. Co-chairs and of Recommendations Assessment, Development and Evalua-
executive committee members were appointed by the Society tion (GRADE) system to guide assessment of quality of evi-
of Critical Care Medicine and European Society of Intensive dence from high (A) to very low (D) and to determine the
Care Medicine governing bodies. Each sponsoring organiza- strength of recommendations (Tables 3 and 4). (911). The
tion appointed a representative who had sepsis expertise. Addi- SSC Steering Committee and individual authors collaborated
tional committee members were appointed by the co-chairs with GRADE representatives to apply the system during the
and executive committee to create continuity with the previous SSC guidelines revision process. The members of the GRADE
committees membership as well as to address content needs group were directly involved, either in person or via e-mail, in
for the development process. Four clinicians with experience all discussions and deliberations among the guidelines com-
in the GRADE process application (referred to in this docu- mittee members as to grading decisions.
ment as GRADE group or Evidence-Based Medicine [EBM] The GRADE system is based on a sequential assessment of
group) took part in the guidelines development. the quality of evidence, followed by assessment of the balance
The guidelines development process began with appoint- between the benefits and risks, burden, and cost, leading to
ment of group heads and assignment of committee members development and grading of a management recommendation.
to groups according to their specific expertise. Each group was Keeping the rating of quality of evidence and strength of
responsible for drafting the initial update to the 2008 edition recommendation explicitly separate constitutes a crucial and
in their assigned area (with major additional elements of infor- defining feature of the GRADE approach. This system classifies
mation incorporated into the evolving manuscript through quality of evidence as high (grade A), moderate (grade B), low
year-end 2011 and early 2012). (grade C), or very low (grade D). Randomized trials begin
With input from the EBM group, an initial group meet- as high-quality evidence but may be downgraded due to
ing was held to establish procedures for literature review and limitations in implementation, inconsistency, or imprecision of
development of tables for evidence analysis. Committees and the results, indirectness of the evidence, and possible reporting
their subgroups continued work via phone and the Internet. bias (Table 3). Examples of indirectness of the evidence
Several subsequent meetings of subgroups and key indi- include population studied, interventions used, outcomes
viduals occurred at major international meetings (nominal measured, and how these relate to the question of interest.
groups), with work continuing via teleconferences and elec- Well-done observational (nonrandomized) studies begin as
tronic-based discussions among subgroups and members low-quality evidence, but the quality level may be upgraded on
of the entire committee. Ultimately, a meeting of all group the basis of a large magnitude of effect. An example of this is
heads, executive committee members, and other key commit- the quality of evidence for early administration of antibiotics.
tee members was held to finalize the draft document for sub- References to supplemental digital content appendices of
mission to reviewers. GRADEpro Summary of Evidence Tables appear throughout
this document.
Search Techniques The GRADE system classifies recommendations as strong
A separate literature search was performed for each clearly (grade 1) or weak (grade 2). The factors influencing this deter-
defined question. The committee chairs worked with subgroup mination are presented in Table 4. The assignment of strong
heads to identify pertinent search terms that were to include, or weak is considered of greater clinical importance than a
at a minimum, sepsis, severe sepsis, septic shock, and sepsis syn- difference in letter level of quality of evidence. The commit-
drome crossed against the subgroups general topic area, as well tee assessed whether the desirable effects of adherence would
as appropriate key words of the specific question posed. All outweigh the undesirable effects, and the strength of a rec-
questions used in the previous guidelines publications were ommendation reflects the groups degree of confidence in
searched, as were pertinent new questions generated by gen- that assessment. Thus, a strong recommendation in favor of
eral topic-related searches or recent trials. The authors were an intervention reflects the panels opinion that the desirable
specifically asked to look for existing meta-analyses related to effects of adherence to a recommendation (beneficial health
their question and search a minimum of one general database outcomes; lesser burden on staff and patients; and cost sav-
(ie, MEDLINE, EMBASE) and the Cochrane Library (both ings) will clearly outweigh the undesirable effects (harm to
The Cochrane Database of Systematic Reviews [CDSR] and health; more burden on staff and patients; and greater costs).
Database of Abstracts of Reviews of Effectiveness [DARE]). The potential drawbacks of making strong recommenda-
Other databases were optional (ACP Journal Club, Evidence- tions in the presence of low-quality evidence were taken into
Based Medicine Journal, Cochrane Registry of Controlled account. A weak recommendation in favor of an intervention
Clinical Trials, International Standard Randomized Controlled indicates the judgment that the desirable effects of adherence
Trial Registry [http://www.controlled-trials.com/isrctn/] or to a recommendation probably will outweigh the undesirable
metaRegister of Controlled Trials [http://www.controlled- effects, but the panel is not confident about these tradeoffs
trials.com/mrct/]. Where appropriate, available evidence was either because some of the evidence is low quality (and thus
summarized in the form of evidence tables. uncertainty remains regarding the benefits and risks) or the
584 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
TABLE 1. Diagnostic Criteria for Sepsis
Infection, documented or suspected, and some of the following:
General variables
Fever (> 38.3C)
Hypothermia (core temperature < 36C)
Heart rate > 90/min1 or more than two SD above the normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (> 20 mL/kg over 24 hr)
Hyperglycemia (plasma glucose > 140 mg/dL or 7.7 mmol/L) in the absence of diabetes
Inflammatory variables
Leukocytosis (WBC count > 12,000 L1)
Leukopenia (WBC count < 4000 L1)
Normal WBC count with greater than 10% immature forms
Plasma C-reactive protein more than two SD above the normal value
Plasma procalcitonin more than two 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 less than two 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 mol/L
Coagulation abnormalities (INR > 1.5 or aPTT > 60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count < 100,000 L1)
Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL or 70 mol/L)
Tissue perfusion variables
Hyperlactatemia (> 1 mmol/L)
Decreased capillary refill or mottling
7"# WHITE BLOOD CELL 3"0 SYSTOLIC BLOOD PRESSURE -!0 MEAN ARTERIAL PRESSURE ).2 INTERNATIONAL NORMALIZED RATIO A044 ACTIVATED PARTIAL THROMBOPLASTIN
TIME
$IAGNOSTIC CRITERIA FOR SEPSIS IN THE PEDIATRIC POPULATION ARE SIGNS AND SYMPTOMS OF INmAMMATION PLUS INFECTION WITH HYPER OR HYPOTHERMIA RECTAL TEMPERATURE
OR # 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
!DAPTED FROM ,EVY -- &INK -0 -ARSHALL *# ET AL 3##-%3)#-!##0!433)3 )NTERNATIONAL 3EPSIS $ElNITIONS #ONFERENCE Crit Care Med
n
benefits and downsides are closely balanced. A strong recom- The implications of calling a recommendation strong
mendation is worded as we recommend and a weak recom- are that most well-informed patients would accept that
mendation as we suggest. intervention and that most clinicians should use it in most
Throughout the document are a number of statements situations. Circumstances may exist in which a strong rec-
that either follow graded recommendations or are listed as ommendation cannot or should not be followed for an
stand-alone numbered statements followed by ungraded individual because of that patients preferences or clinical
in parentheses (UG). In the opinion of the committee, characteristics that make the recommendation less applica-
these recommendations were not conducive for the GRADE ble. A strong recommendation does not automatically imply
process. standard of care. For example, the strong recommendation
#RITICAL #ARE -EDICINE www.ccmjournal.org 585
Dellinger et al
TABLE 2. Severe Sepsis
Severe sepsis definition = sepsis-induced tissue hypoperfusion or organ dysfunction (any of the
following thought to be due to the infection)
Sepsis-induced hypotension
Lactate above upper limits laboratory normal
Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
Acute lung injury with PaO2/FIO2 < 250 in the absence of pneumonia as infection source
Acute lung injury with PaO2/FIO2 < 200 in the presence of pneumonia as infection source
Creatinine > 2.0 mg/dL (176.8 mol/L)
Bilirubin > 2 mg/dL (34.2 mol/L)
Platelet count < 100,000 L
Coagulopathy (international normalized ratio > 1.5)
!DAPTED FROM ,EVY -- &INK -0 -ARSHALL *# ET AL 3##-%3)#-!##0!433)3 )NTERNATIONAL 3EPSIS $ElNITIONS #ONFERENCE Crit Care Med
n
for administering antibiotics within 1 hr of the diagnosis were available for advice throughout the process. Subgroups
of severe sepsis, as well as the recommendation for achiev- agreed electronically on draft proposals that were then
ing a central venous pressure (CVP) of 8 mm Hg and a cen- presented for general discussion among subgroup heads, the
tral venous oxygen saturation (ScVO2) of 70% in the first 6 SSC Steering Committee (two co-chairs, two co-vice chairs,
hrs of resuscitation of sepsis-induced tissue hypoperfusion, and an at-large committee member), and several selected key
although deemed desirable, are not yet standards of care as committee members who met in July 2011 in Chicago. The
verified by practice data. results of that discussion were incorporated into the next
Significant education of committee members on the version of recommendations and again discussed with the
GRADE approach built on the process conducted during 2008 whole group using electronic mail. Draft recommendations
efforts. Several members of the committee were trained in were distributed to the entire committee and finalized during
the use of GRADEpro software, allowing more formal use of an additional nominal group meeting in Berlin in October
the GRADE system (12). Rules were distributed concerning 2011. Deliberations and decisions were then recirculated to the
assessing the body of evidence, and GRADE representatives entire committee for approval. At the discretion of the chairs
TABLE 3. Determination of the Quality of Evidence
Underlying methodology
A (high) RCTs
B (moderate) Downgraded RCTs or upgraded observational studies
C (low) Well-done observational studies with control RCTs
D (very low) Downgraded controlled studies or expert opinion based on other evidence
Factors that may decrease the strength of evidence
1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of bias
2. Inconsistency of results, including problems with subgroup analyses
3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison)
4. Imprecision of results
5. High likelihood of reporting bias
Main factors that may increase the strength of evidence
1. Large magnitude of effect (direct evidence, relative risk > 2 with no plausible confounders)
2. Very large magnitude of effect with relative risk > 5 and no threats to validity (by two levels)
3. Dose-response gradient
2#4 RANDOMIZED CONTROLLED TRIAL
586 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
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 a strong recommendation.
(Is there high or moderate quality
evidence?)
Certainty about the balance of benefits vs. The larger the difference between the desirable and undesirable consequences and
harms and burdens (Is there certainty?) the certainty around that difference, the more likely a strong recommendation. The
smaller the net benefit and the lower the certainty for that benefit, the more likely a
weak recommendation.
Certainty in or similar values The more certainty or similarity in values and preferences, the more likely a strong
(Is there certainty or similarity?) recommendation.
Resource implications The lower the cost of an intervention compared to the alternative and other costs related to
(Are resources worth expected benefits?) the decisionie, fewer resources consumedthe more likely a strong recommendation.
and following discussion, competing proposals for wording they had the least COI. They were required to work within
of recommendations or assigning strength of evidence were their group with full disclosure when a topic for which they
resolved by formal voting within subgroups and at nominal had relevant COI was discussed, and they were not allowed
group meetings. The manuscript was edited for style and form to serve as group head. At the time of final approval of the
by the writing committee with final approval by subgroup document, an update of the COI statement was required. No
heads and then by the entire committee. To satisfy peer review additional COI issues were reported that required further
during the final stages of manuscript approval for publication, adjudication.
several recommendations were edited with approval of the SSC
executive committee group head for that recommendation and MANAGEMENT OF SEVERE SEPSIS
the EBM lead.
Initial Resuscitation and Infection Issues (Table 5)
Conflict of Interest Policy A. Initial Resuscitation
Since the inception of the SSC guidelines in 2004, no members 1. We recommend the protocolized, quantitative resuscitation of
of the committee represented industry; there was no industry patients with sepsis- induced tissue hypoperfusion (defined in
input into guidelines development; and no industry represen- this document as hypotension persisting after initial fluid chal-
tatives were present at any of the meetings. Industry awareness lenge or blood lactate concentration 4 mmol/L). This proto-
or comment on the recommendations was not allowed. No col should be initiated as soon as hypoperfusion is recognized
member of the guidelines committee received honoraria for and should not be delayed pending ICU admission. During the
any role in the 2004, 2008, or 2012 guidelines process. first 6 hrs of resuscitation, the goals of initial resuscitation of
A detailed description of the disclosure process and all sepsis-induced hypoperfusion should include all of the follow-
author disclosures appear in Supplemental Digital Content 1 ing as a part of a treatment protocol (grade 1C):
in the supplemental materials to this document. Appendix B a) CVP 812 mm Hg
shows a flowchart of the COI disclosure process. Committee b) MAP 65 mm Hg
members who were judged to have either financial or nonfi- c) Urine output 0.5 mLkghr
nancial/academic competing interests were recused during the d) Superior vena cava oxygenation saturation (ScvO2) or
closed discussion session and voting session on that topic. Full mixed venous oxygen saturation (SvO2) 70% or 65%,
disclosure and transparency of all committee members poten- respectively.
tial conflicts were sought. 2. We suggest targeting resuscitation to normalize lactate in
On initial review, 68 financial conflict of interest (COI)
patients with elevated lactate levels as a marker of tissue
disclosures and 54 nonfinancial disclosures were submitted
hypoperfusion (grade 2C).
by committee members. Declared COI disclosures from 19
members were determined by the COI subcommittee to be Rationale. In a randomized, controlled, single-center study,
not relevant to the guidelines content process. Nine who early quantitative resuscitation improved survival for emer-
were determined to have COI (financial and nonfinancial) gency department patients presenting with septic shock (13).
were adjudicated by group reassignment and requirement Resuscitation targeting the physiologic goals expressed in rec-
to adhere to SSC COI policy regarding discussion or voting ommendation 1 (above) for the initial 6-hr period was associ-
at any committee meetings where content germane to their ated with a 15.9% absolute reduction in 28-day mortality rate.
COI was discussed. Nine were judged as having conflicts This strategy, termed early goal-directed therapy, was evalu-
that could not be resolved solely by reassignment. One of ated in a multicenter trial of 314 patients with severe sepsis in
these individuals was asked to step down from the commit- eight Chinese centers (14). This trial reported a 17.7% absolute
tee. The other eight were assigned to the groups in which reduction in 28-day mortality (survival rates, 75.2% vs. 57.5%,
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Dellinger et al
p = 0.001). A large number of other observational studies using generally can be relied upon as supporting positive response to
similar forms of early quantitative resuscitation in comparable fluid loading. Either intermittent or continuous measurements
patient populations have shown significant mortality reduction of oxygen saturation were judged to be acceptable. During
compared to the institutions historical controls (Supplemental the first 6 hrs of resuscitation, if ScVO2 less than 70% or SvO2
Digital Content 2, http://links.lww.com/CCM/A615). Phase III equivalent of less than 65% persists with what is judged to be
of the SSC activities, the international performance improve- adequate intravascular volume repletion in the presence of
ment program, showed that the mortality of septic patients persisting tissue hypoperfusion, then dobutamine infusion (to a
presenting with both hypotension and lactate 4 mmol/L was maximum of 20 g/kg/min) or transfusion of packed red blood
46.1%, similar to the 46.6% mortality found in the first trial cited cells to achieve a hematocrit of greater than or equal to 30% in
above (15). As part of performance improvement programs, attempts to achieve the ScvO2 or SvO2 goal are options. The strong
some hospitals have lowered the lactate threshold for triggering recommendation for achieving a CVP of 8 mm Hg and an ScvO2
quantitative resuscitation in the patient with severe sepsis, but of 70% in the first 6 hrs of resuscitation of sepsis-induced tissue
these thresholds have not been subjected to randomized trials. hypoperfusion, although deemed desirable, are not yet the
The consensus panel judged use of CVP and SvO2 targets standard of care as verified by practice data. The publication
to be recommended physiologic targets for resuscitation. of the initial results of the international SSC performance
Although there are limitations to CVP as a marker of improvement program demonstrated that adherence to CVP
intravascular volume status and response to fluids, a low CVP and ScvO2 targets for initial resuscitation was low (15).
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 812 mm Hg
b) Mean arterial pressure (MAP) 65 mm Hg
c) Urine output 0.5 mL/kg/hr
d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C).
2. In patients with elevated lactate levels targeting resuscitation to normalize lactate (grade 2C).
B. Screening for Sepsis and Performance Improvement
1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C).
2. Hospitalbased performance improvement efforts in severe sepsis (UG).
C. Diagnosis
1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s) (grade
1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn
percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted (grade 1C).
2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available and invasive
candidiasis is in differential diagnosis of cause of infection.
3. Imaging studies performed promptly to confirm a potential source of infection (UG).
D. Antimicrobial Therapy
1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe
sepsis without septic shock (grade 1C) as the goal of therapy.
2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or
viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B).
2b. Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B).
3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients
who initially appeared septic, but have no subsequent evidence of infection (grade 2C).
4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, 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).
(Continued)
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TABLE 5. (Continued) Recommendations: Initial Resuscitation and Infection Issues
4b. Empiric combination therapy should not be administered for more than 35 days. De-escalation to the most appropriate single
therapy should be performed as soon as the susceptibility profile is known (grade 2B).
5. Duration of therapy typically 710 days; longer courses may be appropriate in patients who have a slow clinical response,
undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including
neutropenia (grade 2C).
6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C).
7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause
(UG).
E. Source Control
1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or
excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is
made, if feasible (grade 1C).
2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until
adequate demarcation of viable and nonviable tissues has occurred (grade 2B).
3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult
should be used (eg, percutaneous rather than surgical drainage of an abscess) (UG).
4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after
other vascular access has been established (UG).
F. Infection Prevention
1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to
reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care
settings and regions where this methodology is found to be effective (grade 2B).
1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated
pneumonia in ICU patients with severe sepsis (grade 2B).
In mechanically ventilated patients or those with known fluid responsiveness during resuscitation, including flow and
preexisting decreased ventricular compliance, a higher target possibly volumetric indices and microcirculatory changes,
CVP of 12 to 15 mm Hg should be achieved to account for may have advantages (2932). Available technologies allow
the impediment in filling (16). Similar consideration may be measurement of flow at the bedside (33, 34); however, the effi-
warranted in circumstances of increased abdominal pressure cacy of these monitoring techniques to influence clinical out-
(17). Elevated CVP may also be seen with preexisting clini- comes from early sepsis resuscitation remains incomplete and
cally significant pulmonary artery hypertension, making use requires further study before endorsement.
of this variable untenable for judging intravascular volume The global prevalence of severe sepsis patients initially pre-
status. Although the cause of tachycardia in septic patients senting with either hypotension with lactate 4 mmol//L, hypo-
may be multifactorial, a decrease in elevated pulse rate with tension alone, or lactate 4 mmol/L alone, is reported as 16.6%,
fluid resuscitation is often a useful marker of improving intra- 49.5%, and 5.4%, respectively (15). The mortality rate is high in
vascular filling. Published observational studies have dem- septic patients with both hypotension and lactate 4 mmol/L
onstrated an association between good clinical outcome in (46.1%) (15), and is also increased in severely septic patients
septic shock and MAP 65 mm Hg as well as ScvO2 70% with hypotension alone (36.7%) and lactate 4 mmol/L alone
(measured in the superior vena cava, either intermittently or (30%) (15). If ScvO2 is not available, lactate normalization may
continuously [18]). Many studies support the value of early be a feasible option in the patient with severe sepsis-induced
protocolized resuscitation in severe sepsis and sepsis-induced tissue hypoperfusion. ScvO2 and lactate normalization may also
tissue hypoperfusion (1924). Studies of patients with shock be used as a combined endpoint when both are available. Two
indicate that SvO2 runs 5% to 7% lower than ScvO2 (25). While multicenter randomized trials evaluated a resuscitation strat-
the committee recognized the controversy surrounding egy that included lactate reduction as a single target or a tar-
resuscitation targets, an early quantitative resuscitation pro- get combined with ScvO2 normalization (35, 36). The first trial
tocol using CVP and venous blood gases can be readily estab- reported that early quantitative resuscitation based on lactate
lished in both emergency department and ICU settings (26). clearance (decrease by at least 10%) was noninferior to early
Recognized limitations to static ventricular filling pressure quantitative resuscitation based on achieving ScvO2 of 70% or
estimates exist as surrogates for fluid resuscitation (27, 28), but more (35). The intention-to-treat group contained 300, but the
measurement of CVP is currently the most readily obtainable number of patients actually requiring either ScvO2 normalization
target for fluid resuscitation. Targeting dynamic measures of or lactate clearance was small (n = 30). The second trial included
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Dellinger et al
348 patients with lactate levels 3 mmol/L (36). The strategy in 32,000 patient charts gathered from 239 hospitals in 17 countries
this trial was based on a greater than or equal to 20% decrease through September 2011 as part of phase III of the campaign
in lactate levels per 2 hrs of the first 8 hrs in addition to ScvO2 informed the revision of the bundles in conjunction with the
target achievement, and was associated with a 9.6% absolute 2012 guidelines. As a result, for the 2012 version, the management
reduction in mortality (p = 0.067; adjusted hazard ratio, 0.61; bundle was dropped and the resuscitation bundle was broken into
95% CI, 0.430.87; p = 0.006). two parts and modified as shown in Figure 1. For performance
B. Screening for Sepsis and Performance improvement quality indicators, resuscitation target thresholds
Improvement are not considered. However, recommended targets from the
guidelines are included with the bundles for reference purposes.
1. We recommend routine screening of potentially infected
seriously ill patients for severe sepsis to increase the early C. Diagnosis
identification of sepsis and allow implementation of early 1. We recommend obtaining appropriate cultures before anti-
sepsis therapy (grade 1C). microbial therapy is initiated if such cultures do not cause sig-
Rationale. The early identification of sepsis and imple- nificant delay (> 45 minutes) in the start of antimicrobial(s)
mentation of early evidence-based therapies have been doc- administration (grade 1C). To optimize identification of caus-
umented to improve outcomes and decrease sepsis-related ative organisms, we recommend obtaining at least two sets of
mortality (15). Reducing the time to diagnosis of severe sepsis blood cultures (both aerobic and anaerobic bottles) before
is thought to be a critical component of reducing mortality antimicrobial therapy, with at least one drawn percutaneously
from sepsis-related multiple organ dysfunction (35). Lack of and one drawn through each vascular access device, unless
early recognition is a major obstacle to sepsis bundle initiation. the device was recently (< 48 hours) inserted. These blood
Sepsis screening tools have been developed to monitor ICU cultures can be drawn at the same time if they are obtained
patients (3741), and their implementation has been associ- from different sites. Cultures of other sites (preferably quan-
ated with decreased sepsis-related mortality (15). titative where appropriate), such as urine, cerebrospinal fluid,
wounds, respiratory secretions, or other body fluids that may
2. Performance improvement efforts in severe sepsis should be
be the source of infection, should also be obtained before
used to improve patient outcomes (UG).
antimicrobial therapy if doing so does not cause significant
Rationale. Performance improvement efforts in sepsis have delay in antibiotic administration (grade 1C).
been associated with improved patient outcomes (19, 4246).
Improvement in care through increasing compliance with sep- Rationale. Although sampling should not delay timely
sis quality indicators is the goal of a severe sepsis performance administration of antimicrobial agents in patients with severe
improvement program (47). Sepsis management requires a mul- sepsis (eg, lumbar puncture in suspected meningitis), obtain-
tidisciplinary team (physicians, nurses, pharmacy, respiratory, ing appropriate cultures before administration of antimicrobials
dieticians, and administration) and multispecialty collaboration is essential to confirm infection and the responsible pathogens,
(medicine, surgery, and emergency medicine) to maximize the and to allow de-escalation of antimicrobial therapy after receipt
chance for success. Evaluation of process change requires consis- of the susceptibility profile. Samples can be refrigerated or fro-
tent education, protocol development and implementation, data zen if processing cannot be performed immediately. Because
collection, measurement of indicators, and feedback to facilitate rapid sterilization of blood cultures can occur within a few
the continuous performance improvement. Ongoing educational hours after the first antimicrobial dose, obtaining those cultures
sessions provide feedback on indicator compliance and can help before therapy is essential if the causative organism is to be iden-
identify areas for additional improvement efforts. In addition to tified. Two or more blood cultures are recommended (51). In
traditional continuing medical education efforts to introduce patients with indwelling catheters (for more than 48 hrs), at least
guidelines into clinical practice, knowledge translation efforts one blood culture should be drawn through each lumen of each
have recently been introduced as a means to promote the use of vascular access device (if feasible, especially for vascular devices
high-quality evidence in changing behavior (48). Protocol imple- with signs of inflammation, catheter dysfunction, or indicators
mentation associated with education and performance feedback of thrombus formation). Obtaining blood cultures peripherally
has been shown to change clinician behavior and is associated and through a vascular access device is an important strategy. If
with improved outcomes and cost-effectiveness in severe sepsis the same organism is recovered from both cultures, the likeli-
(19, 23, 24, 49). In partnership with the Institute for Healthcare hood that the organism is causing the severe sepsis is enhanced.
Improvement, phase III of the Surviving Sepsis Campaign targeted In addition, if equivalent volumes of blood drawn for cul-
the implementation of a core set (bundle) of recommendations ture and the vascular access device is positive much earlier than
in hospital environments where change in behavior and clinical the peripheral blood culture (ie, more than 2 hrs earlier), the
impact were measured (50). The SSC guidelines and bundles can data support the concept that the vascular access device is the
be used as the basis of a sepsis performance improvement program. source of the infection (36, 51, 52). Quantitative cultures of
Application of the SSC sepsis bundles led to sustained, catheter and peripheral blood may also be useful for determin-
continuous quality improvement in sepsis care and was associated ing whether the catheter is the source of infection. The volume
with reduced mortality (15). Analysis of the data from nearly of blood drawn with the culture tube should be 10 mL (53).
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Special Article
Rationale. The diagnosis of
SURVIVING SEPSIS CAMPAIGN BUNDLES
systemic fungal infection (usu-
TO BE COMPLETED WITHIN 3 HOURS: ally candidiasis) in the critically
1) Measure lactate level ill patient can be challenging,
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics and rapid diagnostic methodolo-
4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L gies, such as antigen and antibody
detection assays, can be helpful in
TO BE COMPLETED WITHIN 6 HOURS:
5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) detecting candidiasis in the ICU
to maintain a mean arterial pressure (MAP) 65 mm Hg patient. These suggested tests have
6) In the event of persistent arterial hypotension despite volume resuscitation (septic
shown positive results significantly
shock) or initial lactate 4 mmol/L (36 mg/dL):
- Measure central venous pressure (CVP)* earlier than standard culture meth-
- Measure central venous oxygen saturation (ScvO2)* ods (6267), but false-positive
7) Remeasure lactate if initial lactate was elevated*
reactions can occur with coloni-
*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg, zation alone, and their diagnostic
ScvO2 of 70%, and normalization of lactate. utility in managing fungal infec-
tion in the ICU needs additional
Figure 1. Surviving Sepsis Campaign Care Bundles.
study (65).
Quantitative (or semiquantitative) cultures of respiratory tract 3. We recommend that imaging studies be performed
secretions are often recommended for the diagnosis of venti- promptly in attempts to confirm a potential source of infec-
lator-associated pneumonia (54), but their diagnostic value tion. Potential sources of infection should be sampled as
remains unclear (55). they are identified and in consideration of patient risk for
The Gram stain can be useful, in particular for respiratory transport and invasive procedures (eg, careful coordination
tract specimens, to determine if inflammatory cells are pres- and aggressive monitoring if the decision is made to trans-
ent (greater than five polymorphonuclear leukocytes/high- port for a CT-guided needle aspiration). Bedside studies,
powered field and less than ten squamous cells/low-powered such as ultrasound, may avoid patient transport (UG).
field) and if culture results will be informative of lower respi-
Rationale. Diagnostic studies may identify a source of
ratory pathogens. Rapid influenza antigen testing during peri-
infection that requires removal of a foreign body or drainage to
ods of increased influenza activity in the community is also
maximize the likelihood of a satisfactory response to therapy.
recommended. A focused history can provide vital informa-
Even in the most organized and well-staffed healthcare facili-
tion about potential risk factors for infection and likely patho-
ties, however, transport of patients can be dangerous, as can
gens at specific tissue sites. The potential role of biomarkers
be placing patients in outside-unit imaging devices that are
for diagnosis of infection in patients presenting with severe
difficult to access and monitor. Balancing risk and benefit is
sepsis remains undefined. The utility of procalcitonin levels or
therefore mandatory in those settings.
other biomarkers (such as C-reactive protein) to discriminate
the acute inflammatory pattern of sepsis from other causes of D. Antimicrobial Therapy
generalized inflammation (eg, postoperative, other forms of 1. The administration of effective intravenous antimicrobials
shock) has not been demonstrated. No recommendation can within the first hour of recognition of septic shock (grade
be given for the use of these markers to distinguish between 1B) and severe sepsis without septic shock (grade 1C)
severe infection and other acute inflammatory states (5658). should be the goal of therapy. Remark: Although the weight
In the near future, rapid, non-culture-based diagnostic meth- of the evidence supports prompt administration of antibi-
ods (polymerase chain reaction, mass spectroscopy, microar- otics following the recognition of severe sepsis and septic
rays) might be helpful for a quicker identification of pathogens shock, the feasibility with which clinicians may achieve this
and major antimicrobial resistance determinants (59). These ideal state has not been scientifically evaluated.
methodologies could be particularly useful for difficult-to-cul-
ture pathogens or in clinical situations where empiric antimi- Rationale. Establishing vascular access and initiating
crobial agents have been administered before culture samples aggressive fluid resuscitation are the first priorities when
were been obtained. Clinical experience remains limited, and managing patients with severe sepsis or septic shock. Prompt
more clinical studies are needed before recommending these infusion of antimicrobial agents should also be a priority and
non-culture molecular methods as a replacement for standard may require additional vascular access ports (68, 69). In the
presence of septic shock, each hour delay in achieving admin-
blood culture methods (60, 61).
istration of effective antibiotics is associated with a measurable
2. We suggest the use of the 1,3 -D-glucan assay (grade 2B), increase in mortality in a number of studies (15, 68, 7072).
mannan and anti-mannan antibody assays (grade 2C) Overall, the preponderance of data support giving antibiot-
when invasive candidiasis is in the differential diagnosis of ics as soon as possible in patients with severe sepsis with or
infection. without septic shock (15, 68, 7077). The administration of
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Dellinger et al
antimicrobial agents with a spectrum of activity likely to treat of amphotericin B) should be tailored to the local pattern of
the responsible pathogen(s) effectively within 1 hr of the diag- the most prevalent Candida species and any recent exposure
nosis of severe sepsis and septic shock. Practical considerations, to antifungal drugs (78). Recent Infectious Diseases Society
for example challenges with clinicians early identification of of America (IDSA) guidelines recommend either fluconazole
patients or operational complexities in the drug delivery chain, or an echinocandin. Empiric use of an echinocandin is pre-
represent unstudied variables that may impact achieving this ferred in most patients with severe illness, especially in those
goal. Future trials should endeavor to provide an evidence base patients who have recently been treated with antifungal agents,
in this regard. This should be the target goal when managing or if Candida glabrata infection is suspected from earlier cul-
patients with septic shock, whether they are located within the ture data. Knowledge of local resistance patterns to antifungal
hospital ward, the emergency department, or the ICU. The agents should guide drug selection until fungal susceptibility
strong recommendation for administering antibiotics within 1 test results, if available, are performed. Risk factors for candi-
hr of the diagnosis of severe sepsis and septic shock, although demia, such as immunosuppressed or neutropenic state, prior
judged to be desirable, is not yet the standard of care as verified intense antibiotic therapy, or colonization in multiple sites,
by published practice data (15). should also be considered when choosing initial therapy.
If antimicrobial agents cannot be mixed and delivered promptly Because patients with severe sepsis or septic shock have little
from the pharmacy, establishing a supply of premixed antibiotics margin for error in the choice of therapy, the initial selection
for such urgent situations is an appropriate strategy for ensuring of antimicrobial therapy should be broad enough to cover all
prompt administration. Many antibiotics will not remain stable if likely pathogens. Antibiotic choices should be guided by local
premixed in a solution. This risk must be taken into consideration prevalence patterns of bacterial pathogens and susceptibility
in institutions that rely on premixed solutions for rapid availabil- data. Ample evidence exists that failure to initiate appropriate
ity of antibiotics. In choosing the antimicrobial regimen, clinicians therapy (ie, therapy with activity against the pathogen that is
should be aware that some antimicrobial agents have the advan- subsequently identified as the causative agent) correlates with
tage of bolus administration, while others require a lengthy infu- increased morbidity and mortality in patients with severe sep-
sion. Thus, if vascular access is limited and many different agents sis or septic shock (68, 71, 79, 80). Recent exposure to anti-
must be infused, bolus drugs may offer an advantage. microbials (within last 3 months) should be considered in
the choice of an empiric antibacterial regimen. Patients with
2a. We recommend that initial empiric anti-infective therapy
severe sepsis or septic shock warrant broad-spectrum therapy
include one or more drugs that have activity against all
until the causative organism and its antimicrobial susceptibili-
likely pathogens (bacterial and/or fungal or viral) and that
ties are defined. Although a global restriction of antibiotics is
penetrate in adequate concentrations into the tissues pre-
an important strategy to reduce the development of antimi-
sumed to be the source of sepsis (grade 1B).
crobial resistance and to reduce cost, it is not an appropri-
Rationale. The choice of empirical antimicrobial therapy ate strategy in the initial therapy for this patient population.
depends on complex issues related to the patients history, However, as soon as the causative pathogen has been identi-
including drug intolerances, recent receipt of antibiotics (previ- fied, de-escalation should be performed by selecting the most
ous 3 months), underlying disease, the clinical syndrome, and appropriate antimicrobial agent that covers the pathogen
susceptibility patterns of pathogens in the community and hos- and is safe and cost-effective. Collaboration with antimicro-
pital, and that previously have been documented to colonize bial stewardship programs, where they exist, is encouraged to
or infect the patient. The most common pathogens that cause ensure appropriate choices and rapid availability of effective
septic shock in hospitalized patients are Gram-positive bac- antimicrobials for treating septic patients. All patients should
teria, followed by Gram-negative and mixed bacterial micro- receive a full loading dose of each agent. Patients with sepsis
organisms. Candidiasis, toxic shock syndromes, and an array often have abnormal and vacillating renal or hepatic function,
of uncommon pathogens should be considered in selected or may have abnormally high volumes of distribution due to
patients. An especially wide range of potential pathogens exists aggressive fluid resuscitation, requiring dose adjustment. Drug
for neutropenic patients. Recently used anti-infective agents serum concentration monitoring can be useful in an ICU set-
should generally be avoided. When choosing empirical therapy, ting for those drugs that can be measured promptly. Significant
clinicians should be cognizant of the virulence and growing expertise is required to ensure that serum concentrations max-
prevalence of oxacillin (methicillin)-resistant Staphylococcus imize efficacy and minimize toxicity (81, 82).
aureus, and resistance to broad-spectrum beta-lactams and car-
2b. The antimicrobial regimen should be reassessed daily for
bapenem among Gram-negative bacilli in some communities
potential de-escalation to prevent the development of resis-
and healthcare settings. Within regions in which the prevalence
tance, to reduce toxicity, and to reduce costs (grade 1B).
of such drug-resistant organisms is significant, empiric therapy
adequate to cover these pathogens is warranted. Rationale. Once the causative pathogen has been identified,
Clinicians should also consider whether candidemia is a the most appropriate antimicrobial agent that covers the pathogen
likely pathogen when choosing initial therapy. When deemed and is safe and cost-effective should be selected. On occasion,
warranted, the selection of empirical antifungal therapy (eg, an continued use of specific combinations of antimicrobials
echinocandin, triazoles such as fluconazole, or a formulation might be indicated even after susceptibility testing is available
592 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
(eg, Pseudomonas spp. only susceptible to aminoglycosides; would include aminoglycoside monotherapy, which should
enterococcal endocarditis; Acinetobacter spp. infections susceptible be generally avoided, particularly for P. aeruginosa sepsis,
only to polymyxins). Decisions on definitive antibiotic choices and for selected forms of endocarditis, where prolonged
should be based on the type of pathogen, patient characteristics, courses of combinations of antibiotics are warranted.
and favored hospital treatment regimens.
Narrowing the spectrum of antimicrobial coverage and Rationale. A propensity-matched analysis, meta-analysis,
reducing the duration of antimicrobial therapy will reduce the and meta-regression analysis, along with additional observa-
likelihood that the patient will develop superinfection with tional studies, have demonstrated that combination therapy
other pathogenic or resistant organisms, such as Candida spe- produces a superior clinical outcome in severely ill, septic
cies, Clostridium difficile, or vancomycin-resistant Enterococcus patients with a high risk of death (8690). In light of the
faecium. However, the desire to minimize superinfections and increasing frequency of resistance to antimicrobial agents
other complications should not take precedence over giving an in many parts of the world, broad-spectrum coverage gen-
adequate course of therapy to cure the infection that caused erally requires the initial use of combinations of antimi-
the severe sepsis or septic shock. crobial agents. Combination therapy used in this context
connotes at least two different classes of antibiotics (usually
3. We suggest the use of low procalcitonin levels or similar a beta-lactam agent with a macrolide, fluoroquinolone, or
biomarkers to assist the clinician in the discontinuation
aminoglycoside for select patients). A controlled trial sug-
of empiric antibiotics in patients who appeared septic, but
gested, however, that when using a carbapenem as empiric
have no subsequent evidence of infection (grade 2C).
therapy in a population at low risk for infection with resis-
Rationale. This suggestion is predicated on the preponder- tant microorganisms, the addition of a fluoroquinolone
ance of the published literature relating to the use of procalcito- does not improve outcomes of patients (85). A number of
nin as a tool to discontinue unnecessary antimicrobials (58, 83). other recent observational studies and some small, pro-
However, clinical experience with this strategy is limited and the spective trials support initial combination therapy for
potential for harm remains a concern (83). No evidence demon- selected patients with specific pathogens (eg, pneumococ-
strates that this practice reduces the prevalence of antimicrobial cal sepsis, multidrug-resistant Gram-negative pathogens)
resistance or the risk of antibiotic-related diarrhea from C. dif- (9193), but evidence from adequately powered, random-
ficile. One recent study failed to show any benefit of daily procal- ized clinical trials is not available to support combination
citonin measurement in early antibiotic therapy or survival (84). over monotherapy other than in septic patients at high risk
4a. Empiric therapy should attempt to provide antimicrobial of death. In some clinical scenarios, combination therapies
activity against the most likely pathogens based upon each are biologically plausible and are likely clinically useful even
patients presenting illness and local patterns of infection. if evidence has not demonstrated improved clinical outcome
We suggest combination empiric therapy for neutropenic (89, 90, 94, 95). Combination therapy for suspected or known
patients with severe sepsis (grade 2B) and for patients with Pseudomonas aeruginosa or other multidrug-resistant Gram-
difficult-to-treat, multidrug-resistant bacterial pathogens negative pathogens, pending susceptibility results, increases
such as Acinetobacter and Pseudomonas spp. (grade 2B). the likelihood that at least one drug is effective against that
For selected patients with severe infections associated with strain and positively affects outcome (88, 96).
respiratory failure and septic shock, combination therapy
5. We suggest that the duration of therapy typically be 7 to 10
with an extended spectrum beta-lactam and either an ami-
days if clinically indicated; longer courses may be appropri-
noglycoside or a fluoroquinolone is suggested for P. aeru-
ginosa bacteremia (grade 2B). Similarly, a more complex ate in patients who have a slow clinical response, undrain-
combination of beta-lactam and a macrolide is suggested able foci of infection, bacteremia with S. aureus; some fungal
for patients with septic shock from bacteremic Streptococ- and viral infections, or immunologic deficiencies, including
cus pneumoniae infections (grade 2B). neutropenia (grade 2C).
Rationale. Complex combinations might be needed in set- Rationale. Although patient factors may influence the length
tings where highly antibiotic-resistant pathogens are preva- of antibiotic therapy, in general, a duration of 7-10 days (in the
lent, with such regimens incorporating carbapenems, colistin, absence of source control issues) is adequate. Thus, decisions to
rifampin, or other agents. However, a recent controlled trial continue, narrow, or stop antimicrobial therapy must be made
suggested that adding a fluoroquinolone to a carbapenem as on the basis of clinician judgment and clinical information. Cli-
empiric therapy did not improve outcome in a population at nicians should be cognizant of blood cultures being negative in
low risk for infection with resistant microorganisms (85). a significant percentage of cases of severe sepsis or septic shock,
4b. We suggest that combination therapy, when used empirically despite the fact that many of these cases are very likely caused
in patients with severe sepsis, should not be administered by bacteria or fungi. Clinicians should be cognizant that blood
for longer than 3 to 5 days. De-escalation to the most appro- cultures will be negative in a significant percentage of cases of
priate single-agent therapy should be performed as soon as severe sepsis or septic shock, despite many of these cases are
the susceptibility profile is known (grade 2B). Exceptions very likely caused by bacteria or fungi.
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Dellinger et al
6. We suggest that antiviral therapy be initiated as early as pos- excluded as rapidly as possible, and intervention be under-
sible in patients with severe sepsis or septic shock of viral taken for source control within the first 12 hr after the diag-
origin (grade 2C). nosis is made, if feasible (grade 1C).
2. We suggest that when infected peripancreatic necrosis is
Rationale. Recommendations for antiviral treatment
identified as a potential source of infection, definitive inter-
include the use of: a) early antiviral treatment of suspected
vention is best delayed until adequate demarcation of viable
or confirmed influenza among persons with severe influenza
and nonviable tissues has occurred (grade 2B).
(eg, those who have severe, complicated, or progressive illness
3. When source control in a severely septic patient is required,
or who require hospitalization); b) early antiviral treatment
the effective intervention associated with the least physi-
of suspected or confirmed influenza among persons at
higher risk for influenza complications; and c) therapy with a ologic insult should be used (eg, percutaneous rather than
neuraminidase inhibitor (oseltamivir or zanamivir) for persons surgical drainage of an abscess) (UG).
with influenza caused by 2009 H1N1 virus, influenza A (H3N2) 4. If intravascular access devices are a possible source
virus, or influenza B virus, or when the influenza virus type or of severe sepsis or septic shock, they should be
influenza A virus subtype is unknown (97, 98). Susceptibility removed promptly after other vascular access has been
to antivirals is highly variable in a rapidly evolving virus such established (UG).
as influenza, and therapeutic decisions must be guided by Rationale. The principles of source control in the manage-
updated information regarding the most active, strain-specific, ment of sepsis include a rapid diagnosis of the specific site of
antiviral agents during influenza epidemics (99, 100). infection and identification of a focus of infection amenable
The role of cytomegalovirus (CMV) and other herpesviruses to source control measures (specifically the drainage of an
as significant pathogens in septic patients, especially those not abscess, debridement of infected necrotic tissue, removal of a
known to be severely immunocompromised, remains unclear. potentially infected device, and definitive control of a source
Active CMV viremia is common (15%35%) in critically ill of ongoing microbial contamination) (105). Foci of infec-
patients; the presence of CMV in the bloodstream has been tion readily amenable to source control measures include an
repeatedly found to be a poor prognostic indicator (101, 102). intra-abdominal abscess or gastrointestinal perforation, chol-
What is not known is whether CMV simply is a marker of dis- angitis or pyelonephritis, intestinal ischemia or necrotizing
ease severity or if the virus actually contributes to organ injury soft tissue infection, and other deep space infection, such as
and death in septic patients (103). No treatment recommen- an empyema or septic arthritis. Such infectious foci should
dations can be given based on the current level of evidence. be controlled as soon as possible following successful initial
In those patients with severe primary or generalized varicella- resuscitation (106108), and intravascular access devices
zoster virus infections, and in rare patients with disseminated that are potentially the source of severe sepsis or septic shock
herpes simplex infections, antiviral agents such as acyclovir should be removed promptly after establishing other sites for
can be highly effective when initiated early in the course of vascular access (109, 110).
infection (104). A randomized, controlled trial (RCT) comparing early
7. We recommend that antimicrobial agents not be used in to delayed surgical intervention for peripancreatic necro-
patients with severe inflammatory states determined to be sis showed better outcomes with a delayed approach (111).
of noninfectious cause (UG). Moreover, a randomized surgical study found that a mini-
mally invasive, step-up approach was better tolerated by
Rationale. When infection is found not to be present, patients and had a lower mortality than open necrosectomy
antimicrobial therapy should be stopped promptly to mini- in necrotizing pancreatitis (112), although areas of uncer-
mize the likelihood that the patient will become infected tainty exist, such as definitive documentation of infection and
with an antimicrobial-resistant pathogen or will develop a appropriate length of delay. The selection of optimal source
drug-related adverse effect. Although it is important to stop control methods must weigh the benefits and risks of the
unnecessary antibiotics early, clinicians should be cogni- specific intervention as well as risks of transfer (113). Source
zant that blood cultures will be negative in more than 50% control interventions may cause further complications, such
of cases of severe sepsis or septic shock if the patients are as bleeding, fistulas, or inadvertent organ injury. Surgical
receiving empiric antimicrobial therapy; yet many of these
intervention should be considered when other interventional
cases are very likely caused by bacteria or fungi. Thus, the
approaches are inadequate or when diagnostic uncertainty
decisions to continue, narrow, or stop antimicrobial therapy
persists despite radiologic evaluation. Specific clinical situa-
must be made on the basis of clinician judgment and clinical
tions require consideration of available choices, the patients
information.
preferences, and the clinicians expertise.
E. Source Control
F. Infection Prevention
1. We recommend that a specific anatomical diagnosis of
infection requiring consideration for emergent source con- 1a. We suggest that selective oral decontamination (SOD)
trol (eg, necrotizing soft tissue infection, peritonitis, chol- and selective digestive decontamination (SDD) should
angitis, intestinal infarction) be sought and diagnosed or be introduced and investigated as a method to reduce the
594 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
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incidence of ventilator-associated pneumonia (VAP); this 3. We suggest the use of albumin in the fluid resuscitation of
infection control measure can then be instituted in health- severe sepsis and septic shock when patients require sub-
care settings and regions where this methodology is found stantial amounts of crystalloids (grade 2C).
to be effective (grade 2B).
Rationale. The absence of any clear benefit following the
1b. We suggest oral chlorhexidine gluconate (CHG) be used administration of colloid solutions compared to crystalloid
as a form of oropharyngeal decontamination to reduce the solutions, together with the expense associated with colloid
risk of VAP in ICU patients with severe sepsis (grade 2B). solutions, supports a high-grade recommendation for the use
of crystalloid solutions in the initial resuscitation of patients
Rationale. Careful infection control practices (eg, hand
with severe sepsis and septic shock.
washing, expert nursing care, catheter care, barrier precau-
Three recent multicenter RCTs evaluating 6% HES
tions, airway management, elevation of the head of the bed,
130/0.4 solutions (tetra starches) have been published. The
subglottic suctioning) should be instituted during the care of
CRYSTMAS study demonstrated no difference in mortality
septic patients as reviewed in the nursing considerations for
with HES vs. 0.9% normal saline (31% vs. 25.3%, p = 0.37)
the Surviving Sepsis Campaign (114). The role of SDD with
in the resuscitation of septic shock patients; however the
systemic antimicrobial prophylaxis and its variants (eg, SOD,
study was underpowered to detect the 6% difference in
CHG) has been a contentious issue ever since the concept was
absolute mortality observed (122). In a sicker patient
first developed more than 30 years ago. The notion of limit-
cohort, a Scandinavian multicenter study in septic patients
ing the acquisition of opportunistic, often multidrug-resistant,
(6S Trial Group) showed increased mortality rates with
healthcare-associated microorganisms has its appeal by pro-
6% HES 130/0.42 fluid resuscitation compared to Ringers
moting colonization resistance from the resident microbi-
acetate (51% vs. 43% p = 0.03) (123). The CHEST study,
ome existing along mucosal surfaces of the alimentary tract.
conducted in a heterogenous population of patients admit-
However, the efficacy of SDD, its safety, propensity to prevent
ted to intensive care (HES vs. isotonic saline, n = 7000
or promote antibiotic resistance, and cost-effectiveness remain
critically ill patients), showed no difference in 90-day mor-
debatable despite a number of favorable meta-analyses and
controlled clinical trials (115). The data indicate an overall tality between resuscitation with 6% HES with a molecular
reduction in VAP but no consistent improvement in mortality, weight of 130 kD/0.40 and isotonic saline (18% vs. 17%,
except in selected populations in some studies. Most studies p = 0.26); the need for renal replacement therapy was higher
do not specifically address the efficacy of SDD in patients who in the HES group (7.0% vs. 5.8%; relative risk [RR], 1.21;
present with sepsis, but some do (116118). 95% confidence interval [CI], 1.001.45; p = 0.04) (124).
Oral CHG is relatively easy to administer, decreases risk of A meta-analysis of 56 randomized trials found no overall
nosocomial infection, and reduces the potential concern over difference in mortality between crystalloids and artificial
promotion of antimicrobial resistance by SDD regimens. This colloids (modified gelatins, HES, dextran) when used for
remains a subject of considerable debate, despite the recent initial fluid resuscitation (125). Information from 3 ran-
evidence that the incidence of antimicrobial resistance does domized trials (n = 704 patients with severe sepsis/septic
not change appreciably with current SDD regimens (119121). shock) did not show survival benefit with use of heta-,
The grade 2B was designated for both SOD and CHG as it hexa-, or pentastarches compared to other fluids (RR, 1.15;
was felt that risk was lower with CHG and the measure better 95% CI, 0.951.39; random effect; I2 = 0%) (126128).
accepted despite less published literature than with SOD. However, these solutions increased the risk of acute kidney
Supplemental Digital Content 3 (http://links.lww.com/ injury (RR, 1.60; 95% CI, 1.262.04; I2 = 0%) (126128).
CCM/A615) shows a GRADEpro Summary of Evidence Table The evidence of harm observed in the 6S and CHEST stud-
for the use of topical digestive tract antibiotics and CHG for ies and the meta-analysis supports a high-level recommen-
prophylaxis against VAP. dation advising against the use of HES solutions in patients
with severe sepsis and septic shock, particularly since other
Hemodynamic Support and Adjunctive Therapy options for fluid resuscitation exist. The CRYSTAL trial,
(Table 6) another large prospective clinical trial comparing crystal-
loids and colloids, was recently completed and will provide
G. Fluid Therapy of Severe Sepsis
additional insight into HES fluid resuscitation.
1. We recommend crystalloids be used as the initial fluid of The SAFE study indicated that albumin administration
choice in the resuscitation of severe sepsis and septic shock was safe and equally as effective as 0.9% saline (129). A
(grade 1B). meta-analysis aggregated data from 17 randomized trials
2. We recommend against the use of hydroxyethyl starches (n = 1977) of albumin vs. other fluid solutions in patients
(HES) for fluid resuscitation of severe sepsis and septic with severe sepsis/septic shock (130); 279 deaths occurred
shock (grade 1B). (This recommendation is based on the among 961 albumin-treated patients vs. 343 deaths among
results of the VISEP [128], CRYSTMAS [122], 6S [123], 1.016 patients treated with other fluids, thus favor-
and CHEST [124] trials. The results of the recently com- ing albumin (odds ratio [OR], 0.82; 95% CI, 0.671.00;
pleted CRYSTAL trial were not considered.) I2 = 0%). When albumin-treated patients were compared
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Dellinger et al
TABLE 6. Recommendations: Hemodynamic Support and Adjunctive Therapy
G. Fluid Therapy of Severe Sepsis
1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B).
2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock (grade 1B).
3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids (grade 2C).
4. 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 (grade 1C).
5. 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. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg (grade 1C).
2. Norepinephrine as the first choice vasopressor (grade 1B).
3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate
blood pressure (grade 2B).
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
tachyarrhythmias and absolute or relative bradycardia) (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 MAP (grade 1C).
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. In treated patients hydrocortisone tapered when vasopressors are no longer required (grade 2D).
4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock (grade 1D).
5. When hydrocortisone is given, use continuous flow (grade 2D).
with those receiving crystalloids (seven trials, n = 1441), the reduction in 28-day mortality (from 26.3% to 24.1%), but
OR of dying was significantly reduced for albumin-treated did not achieve statistical significance. These data support
patients (OR, 0.78; 95% CI, 0.620.99; I2 = 0%). A multi- a low-level recommendation regarding the use of albumin
center randomized trial (n = 794) in patients with septic in patients with sepsis and septic shock (personal com-
shock compared intravenous albumin (20 g, 20%) every munication from J.P. Mira and as presented at the 32nd
8 hrs for 3 days to intravenous saline solution (130); International ISICEM Congress 2012, Brussels and the 25th
albumin therapy was associated with 2.2% absolute ESICM Annual Congress 2012, Lisbon).
596 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
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4. We recommend an initial fluid challenge in patients is a fundamental aspect of the hemodynamic management of
with sepsis-induced tissue hypoperfusion with suspi- patients with septic shock and should ideally be achieved before
cion of hypovolemia to achieve a minimum of 30 mL/ vasopressors and inotropes are used; however, using vasopres-
kg of crystalloids (a portion of this may be albumin sors early as an emergency measure in patients with severe shock
equivalent). More rapid administration and greater is frequently necessary, as when diastolic blood pressure is too
amounts of fluid may be needed in some patients (see Ini- low. When that occurs, great effort should be directed to wean-
tial Resuscitation recommendations) (grade 1C). ing vasopressors with continuing fluid resuscitation.
2. We recommend norepinephrine as the first-choice vaso-
5. We recommend that a fluid challenge technique be applied
pressor (grade 1B).
wherein fluid administration is continued as long as there is
3. We suggest epinephrine (added to and potentially sub-
hemodynamic improvement either based on dynamic (eg,
stituted for norepinephrine) when an additional agent is
change in pulse pressure, stroke volume variation) or static
needed to maintain adequate blood pressure (grade 2B).
(eg, arterial pressure, heart rate) variables (UG).
4. Vasopressin (up to 0.03 U/min) can be added to nor-
Rationale. Dynamic tests to assess patients responsiveness to epinephrine with the intent of raising MAP to target or
fluid replacement have become very popular in recent years in decreasing norepinephrine dosage (UG).
the ICU (131). These tests are based on monitoring changes in 5. Low-dose vasopressin is not recommended as the single ini-
stroke volume during mechanical ventilation or after passive leg tial vasopressor for treatment of sepsis-induced hypoten-
raising in spontaneously breathing patients. A systematic review sion, and vasopressin doses higher than 0.030.04 U/min
(29 trials, n = 685 critically ill patients) looked at the association should be reserved for salvage therapy (failure to achieve an
between stroke volume variation, pulse pressure variation, and/ adequate MAP with other vasopressor agents) (UG).
or stroke volume variation and the change in stroke volume/ 6. We suggest dopamine as an alternative vasopressor agent to
cardiac index after a fluid or positive end-expiratory pressure norepinephrine only in highly selected patients (eg, patients
challenge (132). The diagnostic OR of fluid responsiveness was with low risk of tachyarrhythmias and absolute or relative
59.86 (14 trials, 95% CI, 23.88150.05) and 27.34 (five trials, bradycardia) (grade 2C).
95% CI, 3.4655.53) for the pulse pressure variation and the 7. Phenylephrine is not recommended in the treatment of sep-
stroke volume variation, respectively. Utility of pulse pressure tic shock except in the following circumstances: (a) norepi-
variation and stroke volume variation is limited in the presence nephrine is associated with serious arrhythmias, (b) cardiac
of atrial fibrillation, spontaneous breathing, and low pressure output is known to be high and blood pressure persistently
support breathing. These techniques generally require sedation. low, or (c) as salvage therapy when combined inotrope/
H. Vasopressors vasopressor drugs and low-dose vasopressin have failed to
achieve the MAP target (grade 1C).
1. We recommend that vasopressor therapy initially target a
MAP of 65 mm Hg (grade 1C). Rationale. The physiologic effects of vasopressor and com-
bined inotrope/vasopressors selection in septic shock are set out
Rationale. Vasopressor therapy is required to sustain life in an extensive number of literature entries (135147). Table 7
and maintain perfusion in the face of life-threatening hypoten- depicts a GRADEpro Summary of Evidence Table comparing
sion, even when hypovolemia has not yet been resolved. Below dopamine and norepinephrine in the treatment of septic shock.
a threshold MAP, autoregulation in critical vascular beds can be Dopamine increases MAP and cardiac output, primarily due
lost, and perfusion can become linearly dependent on pressure. to an increase in stroke volume and heart rate. Norepinephrine
Thus, some patients may require vasopressor therapy to achieve increases MAP due to its vasoconstrictive effects, with little
a minimal perfusion pressure and maintain adequate flow (133, change in heart rate and less increase in stroke volume compared
134). The titration of norepinephrine to a MAP as low as 65 mm with dopamine. Norepinephrine is more potent than dopamine
Hg has been shown to preserve tissue perfusion (134). Note that and may be more effective at reversing hypotension in patients
the consensus definition of sepsis-induced hypotension for use with septic shock. Dopamine may be particularly useful in
of MAP in the diagnosis of severe sepsis is different (MAP < patients with compromised systolic function but causes more
70 mm Hg) from the evidence-based target of 65 mm Hg used in tachycardia and may be more arrhythmogenic than norepi-
this recommendation. In any case, the optimal MAP should be nephrine (148). It may also influence the endocrine response via
individualized as it may be higher in patients with atherosclero- the hypothalamic pituitary axis and have immunosuppressive
sis and/or previous hypertension than in young patients without effects. However, information from five randomized trials (n =
cardiovascular comorbidity. For example, a MAP of 65 mm Hg 1993 patients with septic shock) comparing norepinephrine to
might be too low in a patient with severe uncontrolled hyperten- dopamine does not support the routine use of dopamine in the
sion; in a young, previously normotensive patient, a lower MAP management of septic shock (136, 149152). Indeed, the rela-
might be adequate. Supplementing endpoints, such as blood tive risk of short-term mortality was 0.91 (95% CI, 0.841.00;
pressure, with assessment of regional and global perfusion, such fixed effect; I2 = 0%) in favor of norepinephrine. A recent meta-
as blood lactate concentrations, skin perfusion, mental status, analysis showed dopamine was associated with an increased risk
and urine output, is important. Adequate fluid resuscitation (RR, 1.10 [1.011.20]; p = 0.035); in the two trials that reported
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Dellinger et al
TABLE 7. Norepinephrine Compared With Dopamine in Severe Sepsis Summary of Evidence
Norepinephrine compared with 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. N Engl J
Med 2010; 362:779789; Marik PE. JAMA 1994; 272:13541357; Mathur RDAC. Indian J Crit Care Med 2007; 11:186191;
Martin C. Chest 1993; 103:18261831; Patel GP. Shock 2010; 33:375380; Ruokonen E. Crit Care Med 1993; 21:12961303
Illustrative Comparative Risksa
(95% CI) Quality
Relative No. of of the
Assumed Corresponding Effect Participants Evidence
Outcomes Risk Risk (95% CI) (Studies) (GRADE) Comments
Dopamine Norepinephrine
Short-term mortality Study population RR 0.91 2043 (6 studies)
(0.83 to 0.99) moderateb,c
530 per 1000 482 per 1000 (440 to 524)
Serious adverse events Study population RR 0.47 1931 (2 studies)
Supraventricular (0.38 to 0.58) moderateb,c
arrhythmias 229 per 1000 82 per 1000 (34 to 195)
Serious adverse Study population RR 0.35 1931 (2 studies)
events Ventricular (0.19 to 0.66) moderateb,c
arrhythmias 39 per 1000 15 per 1000 (8 to 27)
a
4HE ASSUMED RISK IS THE CONTROL GROUP RISK ACROSS STUDIES 4HE CORRESPONDING RISK AND ITS #) IS BASED ON THE ASSUMED RISK IN THE COMPARISON GROUP AND
THE RELATIVE EFFECT OF THE INTERVENTION AND ITS #) #) CONlDENCE INTERVAL 22 RISK RATIO
b
3TRONG HETEROGENEITY IN THE RESULTS )2 HOWEVER THIS REmECTS DEGREE OF EFFECT NOT DIRECTION OF EFFECT 7E HAVE DECIDED NOT TO LOWER THE EVIDENCE QUALITY
C
%FFECT RESULTS IN PART FROM HYPOVOLEMIC AND CARDIOGENIC SHOCK PATIENTS IN $E "ACKER N Engl J Med 7E HAVE LOWERED THE QUALITY OF EVIDENCE ONE LEVEL FOR
INDIRECTNESS
arrhythmias, these were more frequent with dopamine than has similar effects but is long acting (164). Studies show that
with norepinephrine (RR, 2.34 [1.463.77]; p = 0.001) (153). vasopressin concentrations are elevated in early septic shock, but
Although some human and animal studies suggest decrease to normal range in the majority of patients between 24
epinephrine has deleterious effects on splanchnic circulation and 48 hrs as shock continues (165). This has been called relative
and produces hyperlactatemia, no clinical evidence shows that vasopressin deficiency because in the presence of hypotension,
epinephrine results in worse outcomes, and it should be the vasopressin would be expected to be elevated. The significance
first alternative to norepinephrine. Indeed, information from of this finding is unknown. The VASST trial, an RCT comparing
4 randomized trials (n = 540) comparing norepinephrine norepinephrine alone to norepinephrine plus vasopressin at
to epinephrine found no evidence for differences in the risk 0.03 U/min, showed no difference in outcome in the intent-to-
of dying (RR, 0.96; CI, 0.771.21; fixed effect; I2 = 0%) (142, treat population (166). An a priori defined subgroup analysis
147, 154, 155). Epinephrine may increase aerobic lactate demonstrated that survival among patients receiving < 15 g/
production via stimulation of skeletal muscles 2-adrenergic min norepinephrine at the time of randomization was better
receptors and thus may prevent the use of lactate clearance to with the addition of vasopressin; however, the pretrial rationale
guide resuscitation. With its almost pure -adrenergic effects, for this stratification was based on exploring potential benefit in
phenylephrine is the adrenergic agent least likely to produce the population requiring 15 g/min norepinephrine. Higher
tachycardia, but it may decrease stroke volume and is therefore doses of vasopressin have been associated with cardiac, digital,
not recommended for use in the treatment of septic shock except and splanchnic ischemia and should be reserved for situations
in circumstances where norepinephrine is: a) associated with where alternative vasopressors have failed (167). Information
serious arrhythmias, or b) cardiac output is known to be high, or from seven trials (n = 963 patients with septic shock) comparing
c) as salvage therapy when other vasopressor agents have failed norepinephrine with vasopressin (or terlipressin) does not
to achieve target MAP (156). Vasopressin levels in septic shock support the routine use of vasopressin or its analog terlipressin
have been reported to be lower than anticipated for a shock state (93, 95, 97, 99, 159, 161, 164, 166, 168170). Indeed, the relative
(157). Low doses of vasopressin may be effective in raising blood risk of dying was 1.12 (95% CI, 0.961.30; fixed effects; I2 = 0%).
pressure in patients, refractory to other vasopressors and may However, the risk of supraventricular arrhythmias was increased
have other potential physiologic benefits (158163). Terlipressin with norepinephrine (RR, 7.25; 95% CI, 2.3022.90; fixed effect;
598 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
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I2 = 0%). Cardiac output measurement targeting maintenance J. Corticosteroids
of a normal or elevated flow is desirable when these pure
1. We suggest not using intravenous hydrocortisone as a treat-
vasopressors are instituted.
ment of adult septic shock patients if adequate fluid resus-
8. We recommend that low-dose dopamine not be used for citation and vasopressor therapy are able to restore hemo-
renal protection (grade 1A). dynamic stability (see goals for Initial Resuscitation). If this
is not achievable, we suggest intravenous hydrocortisone
Rationale. A large randomized trial and meta-analysis com-
alone at a dose of 200 mg per day (grade 2C).
paring low-dose dopamine to placebo found no difference in
either primary outcomes (peak serum creatinine, need for renal Rationale. The response of septic shock patients to fluid
replacement, urine output, time to recovery of normal renal and vasopressor therapy seems to be an important factor in
function) or secondary outcomes (survival to either ICU or selection of patients for optional hydrocortisone therapy. One
hospital discharge, ICU stay, hospital stay, arrhythmias) (171, French multicenter RCT of patients in vasopressor-unrespon-
172). Thus, the available data do not support administration of sive septic shock (hypotension despite fluid resuscitation and
low doses of dopamine solely to maintain renal function. vasopressors for more than 60 mins) showed significant shock
9. We recommend that all patients requiring vasopressors have reversal and reduction of mortality rate in patients with rela-
an arterial catheter placed as soon as practical if resources tive adrenal insufficiency (defined as postadrenocorticotropic
are available (UG). hormone [ACTH] cortisol increase 9 g/dL) (175). Two
smaller RCTs also showed significant effects on shock reversal
Rationale. In shock states, estimation of blood pressure with steroid therapy (176, 177). In contrast, a large, European
using a cuff is commonly inaccurate; use of an arterial cannula multicenter trial (CORTICUS) that enrolled patients without
provides a more appropriate and reproducible measurement sustained shock and had a lower risk of death than the French
of arterial pressure. These catheters also allow continuous trial failed to show a mortality benefit with steroid therapy
analysis so that decisions regarding therapy can be based on (178). Unlike the French trial that only enrolled shock patients
immediate and reproducible blood pressure information. with blood pressure unresponsive to vasopressor therapy, the
CORTICUS study included patients with septic shock regard-
I. Inotropic Therapy less of how the blood pressure responded to vasopressors; the
1. We recommend that a trial of dobutamine infusion up to study baseline (placebo) 28-day mortality rate was 61% and
20 g/kg/min be administered or added to vasopressor (if 31%, respectively. The use of the ACTH test (responders and
in use) in the presence of: a) myocardial dysfunction, as nonresponders) did not predict the faster resolution of shock.
suggested by elevated cardiac filling pressures and low car- In recent years, several systematic reviews have examined the
diac output, or b) ongoing signs of hypoperfusion, despite use of low-dose hydrocortisone in septic shock with contradic-
achieving adequate intravascular volume and adequate tory results: Annane et al (179) analyzed the results of 12 stud-
MAP (grade 1C). ies and calculated a significant reduction in 28-day mortality
2. We recommend against the use of a strategy to increase car- with prolonged low-dose steroid treatment in adult septic
diac index to predetermined supranormal levels (grade 1B). shock patients (RR, 0.84; 95% CI, 0.720.97; p = 0.02) (180).
Rationale. Dobutamine is the first choice inotrope for patients In parallel, Sligl and colleagues (180) used a similar technique,
with measured or suspected low cardiac output in the presence of but only identified eight studies for their meta-analysis, six
adequate left ventricular filling pressure (or clinical assessment of of which had a high-level RCT design with low risk of bias
adequate fluid resuscitation) and adequate MAP. Septic patients (181). In contrast to the aforementioned review, this analysis
who remain hypotensive after fluid resuscitation may have low, revealed no statistically significant difference in mortality (RR,
normal, or increased cardiac outputs. Therefore, treatment with 1.00; 95% CI, 0.841.18). Both reviews, however, confirmed
a combined inotrope/vasopressor, such as norepinephrine or the improved shock reversal by using low-dose hydrocortisone
epinephrine, is recommended if cardiac output is not measured. (180, 181). A recent review on the use of steroids in adult sep-
When the capability exists for monitoring cardiac output in addi- tic shock underlined the importance of selection of studies for
tion to blood pressure, a vasopressor, such as norepinephrine, may systematic analysis (181) and identified only 6 high-level RCTs
be used separately to target specific levels of MAP and cardiac as adequate for systematic review (175178, 182, 183). When
output. Large prospective clinical trials, which included critically only these six studies are analyzed, we found that in low risk
ill ICU patients who had severe sepsis, failed to demonstrate ben- patients from three studies (ie, those with a placebo mortal-
efit from increasing oxygen delivery to supranormal targets by use ity rate of less than 50%, which represents the majority of all
of dobutamine (173, 174). These studies did not specifically tar- patients), hydrocortisone failed to show any benefit on out-
get patients with severe sepsis and did not target the first 6 hrs of come (RR, 1.06). The minority of patients from the remain-
resuscitation. If evidence of tissue hypoperfusion persists despite ing three studies, who had a placebo mortality of greater than
adequate intravascular volume and adequate MAP, a viable alter- 60%, showed a nonsignificant trend to lower mortality by using
native (other than reversing underlying insult) is to add inotropic hydrocortisone (see Supplemental Digital Content 4, http://
therapy. links.lww.com/CCM/A615, Summary of Evidence Table).
#RITICAL #ARE -EDICINE www.ccmjournal.org 599
Dellinger et al
2. We suggest not using the ACTH stimulation test to identify Rationale. Several randomized trials on the use of low-dose
the subset of adults with septic shock who should receive hydrocortisone in septic shock patients revealed a significant
hydrocortisone (grade 2B). increase of hyperglycemia and hypernatremia (175) as side
effects. A small prospective study demonstrated that repeti-
Rationale. In one study, the observation of a potential inter-
tive bolus application of hydrocortisone leads to a significant
action between steroid use and ACTH test was not statistically
increase in blood glucose; this peak effect was not detectable
significant (175). Furthermore, no evidence of this distinc-
during continuous infusion. Furthermore, considerable inter-
tion was observed between responders and nonresponders in a
individual variability was seen in this blood glucose peak after
recent multicenter trial (178). Random cortisol levels may still
the hydrocortisone bolus (192). Although an association of
be useful for absolute adrenal insufficiency; however, for septic
hyperglycemia and hypernatremia with patient outcome mea-
shock patients who suffer from relative adrenal insufficiency (no
sures could not be shown, good practice includes strategies for
adequate stress response), random cortisol levels have not been
avoidance and/or detection of these side effects.
demonstrated to be useful. Cortisol immunoassays may over- or
underestimate the actual cortisol level, affecting the assignment
of patients to responders or nonresponders (184). Although the SUPPORTIVE THERAPY OF SEVERE SEPSIS
clinical significance is not clear, it is now recognized that etomi- (TABLE 8)
date, when used for induction for intubation, will suppress the
K. Blood Product Administration
hypothalamic-pituitary-adrenal axis (185, 186). Moreover, a
subanalysis of the CORTICUS trial (178) revealed that the use 1. Once tissue hypoperfusion has resolved and in the absence
of etomidate before application of low-dose steroids was associ- of extenuating circumstances, such as myocardial ischemia,
ated with an increased 28-day mortality rate (187). An inappro- severe hypoxemia, acute hemorrhage, or ischemic coronary
priately low random cortisol level (< 18 g/dL) in a patient with artery disease, we recommend that red blood cell transfu-
shock would be considered an indication for steroid therapy sion occur when the hemoglobin concentration decreases
along traditional adrenal insufficiency guidelines. to < 7.0 g/dL to target a hemoglobin concentration of 7.0 to
9.0 g/dL in adults (grade 1B).
3. We suggest that clinicians taper the treated patient from
steroid therapy when vasopressors are no longer required Rationale. Although the optimum hemoglobin concentra-
(grade 2D). tion for patients with severe sepsis has not been specifically
investigated, the Transfusion Requirements in Critical Care
Rationale. There has been no comparative study between a
trial suggested that a hemoglobin level of 7 to 9 g/dL, compared
fixed-duration and clinically guided regimen or between taper-
with 10 to 12 g/dL, was not associated with increased mortality
ing and abrupt cessation of steroids. Three RCTs used a fixed-
in critically ill adults (193). No significant differences in 30-day
duration protocol for treatment (175, 177, 178), and therapy was
mortality rates were observed between treatment groups in the
decreased after shock resolution in two RCTs (176, 182). In four
subgroup of patients with severe infections and septic shock
studies, steroids were tapered over several days (176178, 182),
(22.8% and 29.7%, respectively; p = 0.36),
and steroids were withdrawn abruptly in two RCTs (175, 183).
Although less applicable to septic patients, results of a ran-
One crossover study showed hemodynamic and immunologic
domized trial in patients undergoing cardiac surgery with car-
rebound effects after abrupt cessation of corticosteroids (188).
diopulmonary bypass support a restrictive transfusion strategy
Furthermore, a study revealed that there is no difference in out-
using a threshold hematocrit of < 24% (hemoglobin 8 g/
come of septic shock patients if low-dose hydrocortisone is used
dL) as equivalent to a transfusion threshold of hematocrit of
for 3 or 7 days; hence, no recommendation can be given with
< 30% (hemoglobin 10 g/dL) (194). Red blood cell transfu-
regard to the optimal duration of hydrocortisone therapy (189).
sion in septic patients increases oxygen delivery but does not
4. We recommend that corticosteroids not be administered for usually increase oxygen consumption (195197). The trans-
the treatment of sepsis in the absence of shock (grade 1D). fusion threshold of 7 g/dL contrasts with early goal-directed
resuscitation protocols that use a target hematocrit of 30% in
Rationale. Steroids may be indicated in the presence of a
patients with low ScvO2 during the first 6 hrs of resuscitation of
history of steroid therapy or adrenal dysfunction, but whether
septic shock (13).
low-dose steroids have a preventive potency in reducing the
incidence of severe sepsis and septic shock in critically ill 2. We recommend not using erythropoietin as a specific treat-
patients cannot be answered. A preliminary study of stress- ment of anemia associated with severe sepsis (grade 1B).
dose level steroids in community-acquired pneumonia showed
Rationale. No specific information regarding erythro-
improved outcome measures in a small population (190), and
poietin use in septic patients is available, but clinical trials
a recent confirmatory RCT revealed reduced hospital length of
of erythropoietin administration in critically ill patients
stay without affecting mortality (191).
show some decrease in red cell transfusion requirement
5. When low-dose hydrocortisone is given, we suggest using with no effect on clinical outcome (198, 199). The effect
continuous infusion rather than repetitive bolus injec- of erythropoietin in severe sepsis and septic shock would
tions (grade 2D). not be expected to be more beneficial than in other critical
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conditions. Patients with severe sepsis and septic shock may L. Immunoglobulins
have coexisting conditions that meet indications for the use
1. We suggest not using intravenous immunoglobulins in
of erythropoietin.
adult patients with severe sepsis or septic shock (grade 2B).
3. We suggest that fresh frozen plasma not be used to correct
Rationale. One larger multicenter RCT (n = 624) (210) in
laboratory clotting abnormalities in the absence of bleeding adult patients and one large multinational RCT in infants with
or planned invasive procedures (grade 2D). neonatal sepsis (n = 3493) (211) found no benefit for intravenous
Rationale. Although clinical studies have not assessed the immunoglobulin (IVIG). (For more on this trial, see the section,
impact of transfusion of fresh frozen plasma on outcomes in Pediatric Considerations.). A meta-analysis by the Cochrane col-
critically ill patients, professional organizations have recom- laboration, which did not include this most recent RCT, iden-
mended it for coagulopathy when there is a documented defi- tified 10 polyclonal IVIG trials (n = 1430) and seven trials on
ciency of coagulation factors (increased prothrombin time, immunoglobulin (Ig) M-enriched polyclonal IVIG (n = 528)
international normalized ratio, or partial thromboplastin time) (212). Compared with placebo, IVIG resulted in a significant
and the presence of active bleeding or before surgical or invasive reduction in mortality (RR, 0.81 and 95% CI, 0.700.93; and RR,
procedures (200203). In addition, transfusion of fresh frozen 0.66 and 95% CI, 0.510.85, respectively). Also the subgroup of
plasma usually fails to correct the prothrombin time in non- IgM-enriched IVIGs (n = 7 trials) showed a significant reduc-
bleeding patients with mild abnormalities (204, 205). No studies tion in mortality rates compared with placebo (RR, 0.66; 95%
suggest that correction of more severe coagulation abnormali- CI, 0.510.85). Trials with low risk of bias showed no reduction
ties benefits patients who are not bleeding. in mortality with polyclonal IVIG (RR, 0.97; 95% CI, 0.811.15;
five trials, n = 945). Three of these trials (210, 213, 214) used stan-
4. We recommend against antithrombin administration for dard polyclonal IVIG and two IgM-enriched IVIG (215, 216).
the treatment of severe sepsis and septic shock (grade 1B). These findings are in accordance with those of two older
Rationale. A phase III clinical trial of high-dose antithrom- meta-analyses (217, 218) from other Cochrane authors. One
bin did not demonstrate any beneficial effect on 28-day all- systematic review (217) included a total of 21 trials and showed
cause mortality in adults with severe sepsis and septic shock. a relative risk of death of 0.77 with immunoglobulin treatment
High-dose antithrombin was associated with an increased risk (95% CI, 0.680.88); however, the results of only high-quality
of bleeding when administered with heparin (206). Although trials (total of 763 patients) showed a relative risk of 1.02 (95%
a post hoc subgroup analysis of patients with severe sepsis and CI, 0.841.24). Similarly, Laupland et al (218) found a significant
reduction in mortality with the use of IVIG treatment (OR, 0.66;
high risk of death showed better survival in patients receiving
95% CI, 0.530.83; p < 0.005). When only high-quality studies
antithrombin, this agent cannot be recommended until further
were pooled, the OR for mortality was 0.96 (95% CI, 0.711.3;
clinical trials are performed (207).
p = 0.78). Two meta-analyses, which used less strict criteria to
5. In patients with severe sepsis, we suggest that platelets be identify sources of bias or did not state their criteria for the
administered prophylactically when counts are 10,000/ assessment of study quality, found significant improvement in
mm3 (10 109/L) in the absence of apparent bleeding, patient mortality with IVIG treatment (219, 220). In contrast
as well when counts are 20,000/mm3 (20 109/L) if the to the most recent Cochrane review, Kreymann et al (219) clas-
patient has a significant risk of bleeding. Higher platelet sified five studies that investigated IgM-enriched preparation as
counts ( 50,000/mm3 [50 109/L]) are advised for active high-quality studies, combining studies in adults and neonates,
bleeding, surgery, or invasive procedures (grade 2D). and found an OR for mortality of 0.5 (95% CI, 0.340.73).
Most IVIG studies are small, some have methodological
Rationale. Guidelines for transfusion of platelets are derived flaws; the only large study (n = 624) showed no effect (210).
from consensus opinion and experience in patients with Subgroup effects between IgM-enriched and nonenriched for-
chemotherapy-induced thrombocytopenia. Patients with severe mulations reveal substantial heterogeneity. In addition, indi-
sepsis are likely to have some limitation of platelet production similar rectness and publication bias were considered in grading this
to that in chemotherapy-treated patients, but they also are likely to recommendation. The low-quality evidence led to the grading
have increased platelet consumption. Recommendations take into as a weak recommendation. The statistical information that
account the etiology of thrombocytopenia, platelet dysfunction, comes from the high-quality trials does not support a benefi-
risk of bleeding, and presence of concomitant disorders (200, 202, cial effect of polyclonal IVIG. We encourage conducting large
203, 208, 209). Factors that may increase the bleeding risk and multicenter studies to further evaluate the effectiveness of
indicate the need for a higher platelet count are frequently present other polyclonal immunoglobulin preparations given intrave-
in patients with severe sepsis. Sepsis itself is considered to be a nously in patients with severe sepsis.
risk factor for bleeding in patients with chemotherapy-induced
thrombocytopenia. Other factors considered to increase the risk of
M. Selenium
bleeding in patients with severe sepsis include temperature higher
than 38C, recent minor hemorrhage, rapid decrease in platelet 1. We suggest not using intravenous selenium to treat severe
count, and other coagulation abnormalities (203, 208, 209). sepsis (grade 2C).
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Dellinger et al
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 predicted body weight in patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg).
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 sepsis- induced moderate or severe
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 ARDS patients in whom the benefits of NIV
have been carefully considered and are thought to outweigh the risks (grade 2B).
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 ARDS 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 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).
(Continued)
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TABLE 8. (Continued) Recommendations: Other Supportive Therapy of Severe Sepsis
3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a PaO2/FIO2
< 150 mm Hg (grade 2C).
Q. Glucose Control
1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when
2 consecutive blood glucose levels are >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. Blood glucose values be monitored every 12 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs
thereafter (grade 1C).
3. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not
accurately estimate arterial blood or plasma glucose values (UG).
R. Renal Replacement Therapy
1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute
renal failure (grade 2B).
2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D).
S. Bicarbonate Therapy
1. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in
patients with hypoperfusion-induced lactic acidemia with pH 7.15 (grade 2B).
T. Deep Vein Thrombosis Prophylaxis
1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). This should
be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C
versus three times daily UFH). If creatinine clearance is <30 mL/min, use dalteparin (grade 1A) or another form of LMWH that
has a low degree of renal metabolism (grade 2C) or UFH (grade 1A).
2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression
devices whenever possible (grade 2C).
3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent
intracerebral hemorrhage) not receive pharmacoprophylaxis (grade 1B), but receive mechanical prophylactic treatment, such
as graduated compression stockings or intermittent compression devices (grade 2C), unless contraindicated. When the risk
decreases start pharmacoprophylaxis (grade 2C).
U. Stress Ulcer Prophylaxis
1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who
have bleeding risk factors (grade 1B).
2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA (grade 2D)
3. Patients without risk factors do not receive prophylaxis (grade 2B).
V. Nutrition
1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only
intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).
2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day),
advancing only as tolerated (grade 2B).
3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in
conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).
4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating
supplementation in patients with severe sepsis (grade 2C).
W. Setting Goals of Care
1. Discuss goals of care and prognosis with patients and families (grade 1B).
2. 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).
#RITICAL #ARE -EDICINE www.ccmjournal.org 603
Dellinger et al
Rationale. Selenium was administered in the hope that it guidelines recommended use of rhAPC in line with the prod-
could correct the known reduction of selenium concentration uct labeling instructions required by the U.S. and European
in sepsis patients and provide a pharmacologic effect through regulatory authorities with a grade B quality of evidence (7, 8).
an antioxidant defense. Although some RCTs are available, By the time of publication of the 2008 SSC guidelines, addi-
the evidence on the use of intravenous selenium is still very tional studies of rhAPC in severe sepsis (as required by regula-
weak. Only one large clinical trial has examined the effect on tory agencies) had shown it ineffective in less severely ill patients
mortality rates, and no significant impact was reported on the with severe sepsis as well as in children (229, 230). The 2008 SSC
intent-to-treat population with severe systemic inflammatory recommendations reflected these findings, and the strength of
response syndrome, sepsis, or septic shock (OR, 0.66; 95% CI, the rhAPC recommendation was downgraded to a suggestion
0.391.10; p = 0.109) (221). Overall, there was a trend toward for use in adult patients with a clinical assessment of high risk of
a concentration-dependent reduction in mortality; no differ- death, most of whom will have Acute Physiology and Chronic
ences in secondary outcomes or adverse events were detected. Health Evaluation (APACHE) II scores 25 or multiple organ
Finally, no comment on standardization of sepsis management failure (grade 2C; quality of evidence was also downgraded from
was included in this study, which recruited 249 patients over a 2004, from B to C) (7). The 2008 guidelines also recommended
period of 6 years (19992004) (221). against use of rhAPC in low-risk adult patients, most of whom
A French RCT in a small population revealed no effect on will have APACHE II scores 20 or single organ failures (grade
primary (shock reversal) or secondary (days on mechanical ven- 1A), and against use in all pediatric patients (grade 1B).
tilation, ICU mortality) endpoints (222). Another small RCT The results of the PROWESS SHOCK trial (1,696 patients)
revealed less early VAP in the selenium group (p = 0.04), but no were released in late 2011, showing no benefit of rhAPC in patients
difference in late VAP or secondary outcomes such as ICU or with septic shock (mortality 26.4% for rhAPC, 24.2% placebo)
hospital mortality (223). This is in accordance with two RCTs with a relative risk of 1.09 and a p value of 0.31 (231). The drug
that resulted in reduced number of infectious episodes (224) or was withdrawn from the market and is no longer available, negat-
increase in glutathione peroxidase concentrations (225); neither ing any need for an SSC recommendation regarding its use.
study, however, showed a beneficial effect on secondary out-
come measures (renal replacement, ICU mortality) (224, 225). O. Mechanical Ventilation of Sepsis-Induced Acute
A more recent large RCT tried to determine if the addition of Respiratory Distress Syndrome
relatively low doses of supplemental selenium (glutamine was 1. We recommend that clinicians target a tidal volume of
also tested in a two-factorial design) to parenteral nutrition in 6 mL/kg predicted body weight in patients with sepsis-
critically ill patients reduces infections and improves outcome induced acute respiratory distress syndrome (ARDS) (grade
(226). Selenium supplementation did not significantly affect the 1A vs. 12 mL/kg).
development of a new infection (OR, 0.81; 95% CI, 0.571.15), 2. We recommend that plateau pressures be measured in
and the 6-month mortality rate was not unaffected (OR, 0.89; patients with ARDS and that the initial upper limit goal for
95% CI, 0.621.29). In addition, length of stay, days of anti- plateau pressures in a passively inflated lung be 30 cm H2O
biotic use, and modified Sequential Organ Failure Assessment (grade 1B).
score were not significantly affected by selenium (227).
In addition to the lack of evidence, the questions of optimal Rationale. Of note, studies used to determine recommen-
dosing and application mode remain unanswered. Reported dations in this section enrolled patients using criteria from the
high-dose regimens have involved a loading dose followed by American-European Consensus Criteria Definition for Acute
an infusion, while animal trials suggest that bolus dosing could Lung Injury (ALI) and ARDS (232). For this document, we
be more effective (227); this, however, has not been tested in have used the updated Berlin definition and used the terms
humans. These unsolved problems require additional trials, and mild, moderate, and severe ARDS (PaO2/FIO2 300, 200, and
we encourage conducting large multicenter studies to further 100 mm Hg, respectively) for the syndromes previously
evaluate the effectiveness of intravenous selenium in patients known as ALI and ARDS (233). Several multicenter random-
with severe sepsis. This recommendation does not exclude the ized trials have been performed in patients with established
use of low-dose selenium as part of the standard minerals and ARDS to evaluate the effects of limiting inspiratory pressure
oligo-elements used during total parenteral nutrition. through moderation of tidal volume (234238). These studies
showed differing results that may have been caused by differ-
N. History of Recommendations Regarding Use of ences in airway pressures in the treatment and control groups
Recombinant Activated Protein C (233, 234, 239). Several meta-analyses suggest decreased mor-
Recombinant human activated protein C (rhAPC) was tality in patients with a pressure- and volume-limited strategy
approved for use in adult patients in a number of countries for established ARDS (240, 241).
in 2001 following the PROWESS (Recombinant Human Acti- The largest trial of a volume- and pressure-limited strategy
vated Protein C Worldwide Evaluation in Severe Sepsis) trial, showed an absolute 9% decrease in all-cause mortality in patients
which enrolled 1,690 severe sepsis patients and showed a sig- with ARDS ventilated with tidal volumes of 6 mL/kg compared
nificant reduction in mortality (24.7%) with rhAPC com- with 12 mL/kg of predicted body weight (PBW), and aiming for
pared with placebo (30.8%, p = 0.005) (228). The 2004 SSC a plateau pressure 30 cm H2O (233). The use of lung-protective
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strategies for patients with ARDS is supported by clinical trials Rationale. Raising PEEP in ARDS keeps lung units open to
and has been widely accepted, but the precise choice of tidal vol- participate in gas exchange. This will increase PaO2 when PEEP
ume for an individual patient with ARDS may require adjust- is applied through either an endotracheal tube or a face mask
ment for such factors as the plateau pressure achieved, the level (252254). In animal experiments, avoidance of end-expira-
of positive end-expiratory pressure chosen, the compliance of the tory alveolar collapse helps minimize ventilator-induced lung
thoracoabdominal compartment, and the vigor of the patients injury when relatively high plateau pressures are in use. Three
breathing effort. Patients with profound metabolic acidosis, high large multicenter trials using higher vs. lower levels of PEEP in
obligate minute ventilations, or short stature may require addi- conjunction with low tidal volumes did not uncover benefit or
tional manipulation of tidal volumes. Some clinicians believe harm (255257). A meta-analysis using individual patient data
it may be safe to ventilate with tidal volumes > 6 mL/kg PBW showed no benefit in all patients with ARDS; however, patients
as long as the plateau pressure can be maintained 30 cm H2O with moderate or severe ARDS (PaO2/FIO2 ratio 200 mm Hg)
(242, 243). The validity of this ceiling value will depend on the had decreased mortality with the use of higher PEEP, whereas
patients effort, as those who are actively breathing generate those with mild ARDS did not (258). Two options are recom-
higher transalveolar pressures for a given plateau pressure than mended for PEEP titration. One option is to titrate PEEP (and
tidal volume) according to bedside measurements of thoraco-
patients who are passively inflated. Conversely, patients with very
pulmonary compliance with the objective of obtaining the best
stiff chest walls may require plateau pressures > 30 cm H2O to
compliance, reflecting a favorable balance of lung recruitment
meet vital clinical objectives. A retrospective study suggested that
and overdistension (259). The second option is to titrate PEEP
tidal volumes should be lowered even with plateau pressures
based on severity of oxygenation deficit and guided by the FIO2
30 cm H2O (244) as lower plateau pressures were associated with
required to maintain adequate oxygenation (234, 255, 256). A
decreased in-hospital mortality (245).
PEEP > 5 cm H2O is usually required to avoid lung collapse (260).
High tidal volumes that are coupled with high plateau pres- The ARDSNet standard PEEP strategy is shown in Appendix C.
sures should be avoided in ARDS. Clinicians should use as a The higher PEEP strategy recommended for ARDS is shown in
starting point the objective of reducing tidal volume over 1 to Appendix D and comes from the ALVEOLI trial (257).
2 hrs from its initial value toward the goal of a low tidal vol-
ume (6 mL/kg PBW) achieved in conjunction with an end- 5. We suggest recruitment maneuvers in sepsis patients with
inspiratory plateau pressure 30 cm H2O. If the plateau pressure severe refractory hypoxemia due to ARDS (grade 2C).
remains > 30 cm H2O after reduction of tidal volume to 6 mL/kg 6. We suggest prone positioning in sepsis-induced ARDS
PBW, tidal volume may be reduced further to as low as 4 mL/kg patients with a PaO2/FIO2 ratio 100 mm Hg in facilities that
PBW per protocol. (Appendix C provides ARDSNet ventilator have experience with such practices (grade 2B).
management and formulas to calculate PBW.) Using volume-
Rationale. Many strategies exist for treating refractory
and pressure-limited ventilation may lead to hypercapnia with
hypoxemia in patients with severe ARDS (261). Temporarily
maximum tolerated set respiratory rates. In such cases, hyper-
raising transpulmonary pressure may facilitate opening atel-
capnia that is otherwise not contraindicated (eg, high intracra-
ectatic alveoli to permit gas exchange (260), but could also
nial pressure) and appears to be tolerated should be allowed.
overdistend aerated lung units leading to ventilator-induced
Sodium bicarbonate or tromethamine (THAM) infusion may be
lung injury and temporary hypotension. The application of
considered in selected patients to facilitate use of limited ventila-
transient sustained use of continuous positive airway pressure
tor conditions that result in permissive hypercapnia (246, 247). appears to improve oxygenation in patients initially, but these
A number of observational trials in mechanically venti- effects can be transient (262). Although selected patients with
lated patients have demonstrated a decreased risk of devel- severe hypoxemia may benefit from recruitment maneuvers in
oping ARDS when smaller trial volumes are used (248251). conjunction with higher levels of PEEP, little evidence supports
Accordingly, high tidal volumes and plateau pressures should the routine use in all ARDS patients (262). Blood pressure and
be avoided in mechanically ventilated patients at risk for devel- oxygenation should be monitored and recruitment maneuvers
oping ARDS, including those with sepsis. discontinued if deterioration in these variables is observed.
No single mode of ventilation (pressure control, volume Several small studies and one large study in patients with
control) has consistently been shown to be advantageous when hypoxemic respiratory failure or ARDS have shown that most
compared with any other that respects the same principles of patients respond to the prone position with improved oxygen-
lung protection. ation (263266). None of the individual trials of prone posi-
3. We recommend that positive end-expiratory pressure tioning in patients with ARDS or hypoxemic respiratory failure
(PEEP) be applied to avoid alveolar collapse at end expira- demonstrated a mortality benefit (267270). One meta-analy-
sis suggested potential benefits for prone positioning in patients
tion (atelectotrauma) (grade 1B).
with profound hypoxemia and PaO2/FIO2 ratio 100 mm Hg, but
4. We suggest strategies based on higher rather than lower lev- not in those with less severe hypoxemia (270). Prone position-
els of PEEP for patients with sepsis-induced moderate to ing may be associated with potentially life-threatening com-
severe ARDS (grade 2C). plications, including accidental dislodging of the endotracheal
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Dellinger et al
and chest tubes; these complications occur more frequently in following criteria: a) arousable; b) hemodynamically stable
patients in the prone compared with supine position (270). (without vasopressor agents); c) no new potentially serious
Other methods to treat refractory hypoxemia, including conditions; d) low ventilatory and end-expiratory pressure
high-frequency oscillatory ventilation, airway pressure release requirements; and e) low FIO2 requirements which can be
ventilation, and extracorporeal membrane oxygenation (271), safely delivered with a face mask or nasal cannula. If the
may be considered as rescue therapies in centers with expertise spontaneous breathing trial is successful, extubation should
and experience with their use (261, 271274). Inhaled nitric be considered (grade 1A).
oxide does not improve mortality rates in patients with ARDS
Rationale. Spontaneous breathing trial options include a
and should not be routinely used (275).
low level of pressure support, continuous positive airway pres-
7. We recommend that mechanically ventilated sepsis patients sure (5 cm H2O), or a use of a T-piece. Studies demonstrated
be maintained with the head of the bed elevated between that daily spontaneous breathing trials in appropriately selected
30 and 45 degrees to limit aspiration risk and to prevent the patients reduce the duration of mechanical ventilation (282,
development of VAP (grade 1B). 283). These breathing trials should be conducted in conjunction
Rationale. The semi-recumbent position has been demon- with a spontaneous awakening trial (284). Successful comple-
strated to decrease the incidence of VAP (276). Enteral feeding tion of spontaneous breathing trials leads to a high likelihood of
increased the risk of developing VAP; 50% of the patients who successful early discontinuation of mechanical ventilation.
were fed enterally in the supine position developed VAP com- 10. We recommend against the routine use of the pulmonary
pared with 9% of those fed in the semi-recumbent position artery catheter for patients with sepsis-induced ARDS
(276). However, the bed position was monitored only once a (grade 1A).
day, and patients who did not achieve the desired bed eleva-
tion were not included in the analysis (276). One study did not Rationale. Although insertion of a pulmonary artery (PA)
show a difference in incidence of VAP between patients main- catheter may provide useful information on a patients volume
tained in supine and semi-recumbent positions (277); patients status and cardiac function, these benefits may be confounded
assigned to the semi-recumbent group did not consistently by differences in the interpretation of results (285287), lack
achieve the desired head of the bed elevation, and the head of of correlation of PA occlusion pressures with clinical response
bed elevation in the supine group approached that of the semi- (288), and an absence of a proven strategy to use catheter
recumbent group by day 7 (277). When necessary, patients results to improve patient outcomes (173). Two multicenter
may be laid flat for procedures, hemodynamic measurements, randomized trials, one in patients with shock or ARDS (289)
and during episodes of hypotension. Patients should not be fed and the other in those with only ARDS (290), failed to show
enterally while supine. benefit with the routine use of PA catheters in ARDS. In addi-
8. We suggest that noninvasive mask ventilation (NIV) be tion, other studies in different types of critically ill patients
used in that minority of sepsis-induced ARDS patients in have failed to show definitive benefit with routine use of the
whom the benefits of NIV have been carefully considered PA catheter (291293). Well-selected patients remain appropri-
and are thought to outweigh the risks (grade 2B). ate candidates for PA catheter insertion only when the answers
to important management decisions depend on information
Rationale. Obviating the need for airway intubation con- solely obtainable from direct measurements made within the
fers multiple advantages: better communication, lower inci- PA (292, 294).
dence of infection, and reduced requirements for sedation.
Two RCTs in patients with acute respiratory failure demon- 11. We recommend a conservative fluid strategy for patients
strated improved outcome with the use of NIV when it can be with established sepsis-induced ARDS who do not have
used successfully (278, 279). Unfortunately, only a small per- evidence of tissue hypoperfusion (grade 1C).
centage of sepsis patients with life-threatening hypoxemia can
Rationale. Mechanisms for the development of pulmo-
be managed in this way (280, 281).
nary edema in patients with ARDS include increased capillary
NIV should be considered in patients with sepsis-induced
permeability, increased hydrostatic pressure, and decreased
ARDS if they are responsive to relatively low levels of pressure
oncotic pressure (295). Small prospective studies in patients
support and PEEP with stable hemodynamics, can be made
with critical illness and ARDS have suggested that low weight
comfortable, and are easily arousable; if they are able to protect
gain is associated with improved oxygenation (296) and fewer
the airway and spontaneously clear the airway of secretions;
days of mechanical ventilation (297, 298). A fluid-conservative
and if they are anticipated to recover rapidly from the precipi-
strategy to minimize fluid infusion and weight gain in patients
tating insult (280, 281). A low threshold for airway intubation
with ARDS, based on either a central venous catheter (CVP <
should be maintained.
4 mm Hg) or a PA catheter (pulmonary artery wedge pressure
9. We recommend that a weaning protocol be in place and that < 8 mm Hg), along with clinical variables to guide treatment,
mechanically ventilated patients with severe sepsis undergo led to fewer days of mechanical ventilation and reduced length
spontaneous breathing trials regularly to evaluate the ability of ICU stay without altering the incidence of renal failure or
to discontinue mechanical ventilation when they satisfy the mortality rates (299). This strategy was only used in patients
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with established ARDS, some of whom had shock present dur- preferentially had significantly more days without ventilation,
ing the ICU stay, and active attempts to reduce fluid volume shorter stay in ICU and hospital, than patients who received
were conducted only outside periods of shock. sedation (propofol and midazolam) in addition to morphine
(307). However, agitated delirium was more frequently detected
12. In the absence of specific indications such as bronchospasm,
in the intervention group. Although not specifically studied
we recommend against the use of 2-agonists for treatment
in patients with sepsis, the administration of intermittent
of patients with sepsis-induced ARDS (grade 1B).
sedation, daily sedative interruption, and systematic titration
Rationale. Patients with sepsis-induced ARDS often develop to a predefined endpoint have been demonstrated to decrease
increased vascular permeability. Preclinical and early clinical data the duration of mechanical ventilation (284, 305, 308, 309).
suggest that -adrenergic agonists may speed resorption of alveo- Patients receiving neuromuscular blocking agents (NMBAs)
lar edema (300). Two randomized clinical trials studied the effect must be individually assessed regarding discontinuation of
of -agonists in patients with ARDS (301, 302). In one, a com- sedative drugs because the neuromuscular blockade must first
parison of aerosolized albuterol and placebo in 282 patients with be reversed. The use of intermittent vs. continuous methods
ARDS, the trial was stopped for futility (301). Patients receiv- for the delivery of sedation in critically ill patients has been
ing albuterol had higher heart rates on day 2, and a trend was examined in an observational study of mechanically ventilated
detected toward decreased ventilator-free days (days alive and off patients that showed that patients receiving continuous
the ventilator). The rates of death before discharge were 23.0% in sedation had significantly longer durations of mechanical
the albuterol group vs. 17.7% in placebo-treated patients. More ventilation and ICU and hospital lengths of stay (310).
than half of the patients enrolled in this trial had pulmonary or Clinical trials have evaluated daily interruption of continu-
nonpulmonary sepsis as the cause of the ARDS (301). ous sedative infusions. A prospective, randomized controlled
The use of intravenous salbutamol was tested in the trial in 128 mechanically ventilated adults receiving continu-
BALTI-2 trial (302). Three hundred twenty-six patients with ous intravenous sedation demonstrated that a daily interrup-
ARDS, 251 of whom had pulmonary or nonpulmonary sepsis tion in the continuous sedative infusion until the patient was
as cause, were randomized to intravenous salbutatmol, 15 g/ awake decreased the duration of mechanical ventilation and
kg of ideal body weight, or placebo for up to 7 days. Patients ICU length of stay (283). Although the patients did receive
treated with salbutamol had increased 28-day mortality rates continuous sedative infusions in this study, the daily inter-
(34% vs. 23%; RR, 1.4; 95% CI, 1.032.08) leading to early ter- ruption and awakening allowed for titration of sedation, in
mination of the trial (302). effect making the dosing intermittent. In addition, a paired
Beta-2 agonists may have specific indications, such as treat- spontaneous awakening trial combined with a spontaneous
ment of bronchospasm and hyperkalemia. In the absence of breathing trial decreased the duration of mechanical venti-
these conditions, we recommend against the routine use of lation, length of ICU and hospital stay, and 1-year mortality
-agonists, either in intravenous or aerosolized form, for the
(284). More recently, a multicenter randomized trial compared
treatment of patients with sepsis-induced ARDS.
protocolized sedation with protocolized sedation plus daily
P. Sedation, Analgesia, and Neuromuscular Blockade sedation interruption in 423 critically ill mechanically venti-
in Sepsis lated medical and surgical patients (311). There were no dif-
1. We recommend that either continuous or intermittent ferences in duration of mechanical ventilation or lengths of
sedation be minimized in mechanically ventilated sepsis stay between the groups; and daily interruption was associated
patients, targeting specific titration endpoints (grade 1B). with higher daily opioid and benzodiazepines doses, as well as
higher nurse workload. Additionally, a randomized prospec-
Rationale. A growing body of evidence indicates that limiting tive blinded observational study demonstrated that although
the use of sedation in critically ill ventilated patients can myocardial ischemia is common in critically ill ventilated
reduce the duration of mechanical ventilation and ICU and patients, daily sedative interruption is not associated with an
hospital lengths of stay (303305). While studies limiting increased occurrence of myocardial ischemia (312). Regardless
sedation have been performed in a wide range of critically ill of sedation approach, early physical rehabilitation should be a
patients, there is little reason to assume that septic patients goal (313).
will not derive benefit from this approach (305). The use of
protocols for sedation is one method to limit sedation use, and 2. We recommend that NMBAs be avoided if possible in the
a randomized, controlled clinical trial found that protocolized septic patient without ARDS due to the risk of prolonged
sedation compared with usual care reduced duration of neuromuscular blockade following discontinuation. If
mechanical ventilation, lengths of stay, and tracheostomy NMBAs must be maintained, either intermittent bolus as
rates (305). Avoidance of sedation is another strategy. A required or continuous infusion with train-of-four moni-
recent observational study of 250 critically ill patients suggests toring of the depth of blockade should be used (grade 1C).
that deep sedation is common in mechanically ventilated 3. We suggest a short course of an NMBA ( 48 hours) for
patients (306). A randomized, controlled clinical trial found patients with early, sepsis-induced ARDS and PaO2/FIO2
that patients treated with intravenous morphine boluses < 150 mm Hg (grace 2C).
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Dellinger et al
Rationale. Although NMBAs are often administered to total dose of NMBAs and shorter intubation times) also may
critically ill patients, their role in the ICU is not well defined. exist, although this has not been studied formally.
No evidence exists that neuromuscular blockade in this patient Q. Glucose Control
population reduces mortality or major morbidity. In addition,
1. We recommend a protocolized approach to blood glucose
no studies have been published that specifically address the use
management in ICU patients with severe sepsis, commenc-
of NMBAs in septic patients.
ing insulin dosing when two consecutive blood glucose lev-
The most common indication for NMBA use in the ICU is
els are > 180 mg/dL. This approach should target an upper
to facilitate mechanical ventilation (314). When appropriately
blood glucose level 180 mg/dL rather than an upper target
used, these agents may improve chest wall compliance, prevent
blood glucose 110 mg/dL (grade 1A).
respiratory dyssynchrony, and reduce peak airway pressures
2. We recommend blood glucose values be monitored every 1
(315). Muscle paralysis may also reduce oxygen consumption
to 2 hrs until glucose values and insulin infusion rates are
by decreasing the work of breathing and respiratory muscle
stable, then every 4 hrs thereafter (grade 1C).
blood flow (316). However, a randomized, placebo-controlled 3. We recommend that glucose levels obtained with point-of-
clinical trial in patients with severe sepsis demonstrated that care testing of capillary blood be interpreted with caution,
oxygen delivery, oxygen consumption, and gastric intramuco- as such measurements may not accurately estimate arterial
sal pH were not improved during deep neuromuscular block- blood or plasma glucose values (UG).
ade (317).
A recent randomized clinical trial of continuous infusions Rationale. One large RCT single-center trial in a predomi-
of cisatracurium in patients with early ARDS and a PaO2/FIO2 nantly cardiac surgical ICU demonstrated a reduction in ICU
< 150 mm Hg showed improved adjusted survival rates and mortality with intensive intravenous insulin (Leuven protocol)
more organ failure-free days without an increased risk in ICU- targeting blood glucose to 80 to 110 mg/dL (326). A second
acquired weakness compared with placebo-treated patients randomized trial of intensive insulin therapy using the Leuven
(318). The investigators used a high fixed dose of cisatracurium protocol enrolled medical ICU patients with an anticipated
without train-of-four monitoring, and half of the patients in the ICU length of stay of more than 3 days in three medical ICUs
placebo group received at least a single dose of NMBA. Whether and overall mortality was not reduced (327).
another NMBA would have similar effects is unknown. Although Since these studies (326, 327) and the previous Surviving
many of the patients enrolled into this trial appeared to meet Sepsis Guidelines (7) appeared, several RCTs (128, 328332)
and meta-analyses (333337) of intensive insulin therapy have
sepsis criteria, it is not clear whether similar results would occur
been performed. The RCTs studied mixed populations of sur-
in sepsis patients. A GRADEpro Summary of Evidence Table
gical and medical ICU patients (128, 328332) and found that
regarding use of NMBA in ARDS appears in Supplemental
intensive insulin therapy did not significantly decrease mortality
Digital Content 5 (http://links.lww.com/CCM/A615).
(128, 328332), whereas the NICE-SUGAR trial demonstrated
An association between NMBA use and myopathies and
an increased mortality (331). All studies (128, 326332) reported
neuropathies has been suggested by case studies and prospec-
a much higher incidence of severe hypoglycemia (glucose 40
tive observational studies in the critical care population (315,
mg/dL) (6%29%) with intensive insulin therapy. Several meta-
319322), but the mechanisms by which NMBAs produce or analyses confirmed that intensive insulin therapy was not associ-
contribute to myopathies and neuropathies in these patients ated with a mortality benefit in surgical, medical, or mixed ICU
are unknown. Although no studies are specific to the septic patients (333, 335, 337). The meta-analysis by Griesdale and col-
patient population, it seems clinically prudent, based on exist- leagues (334), using between-trial comparisons driven mainly by
ing knowledge, that NMBAs not be administered unless there the 2001 study by van den Berghe et al (326), found that inten-
is a clear indication for neuromuscular blockade that cannot be sive insulin therapy was beneficial in surgical ICU patients (risk
safely achieved with appropriate sedation and analgesia (315). ratio, 0.63 [0.440.9]), whereas the meta-analysis by Friedrich
Only one prospective RCT has compared peripheral et al (336), using within-trial comparisons, showed no benefit
nerve stimulation and standard clinical assessment in ICU for surgical patients in mixed medical-surgical ICUs (risk ratio
patients. Rudis et al (323) randomized 77 critically ill ICU 0.99 [0.821.11]) and no subgroup of surgical patients who ben-
patients requiring neuromuscular blockade to receive dosing efited from intensive insulin therapy. Interestingly, the RCTs that
of vecuronium based on train-of-four stimulation or on clini- reported (326, 327) compared intensive insulin therapy to high
cal assessment (control group). The peripheral nerve stimu- controls (180200 mg/dL) (OR, 0.89 [0.731.09]), whereas those
lation group received less drug and recovered neuromuscular that did not demonstrate benefit (330332) compared intensive
function and spontaneous ventilation faster than the control therapy to moderate controls (108180 mg/dL) [OR, 1.14 (1.02
group. Nonrandomized observational studies have suggested to 1.26)]. See Supplemental Digital Content 6 (http://links.
that peripheral nerve monitoring reduces or has no effect on lww.com/CCM/A615) for details.
clinical recovery from NMBAs in the ICU (324, 325). The trigger to start an insulin protocol for blood glucose
Benefits to neuromuscular monitoring, including faster levels > 180 mg/dL with an upper target blood glucose level
recovery of neuromuscular function and shorter intubation < 180 mg/dL derives from the NICE-SUGAR study (331),
times, appear to exist. A potential for cost savings (reduced which used these values for initiating and stopping therapy. The
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NICE-SUGAR trial is the largest, most compelling study to date severe sepsis and acute renal failure because they achieve
on glucose control in ICU patients given its inclusion of multi- similar short-term survival rates (grade 2B).
ple ICUs and hospitals and a general patient population. Several 2. We suggest the use of continuous therapies to facilitate
medical organizations, including the American Association management of fluid balance in hemodynamically unstable
of Clinical Endocrinologists, American Diabetes Association, septic patients (grade 2D).
American Heart Association, American College of Physicians,
and Society of Critical Care Medicine, have published consensus Rationale. Although numerous nonrandomized studies have
statements for glycemic control of hospitalized patients (338 reported a nonsignificant trend toward improved survival using
341). These statements usually targeted glucose levels between continuous methods (357364), two meta-analyses (365, 366)
140 and 180 mg/dL. As there is no evidence that targets between reported the absence of significant difference in hospital mor-
140 and 180 mg/dL are different from targets of 110 to 140 mg/ tality between patients who receive continuous and intermittent
dL, the recommendations use an upper target blood glucose renal replacement therapies. This absence of apparent benefit of
180 mg/dL without a lower target other than hypoglycemia. one modality over the other persists even when the analysis is
Treatment should avoid hyperglycemia (> 180 mg/dL), hypogly- restricted to RCT studies (366). To date, five prospective RCTs
cemia, and wide swings in glucose levels. The continuation of have been published (367371); four found no significant dif-
insulin infusions, especially with the cessation of nutrition, has ference in mortality (368371), whereas one found significantly
been identified as a risk factor for hypoglycemia (332). Balanced higher mortality in the continuous treatment group (367), but
nutrition may be associated with a reduced risk of hypoglyce- imbalanced randomization had led to a higher baseline severity
mia (342). Several studies have suggested that the variability in of illness in this group. When a multivariable model was used
glucose levels over time is an important determinant of mortal- to adjust for severity of illness, no difference in mortality was
ity (343345). Hyperglycemia and glucose variability seem to be apparent between the groups (367). Most studies comparing
unassociated with increased mortality rates in diabetic patients modes of renal replacement in the critically ill have included
compared to nondiabetic patients (346, 347). a small number of patients and some major weaknesses (ie,
Several factors may affect the accuracy and reproducibil- randomization failure, modifications of therapeutic protocol
ity of point-of-care testing of blood capillary blood glucose, during the study period, combination of different types of con-
including the type and model of the device used, user expertise, tinuous renal replacement therapies, small number of hetero-
and patient factors, including hematocrit (false elevation with geneous groups of enrollees). The most recent and largest RCT
anemia), PaO2, and drugs (348). Plasma glucose values by cap- (371) enrolled 360 patients and found no significant difference
illary point-of-care testing have been found to be inaccurate in survival between the continuous and intermittent groups.
with frequent false elevations (349, 350) over the range of glu- Moreover, no evidence supports the use of continuous therapies
cose levels (350), but especially in the hypoglycemic (349, 351) in sepsis independent of renal replacement needs.
and hyperglycemic ranges (351) and in hypotensive patients No evidence supports a better tolerance with continu-
(352) or patients receiving catecholamines (353). A review of ous treatments regarding the hemodynamic tolerance of each
12 published insulin infusion protocols for critically ill patients method. Two prospective studies (369, 372) have reported a bet-
showed wide variability in dose recommendations and variable ter hemodynamic tolerance with continuous treatment, with no
glucose control (354). This lack of consensus about optimal improvement in regional perfusion (372) and no survival ben-
dosing of intravenous insulin may reflect variability in patient efit (369). Four other prospective studies did not find any sig-
factors (severity of illness, surgical vs. medical settings), or prac- nificant difference in mean arterial pressure or drop in systolic
tice patterns (eg, approaches to feeding, intravenous dextrose) pressure between the two methods (368, 370, 371, 373). Two
in the environments in which these protocols were developed studies reported a significant improvement in goal achievement
and tested. Alternatively, some protocols may be more effec- with continuous methods (367, 369) regarding fluid balance
tive than others, conclusion supported by the wide variability management. In summary, the evidence is insufficient to draw
in hypoglycemia rates reported with protocols (128, 326333). strong conclusions regarding the mode of replacement therapy
Thus, the use of established insulin protocols is important not for acute renal failure in septic patients.
only for clinical care but also for the conduct of clinical trials
The effect of dose of continuous renal replacement on out-
to avoid hypoglycemia, adverse events, and premature termina-
comes in patients with acute renal failure has shown mixed
tion of trials before the efficacy signal, if any, can be determined.
results (374, 375). None of these trials was conducted specifi-
Several studies have suggested that computer-based algorithms
cally in patients with sepsis. Although the weight of evidence
result in tighter glycemic control with a reduced risk of hypo-
suggests that higher doses of renal replacement may be associ-
glycemia (355, 356). Further study of validated, safe, and effec-
ated with improved outcomes, these results may not be general-
tive protocols for controlling blood glucose concentrations and
izable. Two large multicenter randomized trials comparing the
variability in the severe sepsis population is needed.
dose of renal replacement (Acute Renal Failure Trial Network
R. Renal Replacement Therapy in the United States and RENAL Renal Replacement Therapy
1. We suggest that continuous renal replacement therapies and Study in Australia and New Zealand) failed to show benefit of
intermittent hemodialysis are equivalent in patients with more aggressive renal replacement dosing. (376, 377). A typical
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Dellinger et al
dose for continuous renal replacement therapy would be 20 to hemodynamically compromised patient) are dire. Therefore,
25 mL/kg/hr of effluent generation. prevention of VTE is highly desirable, especially if it can be
done safely and effectively.
Prophylaxis is generally effective. In particular, nine placebo-
S. Bicarbonate Therapy
controlled RCTs of VTE prophylaxis have been conducted in
1. We recommend against the use of sodium bicarbonate ther- general populations of acutely ill patients (381389). All trials
apy for the purpose of improving hemodynamics or reduc- showed reduction in DVT or pulmonary embolism, a benefit
ing vasopressor requirements in patients with hypoperfu- that is also supported by meta-analyses (390, 391). Thus, the
sion-induced lactic acidemia with pH 7.15 (grade 2B). evidence strongly supports the value of VTE prophylaxis (grade
1A). The prevalence of infection/sepsis was 17% in those studies
Rationale. Although bicarbonate therapy may be useful in
in which this could be ascertained. One study investigated only
limiting tidal volume in ARDS in some situations of permissive
ICU patients only, and 52% of those enrolled had infection/
hypercapnia (see section, Mechanical Ventilation of ARDS), no
sepsis. The need to extrapolate from general, acutely ill patients
evidence supports the use of bicarbonate therapy in the treat-
to critically ill patients to septic patients downgrades the
ment of hypoperfusion-induced lactic acidemia associated with
evidence. That the effect is pronounced and the data are robust
sepsis. Two blinded, crossover RCTs that compared equimolar
somewhat mitigate against the extrapolation, leading to a grade
saline and bicarbonate in patients with lactic acidosis failed to
B determination. Because the patients risk of administration is
reveal any difference in hemodynamic variables or vasopressor
small, the gravity of not administering may be great, and the
requirements (378, 379). The number of patients with < 7.15 pH
cost is low, the strength of the recommendation is strong (1).
in these studies was small. Bicarbonate administration has been
Deciding how to provide prophylaxis is decidedly more
associated with sodium and fluid overload, an increase in lac-
difficult. The Canadian Critical Care Trials Group compared
tate and PCO2, and a decrease in serum ionized calcium, but the
UFH (5000 IU twice daily) to LMWH (dalteparin, 5000
relevance of these variables to outcome is uncertain. The effect
IU once per day and a second placebo injection to ensure
of bicarbonate administration on hemodynamics and vasopres-
parallel-group equivalence) (392). No statistically signifi-
sor requirements at lower pH, as well as the effect on clinical
cant difference in asymptomatic DVTs was found between
outcomes at any pH, is unknown. No studies have examined the
the two groups (hazard ratio, 0.92; 95% CI, 0.681.23; p =
effect of bicarbonate administration on outcomes.
0.57), but the proportion of patients diagnosed with pul-
T. Deep Vein Thrombosis Prophylaxis monary embolism on CT scan, high-probability ventila-
tion perfusion scan, or autopsy was significantly lower in
1. We recommend that patients with severe sepsis receive
the LMWH group (hazard ratio, 0.51; 95% CI, 0.300.88;
daily pharmacoprophylaxis against venous thromboembo-
p = 0.01).The study did not account for the use of other forms
lism (VTE) (grade 1B). We recommend that this be accom-
of LMWH. These data suggest that LMWH (dalteparin) is
plished with daily subcutaneous low-molecular weight
the treatment of choice over UFH administered twice daily
heparin (LMWH) (grade 1B versus unfractionated heparin
in critically ill patients. Also, because the study included sep-
[UFH] twice daily and grade 2C versus UFH given thrice
tic patients, the evidence supporting the use of dalteparin over
daily). If creatinine clearance is < 30 mL/min, we recom-
twice daily UFH in critically ill, and perhaps septic, patients is
mend use of dalteparin (grade 1A) or another form of
strong. Similarly, a meta-analysis of acutely ill, general medical
LMWH that has a low degree of renal metabolism (grade
patients comparing UFH twice and thrice daily demonstrated
2C) or UFH (grade 1A).
that the latter regimen was more effective at preventing VTE,
2. We suggest that patients with severe sepsis be treated with
but twice daily dosing produced less bleeding (393). Both criti-
a combination of pharmacologic therapy and intermit-
cally ill and septic patients were included in these analyses, but
tent pneumatic compression devices whenever possible
their numbers are unclear. Nonetheless, the quality of evidence
(grade 2C).
supporting the use of three times daily, as opposed to twice
3. We recommend that septic patients who have a contraindica-
daily, UFH dosing in preventing VTE in acutely ill medical
tion to heparin use (eg, thrombocytopenia, severe coagulopathy,
patients is high (A). However, comparing LMWH to twice daily
active bleeding, recent intracerebral hemorrhage) not receive
UFH, or twice daily UFH to three times daily UFH, in sepsis
pharmacoprophylaxis (grade 1B). Rather we suggest they
requires extrapolation, downgrading the data. No data exist on
receive mechanical prophylactic treatment, such as graduated
direct comparison of LMWH to UFH administered three times
compression stockings or intermittent compression devices
daily, nor are there any studies directly comparing twice daily
(grade 2C), unless contraindicated. When the risk decreases, we
and thrice daily UFH dosing in septic or critically ill patients.
suggest starting pharmacoprophylaxis (grade 2C).
Therefore, it is not possible to state that LMWH is superior to
Rationale. ICU patients are at risk for deep vein thrombosis three times daily UFH or that three times daily dosing is supe-
(DVT) (380). It is logical that patients with severe sepsis would rior to twice daily administration in sepsis. This downgrades
be at a similar or higher risk than the general ICU population. the quality of the evidence and therefore the recommendation.
The consequences of VTE in the setting of sepsis (increased Douketis et al (394) conducted a study of 120 critically
risk of potentially fatal pulmonary emboli in an already ill patients with acute kidney injury (creatinine clearance
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< 30 mL/min) who received VTE prophylaxis with dalteparin Both old and new meta-analyses show prophylaxis-induced
5000 IU daily for between 4 and 14 days and had at least one reduction in clinically significant upper GI bleeding, which we
trough anti-factor Xa level measured. None of the patients consider significant even in the absence of proven mortality
had bio-accumulation (trough anti-factor Xa level lower than benefit (409411). The benefit of prevention of upper GI
0.06 IU/mL). The incidence of major bleeding was somewhat bleeding must be weighed against the potential (unproven)
higher than in trials of other agents, but most other studies effect of increased stomach pH on a greater incidence of VAP
did not involve critically ill patients, in whom the bleeding risk and C. difficile infection (409, 412, 413). (See Supplemental
is higher. Further, bleeding did not correlate with detectable Digital Content 7 and 8 [http://links.lww.com/CCM/
trough levels (394). Therefore, we recommend that dalteparin A615], Summary of Evidence Tables for effects of treatments
can be administered to critically ill patients with acute renal on specific outcomes.) In an exploratory hypothesis, we
failure (A). Data on other LMWHs are lacking. Consequently, considered (as did the authors of the meta-analysis) (411) the
these forms should probably be avoided or, if used, anti-factor possibility of less benefit and more harm in prophylaxis among
Xa levels should be monitored (grade 2C). UFH is not renally patients receiving enteral nutrition but decided to provide one
cleared and is safe (grade 1A). recommendation while lowering the quality of evidence. The
Mechanical methods (intermittent compression devices and balance of benefits and risks may thus depend on the individual
graduated compression stockings) are recommended when patients characteristics as well as on the local epidemiology of
anticoagulation is contraindicated (395397). A meta-analysis VAP and C. difficile infections. The rationale for considering
of 11 studies, including six RCTs, published in the Cochrane only suppression of acid production (and not sucralfate) is
Library concluded that the combination of pharmacologic and based on the study of 1,200 patients by Cook et al comparing
mechanical prophylaxis was superior to either modality alone H2 blockers and sucralfate (414). More recent meta-analyses
in preventing DVT and was better than compression alone provide low-quality evidence suggesting more effective GI
in preventing pulmonary embolism (398). This analysis did bleeding protection with the use of proton pump inhibitors
than with H2RA (415417). Patients should be periodically
not focus on sepsis or critically ill patients but included stud-
evaluated for the continued need for prophylaxis.
ies of prophylaxis after orthopedic, pelvic, and cardiac surgery.
In addition, the type of pharmacologic prophylaxis varied,
V. Nutrition
including UFH, LMWH, aspirin, and warfarin. Nonetheless,
the minimal risk associated with compression devices lead 1. We suggest administering oral or enteral (if necessary) feed-
us to recommend combination therapy in most cases. In ings, as tolerated, rather than either complete fasting or pro-
very-high-risk patients, LMWH is preferred over UFH (392, vision of only intravenous glucose within the first 48 hrs
399401). Patients receiving heparin should be monitored for after a diagnosis of severe sepsis/septic shock (grade 2C).
development of heparin-induced thrombocytopenia. These 2. We suggest avoiding mandatory full caloric feeding in the
recommendations are consistent with those developed by the first week, but rather suggest low-dose feeding (eg, up to
American College of Chest Physicians (402). 500 kcal per day), advancing only as tolerated (grade 2B).
3. We suggest using intravenous glucose and enteral nutrition
U. Stress Ulcer Prophylaxis rather than total parenteral nutrition (TPN) alone or paren-
teral nutrition in conjunction with enteral feeding in the first 7
1. We recommend that stress ulcer prophylaxis using H2 blocker days after a diagnosis of severe sepsis/septic shock (grade 2B).
or proton pump inhibitor be given to patients with severe 4. We suggest using nutrition with no specific immunomodulat-
sepsis/septic shock who have bleeding risk factors (grade 1B). ing supplementation in patients with severe sepsis (grade 2C).
2. When stress ulcer prophylaxis is used, we suggest the use of
proton pump inhibitors rather than H2 receptor antagonists Rationale. Early enteral nutrition has theoretical advan-
(H2RA) (grade 2C). tages in the integrity of gut mucosa and prevention of bacterial
3. We suggest that patients without risk factors should not translocation and organ dysfunction, but also concerning is the
receive prophylaxis (grade 2B). risk of ischemia, mainly in hemodynamically unstable patients.
Unfortunately, no clinical trial has specifically addressed
Rationale. Although no study has been performed specifi- early feeding in septic patients. Studies on different subpopula-
cally in patients with severe sepsis, trials confirming the benefit tions of critically ill patients, mostly surgical patients, are not
of stress ulcer prophylaxis in reducing upper gastrointestinal consistent, with great variability in the intervention and con-
(GI) bleeding in general ICU populations included 20% to 25% trol groups; all are of low methodological quality (418427)
of patients with sepsis (403406). This benefit should be appli- and none was individually powered for mortality, with very
cable to patients with severe sepsis and septic shock. In addition, low mortality rates (418420, 423, 426). Authors of previously
the risk factors for GI bleeding (eg, coagulopathy, mechanical published meta-analyses of optimal nutrition strategies for the
ventilation for at least 48 hrs, possibly hypotension) are fre- critically ill all reported that the studies they included had high
quently present in patients with severe sepsis and septic shock heterogeneity and low quality(418430). Although no consis-
(407, 408). Patients without these risk factors are unlikely (0.2%; tent effect on mortality was observed, there was evidence of
95% CI, 0.020.5) to have clinically important bleeding (407). benefit from some early enteral feeding on secondary outcomes,
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Dellinger et al
such as reduced incidence of infectious complications (418, in treatment effects across subgroups, including the sepsis sub-
422, 426, 427430), reduced length of mechanical ventilation jects. Therefore, no studies suggest the superiority of TPN over
(421, 427), and reduced ICU (421, 427) and hospital stays (428). enteral alone in the first 24 hrs. In fact, there is a suggestion that
No evidence of harm was demonstrated in any of those studies. enteral nutrition may in fact be superior to TPN vis--vis infec-
Therefore, there is insufficient evidence to issue a strong recom- tious complications and possibly requirement for intensive care
mendation, but the suggestion of benefit and absence of harm and organ support.
supports a suggestion that some enteral feeding is warranted. Immune system function can be modified through altera-
Studies comparing full caloric early enteral feeding to lower tions in the supply of certain nutrients, such as arginine, gluta-
targets in the critically ill have produced inconclusive results. mine, or omega-3 fatty acids. Numerous studies have assessed
In four studies, no effect on mortality was seen (431434); one whether use of these agents as nutritional supplements can
reported fewer infectious complications (431), and the others affect the course of critical illness, but few specifically addressed
reported increased diarrhea and gastric residuals (433, 434) their early use in sepsis. Four meta-analyses evaluated immune-
and increased incidence of infectious complications with full enhancing nutrition and found no difference in mortality, nei-
caloric feeding (432). In another study, mortality was greater ther in surgical nor medical patients (445448). However, they
with higher feeding, but differences in feeding strategies were analyzed all studies together, regardless of the immunocompo-
modest and the sample size was small (435). Therefore, evidence nent used, which could have compromised their conclusions.
is insufficient to support an early target of full caloric intake Other individual studies analyzed diets with a mix of arginine,
and, indeed, some possibility of harm exists. Underfeeding glutamine, antioxidants, and/or omega-3 with negative results
(60%70% of target) or trophic feeding (upper limit of 500 (449, 450) including a small study in septic patients showing a
kcal) is probably a better nutritional strategy in the first week of nonsignificant increase in ICU mortality (451, 452).
severe sepsis/septic shock. This upper limit for trophic feeding
Arginine.
is a somewhat arbitrary number, but based in part on the fact
Arginine availability is reduced in sepsis, which can lead
that the two recent studies used a range of 240480 kcal (433,
to reduced nitric oxide synthesis, loss of microcirculatory
434). Underfeeding/trophic feeding strategies did not exclude
regulation, and enhanced production of superoxide and
advancing diet as tolerated in those who improved quickly.
peroxynitrite. However, arginine supplementation could lead
Some form of parenteral nutrition has been compared to
to unwanted vasodilation and hypotension (452, 453). Human
alternative feeding strategies (eg, fasting or enteral nutrition)
trials of L-arginine supplementation have generally been small
in well over 50 studies, although only one exclusively studied
and reported variable effects on mortality (454457). The
sepsis (436), and eight meta-analyses have been published
only study in septic patients showed improved survival, but
(429, 437443). Two of the meta-analyses summarize com-
had limitations in study design (455). Other studies suggested
parisons of parenteral nutrition vs. fasting or intravenous glu-
no benefit (449, 454, 455) or possible harm (455) in the
cose (437, 438), and six look at parenteral vs. enteral nutrition
subgroup of septic patients. Some authors found improvement
(429, 439443), two of which attempted to explore the effect
in secondary outcomes in septic patients, such as reduced
of early enteral nutrition (441, 442). Recently, a study much
infectious complications (454, 455) and length of hospital
larger than most earlier nutrition trials compared ICU patients
stay (454), but the relevance of these findings in the face of
randomized to early use of parenteral nutrition to augment
potential harm is unclear.
enteral feeding vs. enteral feeding with only late initiation of
parenteral nutrition if necessary (444). Glutamine.
No direct evidence supports the benefits or harm of paren- Glutamine levels are also reduced during critical illness.
teral nutrition in the first 48 hrs in sepsis. Rather, the evidence Exogenous supplementation can improve gut mucosal atrophy
is generated predominantly from surgical, burn, and trauma and permeability, possibly leading to reduced bacterial trans-
patients. None of the meta-analyses reports a mortality ben- location. Other potential benefits are enhanced immune cell
efit with parenteral nutrition, except one suggesting paren- function, decreased pro-inflammatory cytokine production,
teral nutrition may be better than late introduction of enteral and higher levels of glutathione and antioxidative capacity
nutrition (442). Several suggested that parenteral nutrition (452, 453). However, the clinical significance of these findings
had higher infectious complications compared both to fast- is not clearly established.
ing or intravenous glucose and to enteral nutrition (429, 431, Although a previous meta-analysis showed mortality reduc-
438, 439, 442). Enteral feeding was associated with a higher tion (428), four other meta-analyses did not (458462). Other
rate of enteral complications (eg, diarrhea) than parenteral small studies not included in those meta-analyses had similar
nutrition (438). The use of parenteral nutrition to supple- results (463, 464). Three recent well-designed studies also failed
ment enteral feeding was also analyzed by Dhaliwal et al (440), to show a mortality benefit in the primary analyses (227, 465,
who also reported no benefit. The trial by Casaer et al (444) 466), but again, none focused specifically on septic patients.
reported that early initiation of parenteral nutrition led to lon- Two small studies on septic patients showed no benefit in mor-
ger hospital and ICU stays, longer duration of organ support, tality rates (467, 468) but a significant reduction in infectious
and higher incidence of ICU-acquired infection. One-fifth of complications (467) and a faster recovery of organ dysfunc-
patients had sepsis and there was no evidence of heterogeneity tion (468). Some previous individual studies and meta-analyses
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showed positive secondary outcomes, such as reduction in infec- in the ICU highlight the importance of incorporating goals
tious morbidity (461, 462, 465) and organ dysfunction (462). of care along with the prognosis into treatment plans (484).
Beneficial effects were found mostly in trials using parenteral Additionally, discussing the prognosis for achieving the goals
rather than enteral glutamine. However, recent and well-sized of care and level of certainty of prognosis has been identified
studies could not demonstrate a reduction of infectious compli- as an important component of surrogate decision-making
cations (227) or organ dysfunction (465, 466), even with paren- in the ICU (485, 486). However, variations exist in the use
teral glutamine. An ongoing trial (REDOXS) of 1,200 patients of advanced care planning and integration of palliative and
will test both enteral and parenteral glutamine and antioxidant end-of-life care in the ICU, which can lead to conflicts that
supplementation in critically ill, mechanically ventilated patients may threaten overall quality of care (487, 488). The use of
(469). Although no clear benefit could be demonstrated in clini- proactive family care conferences to identify advanced direc-
cal trials with supplemental glutamine, there is no sign of harm. tives and treatment goals within 72 hrs of ICU admission
The omega-3 fatty acids eicosapentaenoic acid (EPA) and promotes communication and understanding between the
gamma-linolenic acid (GLA) are eicosanoid precursors. The patients family and the care team; improves family satisfac-
prostaglandins, leukotrienes, and thromboxanes produced from tion; decreases stress, anxiety, and depression in surviving
EPA/GLA are less potent than their arachidonic acid-derived relatives; facilitates end-of-life decision making; and short-
equivalents, reducing the pro-inflammatory impact on the ens length of stay for patients who die in the ICU (489494).
immune response (452, 453). Three early studies were sum- Clinical practice guidelines for support of the ICU patient
marized in a meta-analysis that reported a significant mortal- and family promote: early and repeated care conferencing to
ity reduction, increased ventilator-free days, and reduced risk of reduce family stress and improve consistency in communica-
new organ dysfunction (470). However, only one study was in tion; open flexible visitation; family presence during clinical
septic patients (471), none was individually powered for mortal- rounds and resuscitation; and attention to cultural and spiri-
ity (472, 473), and all three used a diet with high omega-6 lipid tual support (495). Additionally, the integration of advanced
content in the control group, which is not the usual standard of care planning and palliative care focused on pain manage-
care in the critically ill. The authors who first reported reduced ment, symptom control, and family support has been shown
mortality in sepsis (471) conducted a follow-up multicenter to improve symptom management and patient comfort, and
study and again found improvement in nonmortality outcomes, to improve family communication (484, 490, 496).
though notably with no demonstrable effect on mortality (474).
Other studies using enteral (475477) or parenteral (478480) PEDIATRIC CONSIDERATIONS IN SEVERE
fish oil failed to confirm these findings in general critical illness SEPSIS (TABLE 9)
or acute lung injury. Thus, no large, reproducible findings sug- While sepsis in children is a major cause of death in industrialized
gest a clear benefit in the use of immunomodulating nutritional countries with state-of-the-art ICUs, the overall mortality from
supplements in sepsis, though larger trials are ongoing. severe sepsis is much lower than that in adults, estimated at about
2% to 10% (497499). The hospital mortality rate for severe sepsis
W. Setting Goals of Care is 2% in previously healthy children and 8% in chronically ill chil-
1. We recommend that goals of care and prognosis be dis- dren in the United States (497). Definitions of sepsis, severe sepsis,
cussed with patients and families (grade 1B). septic shock, and multiple organ dysfunction/failure syndromes
2. We recommend that the goals of care be incorporated into are similar to adult definitions but depend on age-specific heart
treatment and end-of-life care planning, utilizing palliative rate, respiratory rate, and white blood cell count cutoff values
care principles where appropriate (grade 1B). (500, 501). This document provides recommendations only for
3. We suggest that goals of care be addressed as early as feasible, term newborns and children in the industrialized resource-rich
but no later than within 72 hrs of ICU admission (grade 2C). setting with full access to mechanical ventilation ICUs.
Rationale. The majority of ICU patients receive full A. Initial Resuscitation
support with aggressive, life-sustaining treatments. Many
patients with multiple organ system failure or severe neu- 1. We suggest starting with oxygen administered by face mask
rologic injuries will not survive or will have a poor quality or, if needed and available, high-flow nasal cannula oxy-
gen or nasopharyngeal continuous positive airway pressure
of life. Decisions to provide less-aggressive life-sustaining
(CPAP) for respiratory distress and hypoxemia. Peripheral
treatments or to withdraw life-sustaining treatments in these
intravenous access or intraosseous access can be used for fluid
patients may be in the patients best interest and may be what
resuscitation and inotrope infusion when a central line is not
patients and their families desire (481). Physicians have dif-
available. If mechanical ventilation is required, then cardio-
ferent end-of-life practices based on their region of practice,
vascular instability during intubation is less likely after appro-
culture, and religion (482). Although the outcome of inten-
priate cardiovascular resuscitation (grade 2C).
sive care treatment in critically ill patients may be difficult
to prognosticate accurately, establishing realistic treatment Rationale. Due to low functional residual capacity, young
goals is important in promoting patient-centered care in the infants and neonates with severe sepsis may require early intu-
ICU (483). Models for structuring initiatives to enhance care bation; however, during intubation and mechanical ventilation,
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Dellinger et al
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: capillary refill of 2 secs, normal blood pressure for age, normal pulses
with no differential between peripheral and central pulses, warm extremities, urine output >1 mLkg-1hr-1, and normal mental status.
ScvO2 saturation 70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter (grade 2C).
3. Follow American College of Critical Care Medicine-Pediatric Life Support ( ACCM-PALS) guidelines for the management of
septic shock (grade 1C).
4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock
(grade 1C).
B. Antibiotics and Source Control
1. Empiric antibiotics be administered within 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 510
minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and
level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be
implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell
crises) blood transfusion is considered superior to crystalloid or albumin bolusing (grade 2C).
D. Inotropes/Vasopressors/Vasodilators
1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid
resuscitation (grade 2C).
2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given
vasodilator therapies in addition to inotropes (grade 2C).
E. Extracorporeal Membrane Oxygenation (ECMO)
1. Consider ECMO for refractory pediatric septic shock and respiratory failure (grade 2C).
F. Corticosteroids
1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute
(classic) adrenal insufficiency (grade 1A).
G. Protein C and Activated Protein Concentrate
No recommendation as no longer available.
H. Blood Products and Plasma Therapies
1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock
(< 70%), hemoglobin levels of 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).
I. Mechanical Ventilation.
1 Lung-protective strategies during mechanical ventilation (grade 2C)
(Continued)
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TABLE 9. (Continued) Recommendations: Special Considerations in Pediatrics
J. Sedation/Analgesia/Drug Toxicities
1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis (grade 1D).
2. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse
drug-related events (grade 1C).
K. Glycemic Control
1. Control hyperglycemia using a similar target as in adults 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).
L. Diuretics and Renal Replacement Therapy
1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration
(CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload (grade 2C).
M. Deep Vein Thrombosis (DVT) Prophylaxis
No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.
N. Stress Ulcer(SU) Prophylaxis
No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.
O. Nutrition
1. Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot (grade 2C).
increased intrathoracic pressure can reduce venous return and 4. We recommend evaluating for and reversing pneumotho-
lead to worsening shock if the patient is not volume loaded. In rax, pericardial tamponade, or endocrine emergencies in
those who desaturate despite administration of face mask oxy- patients with refractory shock (grade 1C).
gen, high-flow nasal cannula oxygen or nasopharyngeal CPAP
can be used to increase functional residual capacity and reduce Rationale. Endocrine emergencies include hypoadrenal-
the work of breathing, allowing for establishment of intrave- ism and hypothyroidism. In select patients, intra-abdominal
nous or intraosseous access for fluid resuscitation and periph- hypertension may also need to be considered (513515).
eral inotrope delivery (502, 503). Drugs used for sedation have
important side effects in these patients. For example, etomidate B. Antibiotics and Source Control
is associated with increased mortality in children with menin-
gococcal sepsis because of adrenal suppression effect (504, 505). 1. We recommend that empiric antimicrobials be adminis-
Because attainment of central access is more difficult in chil- tered within 1 hr of the identification of severe sepsis. Blood
dren than adults, reliance on peripheral or intraosseous access cultures should be obtained before administering antibiot-
can be substituted until and unless central access is available. ics when possible, but this should not delay initiation of
antibiotics. The empiric drug choice should be changed as
2. We suggest that the initial therapeutic endpoints of resuscita- epidemic and endemic ecologies dictate (eg, H1N1, meth-
tion of septic shock be capillary refill of 2 s, normal blood
icillin-resistant S. aureus, chloroquine-resistant malaria,
pressure for age, normal pulses with no differential between
penicillin-resistant pneumococci, recent ICU stay, neutro-
peripheral and central pulses, warm extremities, urine output
penia) (grade 1D).
> 1 mL/kg/hr, and normal mental status. Thereafter, ScvO2
saturation greater than or equal to 70% and cardiac index Rationale. Vascular access and blood drawing is more dif-
between 3.3 and 6.0 L/min/m2 should be targeted (grade 2C). ficult in newborns and children. Antimicrobials can be given
Rationale. Adult guidelines recommend lactate clearance as intramuscularly or orally (if tolerated) until intravenous line
well, but children commonly have normal lactate levels with access is available (516519).
septic shock. Because of the many modalities used to measure 2. We suggest the use of clindamycin and antitoxin therapies
SCVO2 and cardiac index, the specific choice is left to the practi- for toxic shock syndromes with refractory hypotension
tioners discretion (506512). (grade 2D).
3. We recommend following the American College of Critical Rationale. Children are more prone to toxic shock than
Care Medicine-Pediatric Advanced Life Support guidelines adults because of their lack of circulating antibodies to toxins.
for the management of septic shock (grade 1C). Children with severe sepsis and erythroderma and suspected
Rationale. The recommended guidelines are summarized toxic shock should be treated with clindamycin to reduce
in Figure 2 (510512). toxin production. The role of IVIG in toxic shock syndrome
#RITICAL #ARE -EDICINE www.ccmjournal.org 615
Dellinger et al
Figure 2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Reproduced from Brierley
J, Carcillo J, Choong K, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the Ameri-
can College of Critical Care Medicine. Crit Care Med 2009; 37:666688.
is unclear, but it may be considered in refractory toxic shock Rationale. Dbridement and source control is paramount in
syndrome (520527). severe sepsis and septic shock. Conditions requiring dbridement
3. We recommend early and aggressive infection source con- or drainage include necrotizing pneumonia, necrotizing fasciitis,
trol (grade 1D). gangrenous myonecrosis, empyema, and abscesses. Perforated
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viscus requires repair and peritoneal washout. Delay in use of an resuscitation can require 40 to 60 mL/kg or more; however, if
appropriate antibiotic, inadequate source control, and failure to these signs are present, then fluid administration should be
remove infected devices are associated with increased mortality ceased and diuretics should be given. Inotrope infusions and
in a synergistic manner (528538). mechanical ventilation are commonly required for children
with fluid-refractory shock.
4. C. difficile colitis should be treated with enteral antibiotics
if tolerated. Oral vancomycin is preferred for severe disease
(grade 1A). D. Inotropes/Vasopressors/Vasodilators
Rationale. In adults, metronidazole is a first choice; however, 1. We suggest beginning peripheral inotropic support until
response to treatment with C. difficile can be best with enteral central venous access can be attained in children who are
vancomycin. In very severe cases where diverting ileostomy or not responsive to fluid resuscitation (grade 2C).
colectomy is performed, parenteral treatment should be con-
sidered until clinical improvement is ascertained (539541). Rationale. Cohort studies show that delay in the use of
inotropic therapies is associated with major increases in
C. Fluid Resuscitation mortality risk (553, 554). This delay is often related to dif-
ficulty in attaining central access. In the initial resuscitation
1. In the industrialized world with access to inotropes and phase, inotrope/vasopressor therapy may be required to sus-
mechanical ventilation, we suggest that initial resuscita- tain perfusion pressure, even when hypovolemia has not yet
tion of hypovolemic shock begin with infusion of isotonic been resolved. Children with severe sepsis can present with
crystalloids or albumin, with boluses of up to 20 mL/kg low cardiac output and high systemic vascular resistance,
for crystalloids (or albumin equivalent) over 5 to 10 mins. high cardiac output and low systemic vascular resistance,
These should be titrated to reversing hypotension, increas- or low cardiac output and low systemic vascular resistance
ing urine output, and attaining normal capillary refill, shock (555). A child may move from one hemodynamic
peripheral pulses and level of consciousness without induc- state to another. Vasopressor or inotrope therapy should be
ing hepatomegaly or rales. If hepatomegaly or rales develop, used according to the hemodynamic state (555). Dopamine-
inotropic support should be implemented, not fluid resus- refractory shock may reverse with epinephrine or norepi-
citation. In children with severe hemolytic anemia (severe nephrine infusion. In the case of extremely low systemic
malaria or sickle cell crises) who are not hypotensive, blood vascular resistance despite the use of norepinephrine, the use
transfusion is considered superior to crystalloid or albumin of vasopressin and terlipressin has been described in a num-
bolusing (grade 2C). ber of case reports, yet evidence to support this in pediat-
Rationale. Three RCTs compared the use of colloid to ric sepsis, as well as safety data, are still lacking. Indeed, two
crystalloid resuscitation in children with hypovolemic dengue RCTs showed no benefit in outcome with use of vasopres-
shock with near 100% survival in all treatment arms (542 sin or terlipressin in children (556559). Interestingly, while
544). In the industrialized world, two before-and-after studies vasopressin levels are reduced in adults with septic shock,
observed 10-fold reductions in mortality when children with such levels seem to vary extensively in children. When vaso-
purpura/meningococcal septic shock were treated with fluid pressors are used for refractory hypotension, the addition of
boluses, inotropes, and mechanical ventilation in the com- inotropes is commonly needed to maintain adequate cardiac
munity emergency department (545, 546). In one random- output (510, 511, 555).
ized trial, septic shock mortality was reduced (40% to 12%)
2. We suggest that patients with low cardiac output and elevated
when increased fluid boluses, blood, and inotropes were given
systemic vascular resistance states with normal blood pres-
to attain a ScvO2 monitoring goal of greater than 70% (511).
sure be given vasodilator therapies in addition to inotropes
A quality improvement study achieved a reduction in severe
(grade 2C).
sepsis mortality (from 4.0% to 2.4%) with the delivery of fluid
boluses and antibiotics in the first hour in a pediatric emer- Rationale. The choice of vasoactive agent is initially
gency department to reverse clinical signs of shock (547). determined by the clinical examination; however, for the
Children normally have a lower blood pressure than adults, child with invasive monitoring in place and demonstration
and a fall in blood pressure can be prevented by vasoconstric- of a persistent low cardiac output state with high systemic
tion and increasing heart rate. Therefore, blood pressure alone vascular resistance and normal blood pressure despite fluid
is not a reliable endpoint for assessing the adequacy of resus- resuscitation and inotropic support, vasodilator therapy
citation. However, once hypotension occurs, cardiovascular can reverse shock. Type III phosphodiesterase inhibitors
collapse may soon follow. Thus, fluid resuscitation is recom- (amrinone, milrinone, enoximone) and the calcium sensitizer
mended for both normotensive and hypotensive children in levosimendan can be helpful because they overcome receptor
hypovolemic shock (542554). Because hepatomegaly and/or desensitization. Other important vasodilators include
rales occur in children who are fluid overloaded, these find- nitrosovasodilators, prostacyclin, and fenoldopam. In two
ings can be helpful signs of hypervolemia. In the absence of RCTs, pentoxifylline reduced mortality from severe sepsis in
these signs, large fluid deficits can exist, and initial volume newborns (510, 560569).
#RITICAL #ARE -EDICINE www.ccmjournal.org 617
Dellinger et al
E. Extracorporeal Membrane Oxygenation in nosocomial sepsis and lacked clear evidence of equivalence
in outcomes with the restrictive strategy (584, 585). Blood
1. We suggest ECMO in children with refractory septic shock
transfusion is recommended by the World Health Organization
or with refractory respiratory failure associated with sepsis
for severe anemia, hemoglobin value < 5 g/dL, and acidosis. An
(grade 2C).
RCT of early goal-directed therapy for pediatric septic shock
Rationale. ECMO may be used to support children and using the threshold hemoglobin of 10 g/dL for patients with
neonates with septic shock or sepsis-associated respiratory a SvcO2 saturation less than 70% in the first 72 hrs of pediatric
failure (570, 571). The survival of septic patients supported ICU admission showed improved survival in the multimodal
with ECMO is 73% for newborns and 39% for older chil- intervention arm (511).
dren, and is highest in those receiving venovenous ECMO
(572). Forty-one percent of children with a diagnosis of sep- 2. We suggest similar platelet transfusion targets in children as
sis requiring ECMO for respiratory failure survive to hospital in adults (grade 2C).
discharge (573). Venoarterial ECMO is useful in children with 3. We suggest the use of plasma therapies in children to cor-
refractory septic shock (574), with one center reporting 74% rect sepsis-induced thrombotic purpura disorders, includ-
survival to hospital discharge using central cannulation via ing progressive disseminated intravascular coagulation,
sternotomy (575). ECMO has been used successfully in criti- secondary thrombotic microangiopathy, and thrombotic
cally ill H1N1 pediatric patients with refractory respiratory thrombocytopenic purpura (grade 2C).
failure (576, 577). Rationale. We give plasma to reverse thrombotic micro-
angiopathies in children with thrombocytopenia-associated
F. Corticosteroids multiple organ failure and progressive purpura because fresh
1. We suggest timely hydrocortisone therapy in children with frozen plasma contains protein C, antithrombin III, and other
fluid-refractory, catecholamine-resistant shock and sus- anticoagulant proteins. Rapid resuscitation of shock reverses
pected or proven absolute (classic) adrenal insufficiency most disseminated intravascular coagulation; however, pur-
(grade 1A). pura progresses in some children in part due to critical
consumption of antithrombotic proteins (eg, protein C, anti-
Rationale. Approximately 25% of children with septic thrombin III, ADAMTS 13). Plasma is infused with the goal
shock have absolute adrenal insufficiency. Patients at risk for of correcting prolonged prothrombin/partial thromboplastin
absolute adrenal insufficiency include children with severe times and halting purpura. Large volumes of plasma require
septic shock and purpura, those who have previously received concomitant use of diuretics, continuous renal replacement
steroid therapies for chronic illness, and children with pitu- therapy, or plasma exchange to prevent greater than 10% fluid
itary or adrenal abnormalities. Initial treatment is hydrocorti- overload (586611).
sone infusion given at stress doses (50 mg/m2/24 hr); however,
infusions up to 50 mg/kg/d may be required to reverse shock in I. Mechanical Ventilation
the short-term. Death from absolute adrenal insufficiency and
septic shock occurs within 8 hrs of presentation. Obtaining 1. We suggest providing lung-protective strategies during
a serum cortisol level at the time empiric hydrocortisone is mechanical ventilation (grade 2C).
administered may be helpful (578583). Rationale. Some patients with ARDS will require increased
PEEP to attain functional residual capacity and maintain oxy-
G. Protein C and Activated Protein Concentrate genation, and peak pressures above 30 to 35 cm H2O to attain
See section, History of Recommendations Regarding Use of effective tidal volumes of 6 to 8 mL/kg with adequate CO2
Recombinant Activated Protein C. removal. In these patients, physicians generally transition from
conventional pressure control ventilation to pressure release
H. Blood Products and Plasma Therapies ventilation (airway pressure release ventilation) or to high-fre-
1. We suggest similar hemoglobin targets in children as in quency oscillatory ventilation. These modes maintain oxygen-
adults. During resuscitation of low superior vena cava oxy- ation with higher mean airway pressures using an open lung
gen saturation shock (< 70%), hemoglobin levels of 10 g/ ventilation strategy. To be effective, these modes can require
dL are targeted. After stabilization and recovery from shock a mean airway pressure 5 cm H2O higher than that used with
and hypoxemia, then a lower target > 7.0 g/dL can be con- conventional ventilation. This can reduce venous return lead-
sidered reasonable (grade 1B). ing to greater need for fluid resuscitation and vasopressor
requirements (612616).
Rationale. The optimal hemoglobin for a critically ill child
with severe sepsis is not known. A recent multicenter trial
J. Sedation/Analgesia/Drug Toxicities
reported no difference in mortality in hemodynamically stable
critically ill children managed with a transfusion threshold of 7 g/ 1. We recommend use of sedation with a sedation goal in
dL compared with those managed with a transfusion threshold critically ill mechanically ventilated patients with sepsis
of 9.5 g/dL; however, the severe sepsis subgroup had an increase (grade 1D).
618 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
Rationale. Although there are no data supporting any par- fluid overload before continuous venovenous hemofiltration
ticular drugs or regimens, propofol should not be used for had better survival (629631),
long-term sedation in children younger than 3 years because
of the reported association with fatal metabolic acidosis. The M. DVT Prophylaxis
use of etomidate and/or dexmedetomidine during septic shock
1. We make no graded recommendations on the use of DVT
should be discouraged, or at least considered carefully, because prophylaxis in prepubertal children with severe sepsis.
these drugs inhibit the adrenal axis and the sympathetic ner-
vous system, respectively, both of which are needed for hemo- Rationale. Most DVTs in young children are associated
dynamic stability (617620). with central venous catheters. Heparin-bonded catheters may
decrease the risk of catheter-associated DVT. No data exist on
2. We recommend monitoring drug toxicity labs because the efficacy of UFH or LMWH prophylaxis to prevent catheter-
drug metabolism is reduced during severe sepsis, put- related DVT in children in the ICU (632, 633).
ting children at greater risk of adverse drug-related events
(grade 1C). N. Stress Ulcer Prophylaxis
Rationale. Children with severe sepsis have reduced drug 1. We make no graded recommendations on stress ulcer
metabolism (621). prophylaxis.
Rationale. Studies have shown that clinically important GI
K. Glycemic Control
bleeding in children occurs at rates similar to those of adults.
1. We suggest controlling hyperglycemia using a similar target Stress ulcer prophylaxis is commonly used in children who are
as in adults ( 180 mg/dL). Glucose infusion should accom- mechanically ventilated, usually with H2 blockers or proton
pany insulin therapy in newborns and children (grade 2C). pump inhibitors, although its effect is not known (634, 635).
Rationale. In general, infants are at risk for developing
O. Nutrition
hypoglycemia when they depend on intravenous fluids. This
means that a glucose intake of 4 to 6 mg/kg/min or mainte- 1. Enteral nutrition should be used in children who can toler-
nance fluid intake with dextrose 10% normal saline con- ate it, parenteral feeding in those who cannot (grade 2C).
taining solution is advised (68 mg/kg/min in newborns).
Rationale. Dextrose 10% (always with sodium-containing
Associations have been reported between hyperglycemia
solution in children) at maintenance rate provides the glu-
and an increased risk of death and longer length of stay. A
cose delivery requirements for newborns and children (636).
retrospective pediatric ICU study reported associations of
Patients with sepsis have increased glucose delivery needs
hyperglycemia, hypoglycemia, and glucose variability with
which can be met by this regimen. Specific measurement of
increased length of stay and mortality rates. An RCT of strict caloric requirements are thought to be best attained using a
glycemic control compared to moderate control using insulin metabolic cart as they are generally less in the critically ill child
in a pediatric ICU population found a reduction in mortal- than in the healthy child.
ity with an increase in hypoglycemia. Insulin therapy should
only be conducted with frequent glucose monitoring in view
of the risks for hypoglycemia which can be greater in new- SUMMARY AND FUTURE DIRECTIONS
borns and children due to a) relative lack of glycogen stores Although this document is static, the optimum treatment of
and muscle mass for gluconeogenesis, and b) the heterogeneity severe sepsis and septic shock is a dynamic and evolving pro-
of the population with some excreting no endogenous insu- cess. Additional evidence that has appeared since the publica-
lin and others demonstrating high insulin levels and insulin tion of the 2008 guidelines allows more certainty with which
resistance (622628). we make severe sepsis recommendations; however, further
programmatic clinical research in sepsis is essential to optimize
L. Diuretics and Renal Replacement Therapy these evidence-based medicine recommendations.
New interventions will be proven and established inter-
1. We suggest the use of diuretics to reverse fluid overload ventions may need modification. This publication represents
when shock has resolved and if unsuccessful, then continu- an ongoing process. The Surviving Sepsis Campaign and the
ous venovenous hemofiltration or intermittent dialysis to consensus committee members are committed to updating the
prevent greater than 10% total body weight fluid overload guidelines regularly as new interventions are tested and results
(grade 2C). published.
Rationale. A retrospective study of children with meningo-
coccemia showed an associated mortality risk when children ACKNOWLEDGMENT
received too little or too much fluid resuscitation (549, 553). The revision process was funded through a grant from the
A retrospective study of 113 critically ill children with multiple Gordon and Betty Irene Moore Foundation. We would also
organ dysfunction syndrome reported that patients with less like to acknowledge the dedication and untold hours of
#RITICAL #ARE -EDICINE www.ccmjournal.org 619
Dellinger et al
donated time of committee members over the last 2 years; 6ARPULA - 4ALLGREN - 3AUKKONEN + ET AL (EMODYNAMIC VARIABLES
RELATED TO OUTCOME IN SEPTIC SHOCK Intensive Care Med
the sponsoring organizations that worked with us toward the
n
reality of a consensus document across so many disciplines, +ORTGEN ! .IEDERPRM 0 "AUER - )MPLEMENTATION OF AN EVIDENCE
specialties, and continents; and those that contribute in so BASED hSTANDARD OPERATING PROCEDUREv AND OUTCOME IN SEPTIC SHOCK
many ways to create the new science to move us forward in Crit Care Med n
treating this potentially devastating disease: the funders of 3EBAT & *OHNSON $ -USTHAFA !! ET AL ! MULTIDISCIPLINARY COMMUNITY
HOSPITAL PROGRAM FOR EARLY AND RAPID RESUSCITATION OF SHOCK IN NON-
research, the investigators, the subjects, and those associated TRAUMA PATIENTS Chest n
with the evidence publishing bodies. Finally, we thank 3HAPIRO .) (OWELL -$ 4ALMOR $ ET AL )MPLEMENTATION AND OUT-
Deborah McBride for the incredible editorial support provided COMES OF THE -ULTIPLE 5RGENT 3EPSIS 4HERAPIES -534 PROTOCOL Crit
persistently over months that brought the manuscript to life Care Med n
and finalization. -ICEK 34 2OUBINIAN . (EURING 4 ET AL "EFORE
AFTER STUDY OF A STAN-
DARDIZED HOSPITAL ORDER SET FOR THE MANAGEMENT OF SEPTIC SHOCK Crit
Care Med n
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DRUG METABOLISM IS REDUCED IN CHILDREN WITH SEPSIS INDUCED MULTIPLE "ROPHY 0$ 2ENAL SUPPORTIVE THERAPY FOR PEDIATRIC ACUTE KIDNEY
ORGAN FAILURE Intensive Care Med n INJURY IN THE SETTING OF MULTIORGAN DYSFUNCTION SYNDROMESEPSIS
"RANCO 2' 'ARCIA 0# 0IVA *0 ET AL 'LUCOSE LEVEL AND RISK OF Semin Nephrol n
MORTALITY IN PEDIATRIC SEPTIC SHOCK Pediatr Crit Care Med +RAFTE *ACOBS " 3IVIT #* -EJIA 2 ET AL #ATHETER RELATED THROMBOSIS
n IN CRITICALLY ILL CHILDREN #OMPARISON OF CATHETERS WITH AND WITHOUT
&AUSTINO %6 !PKON - 0ERSISTENT HYPERGLYCEMIA IN CRITICALLY ILL CHILDREN HEPARIN BONDING J Pediatr n
J Pediatr n 0IERCE #- 7ADE ! -OK 1 (EPARIN BONDED CENTRAL VENOUS LINES
*ESCHKE -' +ULP '! +RAFT 2 ET AL )NTENSIVE INSULIN THERAPY IN REDUCE THROMBOTIC AND INFECTIVE COMPLICATIONS IN CRITICALLY ILL CHILDREN
SEVERELY BURNED PEDIATRIC PATIENTS ! PROSPECTIVE RANDOMIZED TRIAL Intensive Care Med n
Am J Respir Crit Care Med n #HABOU - 4UCCI - $UGAS -! ET AL #LINICALLY SIGNIlCANT UPPER
$AY +- (AUB . "ETTS ( ET AL (YPERGLYCEMIA IS ASSOCIATED WITH GASTROINTESTINAL BLEEDING ACQUIRED IN A PEDIATRIC INTENSIVE CARE UNIT
MORBIDITY IN CRITICALLY ILL CHILDREN WITH MENINGOCOCCAL SEPSIS Pediatr ! PROSPECTIVE STUDY Pediatrics 0T n
Crit Care Med n 'AUVIN & $UGAS -! #HABOU - ET AL 4HE IMPACT OF CLINICALLY SIG-
'ARCIA "RANCO 2 4ASKER 2# 2AMOS 'ARCIA 0# ET AL 'LYCEMIC NIlCANT UPPER GASTROINTESTINAL BLEEDING ACQUIRED IN A PEDIATRIC INTEN-
CONTROL AND INSULIN THERAPY IN SEPSIS AND CRITICAL ILLNESS J Pediatr SIVE CARE UNIT Pediatr Crit Care Med n
(Rio J) 3UPPL 3n3 3HERIDAN 2, 9U 9- 0RELACK + ET AL -AXIMAL PARENTERAL GLUCOSE
6ERHOEVEN ** DEN "RINKER - (OKKEN +OELEGA !# ET AL 0ATHOPHYSI- OXIDATION IN HYPERMETABOLIC YOUNG CHILDREN ! STABLE ISOTOPE STUDY
OLOGICAL ASPECTS OF HYPERGLYCEMIA IN CHILDREN WITH MENINGOCOCCAL JPEN J Parenter Enteral Nutr n
APPENDIX A Intensive Care; 4Indian Society of Critical Care Medicine;
2012 Surviving Sepsis Campaign Guidelines
5
Chinese Society of Critical Care Medicine; 6Japanese Association
Committee for Acute Medicine; 7American Association of Critical-Care
R. Phillip Dellinger, (Co-Chair); Rui Moreno (Co-Chair); Nurses, 8Japanese Society of Intensive Care Medicine; 9Society of
Leanne Aitken,1 Hussain Al Rahma,2 Derek C. Angus, Dijillali Hospital Medicine; 10World Federation of Societies of Intensive
Annane, Richard J. Beale, Gordon R. Bernard, Paolo Biban,3 and Critical Care Medicine; 11Society of Academic Emergency
Julian F. Bion, Thierry Calandra, Joseph A. Carcillo, Terry P. Medicine; 12European Society of Clinical Microbiology
Clemmer, Clifford S. Deutschman, J.V. Divatia,4 Ivor S. Doug- and Infectious Diseases; 13Asia Pacific Association of Critical
las, Bin Du,5 Seitaro Fujishima, Satoshi Gando,6 Herwig Ger- Care Medicine; 14Society of Critical Care Medicine; 15Latin
lach, Caryl Goodyear-Bruch,7 Gordon Guyatt, Jan A. Hazelzet, American Sepsis Institute; 16Canadian Critical Care Society;
Hiroyuki Hirasawa,8 Steven M. Hollenberg, Judith Jacobi, 17
Surgical Infection Society; 18Infectious Diseases Society of
Roman Jaeschke, Ian Jenkins,9 Edgar Jimenez,10 Alan E. Jones,11 America; 19American College of Emergency Physicians; 20Chinese
Robert M. Kacmarek, Winfried Kern,12 Ruth M. Kleinpell,1 Society of Critical Care-China Medical Association; 21German
Shin Ok Koh,13 Joji Kotani, Mitchell Levy,14 Flavia Machado,15 Sepsis Society; 22Brazilian Society of Critical Care (AMIB);
John Marini, John C. Marshall, Henry Masur, Sangeeta Mehta, 23
European Society of Intensive Care Medicine; 24American
John Muscedere,16 Lena M. Napolitano,17 Mark E. Nunnally, Thoracic Society; 25International Pan Arab Critical Care Medicine
Steven M. Opal,18 Tiffany M. Osborn,19 Margaret M. Parker, Society; 26Pediatric Acute Lung Injury and Sepsis Investigators;
Joseph E. Parrrillo, Haibo Qiu,20 Adrienne G. Randolph, 27
American College of Chest Physicians; 28Australian and New
Konrad Reinhart,21 Jordi Rello, Ederlon Resende,22 Andrew
Zealand Intensive Care Society; 29European Respiratory Society;
Rhodes,23 Emanuel P. Rivers, Gordon D. Rubenfeld,24 Christa
World Federation of Pediatric Intensive and Critical Care Societies.
A. Schorr, Jonathan E. Sevransky, Khalid Shukri,25 Eliezer Silva,
Mark D. Soth, Charles L. Sprung, Ann E. Thompson,26 Sean
R. Townsend, Jeffery S. Vender,27 Jean-Louis Vincent, Steve A. Pediatric Subgroup
Webb,28 Tobias Welte,29 Janice L. Zimmerman. Jan A. Hazelzet, Adrienne G. Randolph, Margaret M. Parker,
1
World Federation of Critical Care Nurses; 2Emirates Intensive Ann E. Thompson, Paolo Biban, Alan Duncan, Cristina Mangia,
Care Society; 3European Society of Pediatric and Neonatal Niranjan Kissoon, and Joseph A. Carcillo (Head).
#RITICAL #ARE -EDICINE www.ccmjournal.org 635
Dellinger et al
APPENDIX B
Conflict of Interest Process
636 www.ccmjournal.org &EBRUARY s 6OLUME s .UMBER
Special Article
APPENDIX C
ARDSnet Ventilator Management
Assist control modevolume ventilation
Reduce tidal volume to 6 mL/kg lean body weight
Keep plateau pressure < 30 cm H2O
Reduce tidal volume as low as 4 mL/kg predicted body weight to limit plateau pressure
Maintain SaO2/SpO2 between 88% and 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]
Female45.5 + 2.3 [height (inches) 60] or 45.5 + 0.91 [height (cm) 152.4]
3AO2 ARTERIAL OXYGEN SATURATION 0%%0 POSITIVE END
EXPIRATORY PRESSURE 3PO2 OXYGEN SATURATION ON PULSE OXIMETRY !DAPTED FROM !CUTE 2ESPIRATORY
$ISTRESS 3YNDROME .ETWORK 6ENTILATION WITH LOWER TIDAL VOLUMES AS COMPARED WITH TRADITIONAL TIDAL VOLUMES FOR ACUTE LUNG INJURY AND THE ACUTE RESPIRATORY
DISTRESS SYNDROME
N Engl J Med n
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 H2O
Ventilator rate and pH goal 635, adjusted to achieve arterial pH 7.30 if possible
Inspiration expiration time 1:11:3
Oxygenation goal
PaO2 5580 mm Hg
SpO2 88%95%
Weaning Weaning attempted by means of pressure support when level of arterial oxygenation
acceptable with PEEP < 8 cm H2O and FIO2 < 0.40
Allowable combinations of PEEP and FIO2a
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 0.50.8 0.8 0.9 1
PEEP 12 14 14 16 16 18 20 22 22 2224
.OTE #OMPLETE VENTILATOR PROCEDURES AND ELIGIBILITY CRITERIA CAN BE FOUND AT WWWARDSNETORG
3P/2 OXYHEMOGLOBIN SATURATION AS MEASURED BY PULSE OXIMETRY &)/2 FRACTION OF INSPIRED OXYGEN 0%%0 POSITIVE END
EXPIRATORY PRESSURE
a
)N BOTH STUDY GROUPS LOWER AND HIGHER 0%%0 ADDITIONAL INCREASES IN 0%%0 TO CM (2/ WERE ALLOWED BUT NOT REQUIRED AFTER &)/2 HAD BEEN
INCREASED TO ACCORDING TO THE PROTOCOL
!DAPTED FROM "ROWER 2' ,ANKEN 0. -AC)NTYRE . ET AL (IGHER VS LOWER POSITIVE END
EXPIRATORY PRESSURES IN PATIENTS WITH THE ACUTE RESPIRATORY
DISTRESS SYNDROME
N Engl J Med n
#RITICAL #ARE -EDICINE www.ccmjournal.org 637
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