sepsis and septin shock

Special Article

Surviving Sepsis Campaign: International guidelines formanagement of severe sepsis and septic shock: 2008

R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Jean M. Carlet, MD; Julian Bion, MD; Margaret M. Parker, MD; Roman Jaeschke, MD;Konrad Reinhart, MD; Derek C. Angus, MD, MPH; Christian Brun-Buisson, MD; Richard Beale, MD; Thierry Calandra, MD, PhD;Jean-Francois Dhainaut, MD; Herwig Gerlach, MD; Maurene Harvey, RN; John J. Marini, MD; John Marshall, MD; Marco Ranieri, MD;Graham Ramsay, MD; Jonathan Sevransky, MD; B. Taylor Thompson, MD; Sean Townsend, MD; Jeffrey S. Vender, MD;Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; for the International Surviving Sepsis Campaign Guidelines Committee

From Cooper University Hospital, Camden, NJ (RPD);Rhode Island Hospital, Providence, RI (MML); Hospital Saint-Joseph, Paris, France (JMC); Birmingham University, Bir-mingham, UK (JB); SUNY at Stony Brook, Stony Brook, NY(MMP); McMaster University, Hamilton, Ontario, Canada (RJ);Friedrich-Schiller-University of Jena, Jena, Germany (KR);University of Pittsburgh, Pittsburgh, PA (DCA); Hopital HenriMondor, Créteil, France (CBB); Guy’s and St Thomas’ Hos-pital Trust, London, UK (RB); Centre Hospitalier UniversitaireVaudois, Lausanne, Switzerland (TC); French Agency forEvaluation of Research and Higher Education, Paris, France(JFD); Vivantes-Klinikum Neukoelin, Berlin, Germany (HG);Consultants in Critical Care, Inc, Glenbrook, NV (MH); Univer-sity of Minnesota, St. Paul, MN (JJM); St. Michael’s Hospital,Toronto, Ontario, Canada (JM); Università di Torino, Torino,

Italy (MR); West Hertfordshire Health Trust, Hemel Hemp-stead, UK (GR); The Johns Hopkins University School ofMedicine, Baltimore, MD (JS); Massachusetts General Hos-pital, Boston, MA (BTT); Rhode Island Hospital, Providence, RI(ST); Evanston Northwestern Healthcare, Evanston, IL (JSV);The Methodist Hospital, Houston, TX (JLZ); Erasme UniversityHospital, Brussels, Belgium (JLV).

Sponsoring organizations: American Association of Crit-ical-Care Nurses,* American College of Chest Physicians,*American College of Emergency Physicians,* Canadian Crit-ical Care Society, European Society of Clinical Microbiologyand Infectious Diseases,* European Society of Intensive CareMedicine,* European Respiratory Society,* International Sep-sis Forum,* Japanese Association for Acute Medicine, Jap-anese Society of Intensive Care Medicine; Society of CriticalCare Medicine,* Society of Hospital Medicine,** Surgical

Infection Society,* World Federation of Societies of Intensiveand Critical Care Medicine.** Participation and endorsementby the German Sepsis Society and the Latin American SepsisInstitute. *Sponsor of 2004 guidelines. **Sponsors of 2008guidelines who did not participate formally in revision pro-cess. Members of the 2008 SSC Guidelines Committee arelisted in Appendix I. Appendix J provides author disclosureinformation.

Also published in Intensive Care Medicine (January2008).

For information regarding this article, E-mail:[email protected]

Copyright © 2007 by the Society of Critical CareMedicine

DOI: 10.1097/01.CCM.0000298158.12101.41

Objective: To provide an update to the original Surviving Sepsis Campaignclinical management guidelines, “Surviving Sepsis Campaign Guidelines for Man-agement of Severe Sepsis and Septic Shock,” published in 2004.

Design: Modified Delphi method with a consensus conference of 55 interna-tional experts, several subsequent meetings of subgroups and key individuals,teleconferences, and electronic-based discussion among subgroups and amongthe entire committee. This process was conducted independently of any industryfunding.

Methods: We used the Grades of Recommendation, Assessment, Developmentand Evaluation (GRADE) system to guide assessment of quality of evidence fromhigh (A) to very low (D) and to determine the strength of recommendations. Astrong recommendation (1) indicates that an intervention’s desirable effectsclearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weakrecommendations (2) indicate that the tradeoff between desirable and undesirableeffects is less clear. The grade of strong or weak is considered of greater clinicalimportance than a difference in letter level of quality of evidence. In areas withoutcomplete agreement, a formal process of resolution was developed and applied.Recommendations are grouped into those directly targeting severe sepsis, rec-ommendations targeting general care of the critically ill patient that are consid-ered high priority in severe sepsis, and pediatric considerations.

Results: Key recommendations, listed by category, include early goal-directedresuscitation of the septic patient during the first 6 hrs after recognition (1C);blood cultures before antibiotic therapy (1C); imaging studies performed promptlyto confirm potential source of infection (1C); administration of broad-spectrumantibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsiswithout septic shock (1D); reassessment of antibiotic therapy with microbiologyand clinical data to narrow coverage, when appropriate (1C); a usual 7–10 daysof antibiotic therapy guided by clinical response (1D); source control with atten-tion to the balance of risks and benefits of the chosen method (1C); administrationof either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restoremean circulating filling pressure (1C); reduction in rate of fluid administration withrising filing pressures and no improvement in tissue perfusion (1D); vasopressorpreference for norepinephrine or dopamine to maintain an initial target of meanarterial pressure >65 mm Hg (1C); dobutamine inotropic therapy when cardiacoutput remains low despite fluid resuscitation and combined inotropic/vasopres-sor therapy (1C); stress-dose steroid therapy given only in septic shock after blood

pressure is identified to be poorly responsive to fluid and vasopressor therapy(2C); recombinant activated protein C in patients with severe sepsis and clinicalassessment of high risk for death (2B except 2C for postoperative patients). In theabsence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage,target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation ofinspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respi-ratory distress syndrome (ARDS); application of at least a minimal amount ofpositive end-expiratory pressure in acute lung injury (1C); head of bed elevation inmechanically ventilated patients unless contraindicated (1B); avoiding routine useof pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanicalventilation and ICU length of stay, a conservative fluid strategy for patients withestablished ALI/ARDS who are not in shock (1C); protocols for weaning andsedation/analgesia (1B); using either intermittent bolus sedation or continuousinfusion sedation with daily interruptions or lightening (1B); avoidance of neuro-muscular blockers, if at all possible (1B); institution of glycemic control (1B),targeting a blood glucose <150 mg/dL after initial stabilization (2C); equivalencyof continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophy-laxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to preventupper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors(1B); and consideration of limitation of support where appropriate (1D). Recom-mendations specific to pediatric severe sepsis include greater use of physicalexamination therapeutic end points (2C); dopamine as the first drug of choice forhypotension (2C); steroids only in children with suspected or proven adrenalinsufficiency (2C); and a recommendation against the use of recombinant acti-vated protein C in children (1B).

Conclusions: There was strong agreement among a large cohort of interna-tional experts regarding many level 1 recommendations for the best current careof patients with severe sepsis. Evidenced-based recommendations regarding theacute management of sepsis and septic shock are the first step toward improvedoutcomes for this important group of critically ill patients. (Crit Care Med2008; 36:296–327)

KEY WORDS: sepsis; severe sepsis; septic shock; sepsis syndrome; infection;Grades of Recommendation, Assessment, Development and Evaluation criteria;GRADE; guidelines; evidence-based medicine; Surviving Sepsis Campaign; sepsisbundles

296 Crit Care Med 2008 Vol. 36, No. 1

Severe sepsis (acute organ dys-function secondary to infec-tion) and septic shock (severesepsis plus hypotension not re-

versed with fluid resuscitation) are majorhealthcare problems, affecting millions ofindividuals around the world each year,killing one in four (and often more), andincreasing in incidence (1–5). Similar topolytrauma, acute myocardial infarction,or stroke, the speed and appropriatenessof therapy administered in the initialhours after severe sepsis develops arelikely to influence outcome. In 2004, aninternational group of experts in the di-agnosis and management of infection andsepsis, representing 11 organizations,published the first internationally ac-cepted guidelines that the bedside clini-cian could use to improve outcomes insevere sepsis and septic shock (6, 7).These guidelines represented phase II ofthe Surviving Sepsis Campaign (SSC), aninternational effort to increase awarenessand improve outcomes in severe sepsis.Joined by additional organizations, thegroup met again in 2006 and 2007 toupdate the guidelines document using anew evidence-based methodology systemfor assessing quality of evidence andstrength of recommendations (8–11).

These recommendations are intendedto provide guidance for the clinician car-ing for a patient with severe sepsis orseptic shock. Recommendations fromthese guidelines cannot replace the clini-cian’s decision-making capability whenhe or she is provided with a patient’sunique set of clinical variables. Most ofthese recommendations are appropriatefor the severe sepsis patient in both theintensive care unit (ICU) and non-ICUsettings. In fact, the committee believesthat currently, the greatest outcome im-provement can be made through educa-tion and process change for those caringfor severe sepsis patients in the non-ICUsetting and across the spectrum of acutecare. It should also be noted that re-source limitations in some institutionsand countries may prevent physiciansfrom accomplishing particular recom-mendations.

METHODS

Sepsis is defined as infection plus sys-temic manifestations of infection (Table1) (12). Severe sepsis is defined as sepsisplus sepsis-induced organ dysfunction ortissue hypoperfusion. The threshold for

this dysfunction has varied somewhat fromone severe sepsis research study to another.An example of typical thresholds identifica-tion of severe sepsis is shown in Table 2(13). Sepsis-induced hypotension is definedas a systolic blood pressure (SBP) �90 mmHg or mean arterial pressure �70 mm Hgor a SBP decrease �40 mm Hg or �2 SD

below normal for age in the absence ofother causes of hypotension. Septic shockis defined as sepsis-induced hypotensionpersisting despite adequate fluid resuscita-tion. Sepsis-induced tissue hypoperfusionis defined as either septic shock, an elevatedlactate, or oliguria.

The current clinical practice guidelinesbuild on the first and second editions from2001 (discussed subsequently) and 2004 (6,7, 14). The 2001 publication incorporated aMEDLINE search for clinical trials in thepreceding 10 yrs, supplemented by a man-ual search of other relevant journals (14).The 2004 publication incorporated the ev-idence available through the end of 2003.The current publication is based on an up-

dated search into 2007 (see following meth-ods and rules).

The 2001 guidelines were coordinatedby the International Sepsis Forum; the2004 guidelines were funded by unre-stricted educational grants from industryand administered through the Society ofCritical Care Medicine (SCCM), the Eu-ropean Society of Intensive Care Medi-cine (ESICM), and the International Sep-sis Forum. Two of the SSC administeringorganizations receive unrestricted indus-try funding to support SSC activities (ES-ICM and SCCM), but none of this fundingwas used to support the 2006/2007 com-mittee meetings.

It is important to distinguish betweenthe process of guidelines revision and theSSC. The SSC is partially funded by un-restricted educational industry grants,including those from Edwards Life-Sciences, Eli Lilly and Company, andPhilips Medical Systems. SSC also re-ceived funding from the Coalition forCritical Care Excellence of the Society of

Table 1. Determination of the quality of evidence

● Underlying methodologyA. RCTB. Downgraded RCT or upgraded observational studiesC. Well-done observational studiesD. Case series or expert opinion

● Factors that may decrease the strength of evidence1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of

bias2. Inconsistency of results (including problems with subgroup analyses)3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison)4. Imprecision of results5. High likelihood of reporting bias

● Main factors that may increase the strength of evidence1. Large magnitude of effect (direct evidence, RR �2 with no plausible confounders)2. Very large magnitude of effect with RR �5 and no threats to validity (by two levels)3. Dose-response gradient

RCT, randomized controlled trial; RR, relative risk.

Table 2. Factors determining strong vs. weak recommendation

What Should Be Considered Recommended Process

Quality of evidence The lower the quality of evidence, the less likely a strongrecommendation

Relative importance of theoutcomes

If values and preferences vary widely, a strongrecommendation becomes less likely

Baseline risks of outcomes The higher the risk, the greater the magnitude of benefitMagnitude of relative risk,

including benefits, harms, andburden

Larger relative risk reductions or larger increases inrelative risk of harm make a strong recommendationmore or less likely, respectively

Absolute magnitude of the effect The larger the absolute benefits and harms, the greater orlesser likelihood, respectively, of a strongrecommendation

Precision of the estimates of theeffects

The greater the precision, the more likely a strongrecommendation

Costs The higher the cost of treatment, the less likely a strongrecommendation

297Crit Care Med 2008 Vol. 36, No. 1

Critical Care Medicine. The great major-ity of industry funding has come from EliLilly and Company.

Current industry funding for the SSCis directed to the performance improve-ment initiative. No industry funding wasused in the guidelines revision process.

For both the 2004 and the 2006/2007efforts, there were no members of thecommittee from industry, no industryinput into guidelines development, andno industry presence at any of themeetings. Industry awareness or com-ment on the recommendations was notallowed. No member of the guidelinecommittee received any honoraria forany role in the 2004 or 2006/2007guidelines process. The committee con-sidered the issue of recusement of indi-vidual committee members during de-liberation and decision making in areaswhere committee members had eitherfinancial or academic competing inter-ests; however, consensus as to thresh-old for exclusion could not be reached.Alternatively, the committee agreed toensure full disclosure and transparencyof all committee members’ potentialconflicts at time of publication. (Seedisclosures at the end of this docu-ment.)

The guidelines process included amodified Delphi method, a consensusconference, several subsequent meetingsof subgroups and key individuals, tele-conferences and electronic-based discus-sions among subgroups and members ofthe entire committee, and two follow-upnominal group meetings in 2007.

Subgroups were formed, each chargedwith updating recommendations in spe-cific areas, including corticosteroids,blood products, activated protein C, renalreplacement therapy, antibiotics, sourcecontrol, and glucose control. Each sub-group was responsible for updating theevidence (into 2007, with major addi-tional elements of information incorpo-rated into the evolving manuscriptthroughout 2006 and 2007). A separatesearch was performed for each clearly de-fined question. The committee chairworked with subgroup heads to identifypertinent search terms that always in-cluded, at a minimum, sepsis, severe sep-sis, septic shock, and sepsis syndromecrossed against the general topic area ofthe subgroup as well as pertinent keywords of the specific question posed. Allquestions of the previous guidelines pub-lications were searched, as were pertinentnew questions generated by general top-

ic-related search or recent trials. Qualityof evidence was judged by predefinedGrades of Recommendation, Assessment,Development and Evaluation (GRADE)criteria (discussed subsequently). Signif-icant education of committee memberson the GRADE approach was performedvia e-mail before the first committeemeeting and at the first meeting. Ruleswere distributed concerning assessingthe body of evidence, and GRADE expertswere available for questions throughoutthe process. Subgroups agreed electroni-cally on draft proposals that were pre-sented to committee meetings for generaldiscussion. In January 2006, the entiregroup met during the 35th SCCM CriticalCare Congress in San Francisco, Califor-nia. The results of that discussion wereincorporated into the next version of rec-ommendations and again discussed usingelectronic mail. Recommendations werefinalized during nominal group meetings(composed of a subset of the committeemembers) at the 2007 SCCM (Orlando,FL) and 2007 International Symposiumon Intensive Care and Emergency Medi-cine (Brussels) meetings with recircula-tion of deliberations and decisions to theentire group for comment or approval. Atthe discretion of the chair and followingadequate discussion, competing propos-als for wording of recommendations orassigning strength of evidence were re-solved by formal voting. On occasions,voting was performed to give the com-mittee a sense of distribution of opinionsto facilitate additional discussion. Themanuscript was edited for style and formby the writing committee with final ap-proval by section leads for their respec-tive group assignment and then by theentire committee.

The development of guidelines andgrading of recommendations for the 2004guideline development process werebased on a system proposed by Sackett(15) in 1989, during one of the firstAmerican College of Chest Physicians(ACCP) conferences on the use of anti-thrombotic therapies. The revised guide-lines recommendations are based on theGRADE system, a structured system forrating quality of evidence and gradingstrength of recommendation in clinicalpractice (8–11). The SSC Steering Com-mittee and individual authors collabo-rated with GRADE representatives to ap-ply the GRADE system to the SSCguidelines revision process. The mem-bers of GRADE group were directly in-volved, either in person or via e-mail, in

all discussions and deliberations amongthe guidelines committee members as tograding decisions. Subsequently, the SSCauthors used written material preparedby the GRADE group and conferred withGRADE group members who were avail-able at the first committee meeting andsubsequent nominal group meetings.GRADE representatives were also used asa resource throughout subgroup deliber-ation.

The GRADE system is based on a se-quential assessment of the quality of ev-idence, followed by assessment of the bal-ance between benefits vs. risks, burden,and cost and, based on the preceding, de-velopment and grading of a managementrecommendations (9–11). Keeping the rat-ing of quality of evidence and strength ofrecommendation explicitly separate consti-tutes a crucial and defining feature of theGRADE approach. This system classifiesquality of evidence as high (grade A), mod-erate (grade B), low (grade C), or very low(grade D). Randomized trials begin as high-quality evidence but may be downgradeddue to limitations in implementation, in-consistency or imprecision of the results,indirectness of the evidence, and possiblereporting bias (Table 1). Examples of indi-rectness of the evidence include populationstudied, interventions used, outcomes mea-sured, and how these relate to the questionof interest. Observational (nonrandomized)studies begin as low-quality evidence, butthe quality level may be upgraded on thebasis of large magnitude of effect. An exam-ple of this is the quality of evidence for earlyadministration of antibiotics.

The GRADE system classifies recom-mendations as strong (grade 1) or weak(grade 2). The grade of strong or weak isconsidered of greater clinical importancethan a difference in letter level of qualityof evidence. The committee assessedwhether the desirable effects of adher-ence will outweigh the undesirable ef-fects, and the strength of a recommenda-tion reflects the group’s degree ofconfidence in that assessment. A strongrecommendation in favor of an interven-tion reflects that the desirable effects ofadherence to a recommendation (benefi-cial health outcomes, less burden on staffand patients, and cost savings) willclearly outweigh the undesirable effects(harms, more burden, and greater costs).A weak recommendation in favor of anintervention indicates that the desirableeffects of adherence to a recommendationprobably will outweigh the undesirableeffects, but the panel is not confident


about these tradeoffs— either becausesome of the evidence is low quality (andthus there remains uncertainty regardingthe benefits and risks) or the benefits anddownsides are closely balanced. While thedegree of confidence is a continuum andthere is no precise threshold between astrong and a weak recommendation, thepresence of important concerns aboutone or more of the preceding factorsmakes a weak recommendation morelikely. A strong recommendation isworded as “we recommend” and a weakrecommendation as “we suggest.”

The implications of calling a recom-mendation strong are that most well-informed patients would accept that inter-vention and that most clinicians should useit in most situations. There may be circum-stances in which a strong recommendationcannot or should not be followed for anindividual patient because of that patient’spreferences or clinical characteristics thatmake the recommendation less applicable.Being a strong recommendation does notautomatically imply standard of care. Forexample, the strong recommendation foradministering antibiotics within 1 hr of thediagnosis of severe sepsis, although desir-able, is not currently standard of care asverified by current practice (M Levy, per-sonal communication, from first 8,000 pa-tients entered internationally into the SSCperformance improvement database). Theimplication of a weak recommendation isthat although a majority of well-informedpatients would accept it (but a substantialproportion would not), clinicians shouldconsider its use according to particular cir-cumstance.

Differences of opinion among commit-tee members about interpretation of evi-dence, wording of proposals, or strength ofrecommendations were resolved using aspecifically developed set of rules. We willdescribe this process in detail in a separatepublication. In summary, the main ap-proach for converting diverse opinions intoa recommendation was as follows: 1) togive a recommendation a direction (for oragainst the given action), a majority ofvotes were to be in favor of that direction,with �20% preferring the opposite direc-tion (there was a neutral vote allowed aswell); 2) to call a given recommendationstrong rather than weak, �70% “strong”votes were required; 3) if �70% of votesindicated “strong” preference, the recom-mendation was assigned a weak category ofstrength. We used a combination of modi-fied Delphi process and nominal (expert)group techniques to ensure both depth and

breadth of review. The entire review group(together with their parent organizationsas required) participated in the larger, iter-ative, modified Delphi process. The smallerworking group meetings, which took placein person, functioned as the nominalgroups. If a clear consensus could not beobtained by polling within the nominalgroup meetings, the larger group was spe-cifically asked to use the polling process.This was only required for corticosteroidsand glycemic control. The larger group hadthe opportunity to review all outputs. Inthis way the entire review combined in-

tense focused discussion (nominal group)with broader review and monitoring usingthe Delphi process.

Note: Refer to Tables 3–5 for con-densed adult recommendations.

I. MANAGEMENT OF SEVERESEPSIS

A. Initial Resuscitation

1. We recommend the protocolized re-suscitation of a patient with sepsis-

Table 3. Initial resuscitation and infection issues

Strength of recommendation and quality of evidence have been assessed using the GRADE criteria,presented in parentheses after each guideline● Indicates a strong recommendation, or “we recommend”� Indicates a weak recommendation, or “we suggest”

Initial resuscitation (first 6 hrs)● Begin resuscitation immediately in patients with hypotension or elevated serum lactate �4

mmol/L; do not delay pending ICU admission (1C)● Resuscitation goals (1C)

CVP 8–12 mm Hga

Mean arterial pressure � 65 mm HgUrine output �0.5 mL�kg�1�hr�1

Central venous (superior vena cava) oxygen saturation �70% or mixed venous �65%� If venous oxygen saturation target is not achieved (2C)

Consider further fluidTransfuse packed red blood cells if required to hematocrit of �30% and/orStart dobutamine infusion, maximum 20 �g�kg�1�min�1

Diagnosis● Obtain appropriate cultures before starting antibiotics provided this does not significantly

delay antimicrobial administration (1C)Obtain two or more BCsOne or more BCs should be percutaneousOne BC from each vascular access device in place �48 hrsCulture other sites as clinically indicated

● Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)Antibiotic therapy

● Begin intravenous antibiotics as early as possible and always within the first hour ofrecognizing severe sepsis (1D) and septic shock (1B)

● Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and withgood penetration into presumed source (1B)

● Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity,and minimize costs (1C)

� Consider combination therapy in Pseudomonas infections (2D)� Consider combination empiric therapy in neutropenic patients (2D)� Combination therapy �3–5 days and de-escalation following susceptibilities (2D)● Duration of therapy typically limited to 7–10 days; longer if response is slow or there are

undrainable foci of infection or immunologic deficiencies (1D)● Stop antimicrobial therapy if cause is found to be noninfectious (1D)

Source identification and control● A specific anatomic site of infection should be established as rapidly as possible (1C) and

within first 6 hrs of presentation (1D)● Formally evaluate patient for a focus of infection amenable to source control measures (e.g.

abscess drainage, tissue debridement) (1C)● Implement source control measures as soon as possible following successful initial

resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is bestdelayed) (2B)

● Choose source control measure with maximum efficacy and minimal physiologic upset (1D)● Remove intravascular access devices if potentially infected (1C)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ICU, intensivecare unit; CVP, central venous pressure; BC, blood culture.

aA higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical ventilationor preexisting decreased ventricular compliance.


induced shock, defined as tissue hypo-perfusion (hypotension persistingafter initial fluid challenge or bloodlactate concentration �4 mmol/L).This protocol should be initiated assoon as hypoperfusion is recognizedand should not be delayed pendingICU admission. During the first 6 hrsof resuscitation, the goals of initialresuscitation of sepsis-induced hypo-perfusion should include all of the fol-lowing as one part of a treatment pro-tocol:

Central venous pressure 8–12 mmHgMean arterial pressure (MAP) �65mm Hg

Urine output �0.5 mL·kg�1·hr �1

Central venous (superior venacava) or mixed venous oxygen sat-uration �70% or �65%, respec-tively (grade 1C)

Rationale. Early goal-directed resusci-tation has been shown to improve sur-vival for emergency department patientspresenting with septic shock in a ran-domized, controlled, single-center study(16). Resuscitation directed toward thepreviously mentioned goals for the initial6-hr period of the resuscitation was ableto reduce 28-day mortality rate. The con-sensus panel judged use of central venousand mixed venous oxygen saturation tar-

gets to be equivalent. Either intermittentor continuous measurements of oxygensaturation were judged to be acceptable.Although blood lactate concentrationmay lack precision as a measure of tissuemetabolic status, elevated levels in sepsissupport aggressive resuscitation. In me-chanically ventilated patients or patientswith known preexisting decreased ven-tricular compliance, a higher target cen-tral venous pressure of 12–15 mm Hg isrecommended to account for the imped-iment to filling (17). Similar consider-ation may be warranted in circumstancesof increased abdominal pressure or dia-stolic dysfunction (18). Elevated centralvenous pressures may also be seen withpreexisting clinically significant pulmo-nary artery hypertension. Although thecause of tachycardia in septic patientsmay be multifactorial, a decrease in ele-vated pulse rate with fluid resuscitation isoften a useful marker of improving intra-vascular filling. Recently published ob-servational studies have demonstrated anassociation between good clinical out-come in septic shock and MAP �65 mmHg as well as central venous oxygen sat-uration (ScvO2, measured in superiorvena cava, either intermittently or con-tinuously) of �70% (19). Many recentstudies support the value of early proto-colized resuscitation in severe sepsis andsepsis-induced tissue hypoperfusion (20–25). Studies of patients with shock indi-cate that mixed venous oxygen saturation(SV̄O2) runs 5–7% lower than central ve-nous oxygen saturation (ScvO2) (26) andthat an early goal-directed resuscitationprotocol can be established in a nonre-search general practice venue (27).

There are recognized limitations toventricular filling pressure estimates assurrogates for fluid resuscitation (28, 29).However, measurement of central venouspressure is currently the most readily ob-tainable target for fluid resuscitation.There may be advantages to targetingfluid resuscitation to flow and perhaps tovolumetric indices (and even to microcir-culation changes) (30–33). Technologiescurrently exist that allow measurementof flow at the bedside (34, 35). Futuregoals should be making these technolo-gies more accessible during the criticalearly resuscitation period and research tovalidate utility. These technologies arealready available for early ICU resuscita-tion.

2. We suggest that during the first 6 hrsof resuscitation of severe sepsis or sep-

Table 4. Hemodynamic support and adjunctive therapy

Strength of recommendation and quality of evidence have been assessed using the GRADE criteria,presented in parentheses after each guideline.● Indicates a strong recommendation, or “we recommend”� Indicates a weak recommendation, or “we suggest”

Fluid therapy● Fluid-resuscitate using crystalloids or colloids (1B)● Target a CVP of �8 mm Hg (�12 mm Hg if mechanically ventilated) (1C)● Use a fluid challenge technique while associated with a hemodynamic improvement (1D)● Give fluid challenges of 1000 mL of crystalloids or 300–500 mL of colloids over 30 mins. More

rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion (1D)● Rate of fluid administration should be reduced if cardiac filling pressures increase without

concurrent hemodynamic improvement (1D)Vasopressors

● Maintain MAP �65 mm Hg (1C)● Norepinephrine and dopamine centrally administered are the initial vasopressors of choice (1C)� Epinephrine, phenylephrine, or vasopressin should not be administered as the initial

vasopressor in septic shock (2C). Vasopressin 0.03 units/min may be subsequently added tonorepinephrine with anticipation of an effect equivalent to norepinephrine alone

� Use epinephrine as the first alternative agent in septic shock when blood pressure is poorlyresponsive to norepinephrine or dopamine (2B).

● Do not use low-dose dopamine for renal protection (1A)● In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D)

Inotropic therapy● Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac

filling pressures and low cardiac output (1C)● Do not increase cardiac index to predetermined supranormal levels (1B)

Steroids� Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly

to adequate fluid resuscitation and vasopressors (2C)� ACTH stimulation test is not recommended to identify the subset of adults with septic shock

who should receive hydrocortisone (2B)� Hydrocortisone is preferred to dexamethasone (2B)� Fludrocortisone (50 �g orally once a day) may be included if an alternative to hydrocortisone

is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional ifhydrocortisone is used (2C)

� Steroid therapy may be weaned once vasopressors are no longer required (2D)● Hydrocortisone dose should be �300 mg/day (1A)● Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s

endocrine or corticosteroid history warrants it (1D)Recombinant human activated protein C

� Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinicalassessment of high risk of death (typically APACHE II �25 or multiple organ failure) if thereare no contraindications (2B, 2C for postoperative patients).

● Adult patients with severe sepsis and low risk of death (typically, APACHE II �20 or oneorgan failure) should not receive rhAPC (1A)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; CVP, centralvenous pressure; MAP, mean arterial pressure; ACTH, adrenocorticotropic hormone; rhAPC, recom-binant human activated protein C; APACHE, Acute Physiology and Chronic Health Evaluation.


tic shock, if ScvO2 or SV̄O2 of 70% or65%, respectively, is not achieved withfluid resuscitation to the central ve-nous pressure target, then transfusionof packed red blood cells to achieve a

hematocrit of �30% and/or adminis-tration of a dobutamine infusion (upto a maximum of 20 �g·kg�1·min�1)be used to achieve this goal (grade2C).

Rationale. The protocol used in thestudy cited previously targeted an increasein ScvO2 to �70% (16). This was achievedby sequential institution of initial fluid re-suscitation, packed red blood cells, and

Table 5. Other supportive therapy of severe sepsis

Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in parentheses after each guideline● Indicates a strong recommendation, or “we recommend”� Indicates a weak recommendation, or “we suggest”

Blood product administration● Give red blood cells when hemoglobin decreases to �7.0 g/dL (�70 g/L) to target a hemoglobin of 7.0–9.0 g/dL in adults (1B). A higher

hemoglobin level may be required in special circumstances (e.g., myocardial ischaemia, severe hypoxemia, acute hemorrhage, cyanotic heartdisease, or lactic acidosis)

� Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons (1B)� Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures (2D)● Do not use antithrombin therapy (1B)� Administer platelets when (2D)

Counts are �5000/mm3 (5 � 109/L) regardless of bleedingCounts are 5000–30,000/mm3 (5–30 � 109/L) and there is significant bleeding riskHigher platelet counts (�50,000/mm3 [50 � 109/L]) are required for surgery or invasive procedures

Mechanical ventilation of sepsis-induced ALI/ARDS● Target a tidal volume of 6 mL/kg (predicted) body weight in patients with ALI/ARDS (1B)● Target an initial upper limit plateau pressure �30 cm H2O. Consider chest wall compliance when assessing plateau pressure (1C)● Allow PaCO2 to increase above normal, if needed, to minimize plateau pressures and tidal volumes (1C)● Set PEEP to avoid extensive lung collapse at end-expiration (1C)� Consider using the prone position for ARDS patients requiring potentially injurious levels of FIO2 or plateau pressure, provided they are not put

at risk from positional changes (2C)● Maintain mechanically ventilated patients in a semirecumbent position (head of the bed raised to 45°) unless contraindicated (1B), between 30°

and 45° (2C)� Noninvasive ventilation may be considered in the minority of ALI/ARDS patients with mild to moderate hypoxemic respiratory failure. The

patients need to be hemodynamically stable, comfortable, easily arousable, able to protect/clear their airway, and expected to recover rapidly (2B)● Use a weaning protocol and an SBT regularly to evaluate the potential for discontinuing mechanical ventilation (1A)

● SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T piece● Before the SBT, patients should

be arousablebe hemodynamically stable without vasopressorshave no new potentially serious conditionshave low ventilatory and end-expiratory pressure requirementrequire FIO2 levels that can be safely delivered with a face mask or nasal cannula

● Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ARDS (1A)● Use a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion (1C)

Sedation, analgesia, and neuromuscular blockade in sepsis● Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients (1B)● Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily

interruption/lightening to produce awakening. Re-titrate if necessary (1B)● Avoid neuromuscular blockers where possible. Monitor depth of block with train-of-four when using continuous infusions (1B)

Glucose control● Use intravenous insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B)● Aim to keep blood glucose �150 mg/dL (8.3 mmol/L) using a validated protocol for insulin dose adjustment (2C)● Provide a glucose calorie source and monitor blood glucose values every 1–2 hrs (4 hrs when stable) in patients receiving intravenous insulin (1C)● Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood or plasma

glucose values (1B)Renal replacement

� Intermittent hemodialysis and CVVH are considered equivalent (2B)� CVVH offers easier management in hemodynamically unstable patients (2D)

Bicarbonate therapy● Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-

induced lactic acidemia with pH �7.15 (1B)Deep vein thrombosis prophylaxis

● Use either low-dose UFH or LMWH, unless contraindicated (1A)● Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when heparin is contraindicated (1A)� Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for deep vein thrombosis (2C)� In patients at very high risk, LMWH should be used rather than UFH (2C)

Stress ulcer prophylaxis● Provide stress ulcer prophylaxis using H2 blocker (1A) or proton pump inhibitor (1B). Benefits of prevention of upper gastrointestinal bleed must

be weighed against the potential for development of ventilator-acquired pneumoniaConsideration for limitation of support

● Discuss advance care planning with patients and families. Describe likely outcomes and set realistic expectations (1D)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ALI, acute lung injury; ARDS, acute respiratory distress syndrome;PEEP, positive end-expiratory pressure; SBT, spontaneous breathing trial; ICU, intensive care unit; CVVH, continuous veno-venous hemofiltration; UFH,unfractionated heparin; LMWH, low-molecular weight heparin.


then dobutamine. This protocol was asso-ciated with an improvement in survival.Based on bedside clinical assessment andpersonal preference, a clinician may deemeither blood transfusion (if hematocrit is�30%) or dobutamine the best initialchoice to increase oxygen delivery andthereby elevate ScvO2, when fluid resusci-tation is believed to be already adequate.The design of the aforementioned trial didnot allow assessment of the relative contri-bution of these two components (i.e., in-creasing oxygen content or increasing car-diac output) of the protocol onachievement of improved outcome.

B. Diagnosis

1. We recommend obtaining appropri-ate cultures before antimicrobialtherapy is initiated if such culturesdo not cause significant delay in an-tibiotic administration. To optimizeidentification of causative organisms,we recommend at least two bloodcultures be obtained before antibiot-ics with at least one drawn percuta-neously and one drawn through eachvascular access device, unless the de-vice was recently (�48 hrs) inserted.Cultures of other sites (preferablyquantitative where appropriate), suchas urine, cerebrospinal fluid, wounds,respiratory secretions, or other bodyfluids that may be the source of in-fection should also be obtained be-fore antibiotic therapy if not associ-ated with significant delay inantibiotic administration (grade 1C).

Rationale. Although sampling shouldnot delay timely administration of antibi-otics in patients with severe sepsis (e.g.,lumbar puncture in suspected meningi-tis), obtaining appropriate cultures be-fore administration of antibiotics is es-sential to confirm infection and theresponsible pathogens and to allow de-escalation of antibiotic therapy after re-ceipt of the susceptibility profile. Samplescan be refrigerated or frozen if processingcannot be performed immediately. Im-mediate transport to a microbiologicallab is necessary. Because rapid steriliza-tion of blood cultures can occur within afew hours after the first antibiotic dose,obtaining those cultures before startingtherapy is essential if the causative organ-ism is to be identified. Two or more bloodcultures are recommended (36). In pa-tients with indwelling catheters (for �48hrs), at least one blood culture should bedrawn through each lumen of each vas-

cular access device. Obtaining bloodcultures peripherally and through avascular access device is an importantstrategy. If the same organism is recov-ered from both cultures, the likelihoodthat the organism is causing the severesepsis is enhanced. In addition, if theculture drawn through the vascular ac-cess device is positive much earlier thanthe peripheral blood culture (i.e., �2 hrsearlier), the data support the concept thatthe vascular access device is the source ofthe infection (37). Quantitative culturesof catheter and peripheral blood are alsouseful for determining whether the cath-eter is the source of infection. Volume ofblood drawn with the culture tube shouldbe �10 mL (38). Quantitative (or semi-quantitative) cultures of respiratory tractsecretions are recommended for the di-agnosis of ventilator-associated pneumo-nia (39). Gram-negative stain can be use-ful, in particular for respiratory tractspecimens, to help decide the micro-organisms to be targeted. The potentialrole of biomarkers for diagnosis of in-fection in patients presenting with se-vere sepsis remains undefined. The pro-calcitonin level, although often useful,is problematic in patients with an acuteinflammatory pattern from othercauses (e.g., postoperative, shock) (40).In the near future, rapid diagnosticmethods (polymerase chain reaction,micro-arrays) might prove extremelyhelpful for a quicker identification ofpathogens and major antimicrobial re-sistance determinants (41).

2. We recommend that imaging studiesbe performed promptly in attemptsto confirm a potential source of in-fection. Sampling of potentialsources of infection should occur asthey are identified; however, somepatients may be too unstable to war-rant certain invasive procedures ortransport outside of the ICU. Bedsidestudies, such as ultrasound, are use-ful in these circumstances (grade1C).

Rationale. Diagnostic studies mayidentify a source of infection that re-quires removal of a foreign body or drain-age to maximize the likelihood of a sat-isfactory response to therapy. However,even in the most organized and well-staffed healthcare facilities, transport ofpatients can be dangerous, as can placingpatients in outside-unit imaging devicesthat are difficult to access and monitor.

Balancing risk and benefit is thereforemandatory in those settings.

C. Antibiotic Therapy

1. We recommend that intravenous an-tibiotic therapy be started as early aspossible and within the first hour ofrecognition of septic shock (1B) andsevere sepsis without septic shock(1D). Appropriate cultures should beobtained before initiating antibiotictherapy but should not preventprompt administration of antimicro-bial therapy (grade 1D).

Rationale. Establishing vascular ac-cess and initiating aggressive fluid resus-citation are the first priority when man-aging patients with severe sepsis or septicshock. However, prompt infusion of anti-microbial agents should also be a priorityand may require additional vascular ac-cess ports (42, 43). In the presence ofseptic shock, each hour delay in achiev-ing administration of effective antibioticsis associated with a measurable increasein mortality (42). If antimicrobial agentscannot be mixed and delivered promptlyfrom the pharmacy, establishing a supplyof premixed antibiotics for such urgentsituations is an appropriate strategy forensuring prompt administration. Inchoosing the antimicrobial regimen, cli-nicians should be aware that some anti-microbial agents have the advantage ofbolus administration, while others re-quire a lengthy infusion. Thus, if vascularaccess is limited and many differentagents must be infused, bolus drugs mayoffer an advantage.

2a. We recommend that initial empiricalanti-infective therapy include one ormore drugs that have activity againstall likely pathogens (bacterial and/orfungal) and that penetrate in ade-quate concentrations into the pre-sumed source of sepsis (grade 1B).

Rationale. The choice of empirical an-tibiotics depends on complex issues re-lated to the patient’s history, includingdrug intolerances, underlying disease,the clinical syndrome, and susceptibilitypatterns of pathogens in the community,in the hospital, and that previously havebeen documented to colonize or infectthe patient. There is an especially widerange of potential pathogens for neutro-penic patients.

Recently used antibiotics should gener-ally be avoided. When choosing empiricaltherapy, clinicians should be cognizant of


the virulence and growing prevalence ofoxacillin (methicillin)-resistant Staphylo-coccus aureus (ORSA or MRSA) in somecommunities and healthcare settings (espe-cially in the United States). If the preva-lence is significant, and in consideration ofthe virulence of this organism, empiricaltherapy adequate for this pathogen wouldbe warranted. Clinicians should also con-sider whether candidemia is a likely patho-gen when choosing initial therapy. Whendeemed warranted, the selection of empir-ical antifungal therapy (e.g., fluconazole,amphotericin B, or echinocandin) will betailored to the local pattern of the mostprevalent Candida species and any prioradministration of azoles drugs (44). Riskfactors for candidemia should also be con-sidered when choosing initial therapy.

Because patients with severe sepsis orseptic shock have little margin for errorin the choice of therapy, the initial selec-tion of antimicrobial therapy should bebroad enough to cover all likely patho-gens. There is ample evidence that failureto initiate appropriate therapy (i.e., ther-apy with activity against the pathogenthat is subsequently identified as thecausative agent) correlates with increasedmorbidity and mortality (45–48).

Patients with severe sepsis or septicshock warrant broad-spectrum therapyuntil the causative organism and its an-tibiotic susceptibilities are defined. Re-striction of antibiotics as a strategy toreduce the development of antimicrobialresistance or to reduce cost is not anappropriate initial strategy in this patientpopulation.

All patients should receive a full load-ing dose of each antimicrobial. However,patients with sepsis or septic shock oftenhave abnormal renal or hepatic functionand may have abnormal volumes of dis-tribution due to aggressive fluid resusci-tation. Drug serum concentration moni-toring can be useful in an ICU setting forthose drugs that can be measuredpromptly. An experienced physician orclinical pharmacist should be consultedto ensure that serum concentrations areattained that maximize efficacy and min-imize toxicity (49–52).

2b. We recommend that the antimicro-bial regimen be reassessed daily tooptimize activity, to prevent the de-velopment of resistance, to reducetoxicity, and to reduce costs (grade1C).

Rationale. Although restriction of an-tibiotics as a strategy to reduce the devel-

opment of antimicrobial resistance or toreduce cost is not an appropriate initialstrategy in this patient population, oncethe causative pathogen has been identi-fied, it may become apparent that none ofthe empirical drugs offers optimal ther-apy; that is, there may be another drugproven to produce superior clinical out-come that should therefore replace em-pirical agents.

Narrowing the spectrum of antibioticcoverage and reducing the duration ofantibiotic therapy will reduce the likelihoodthat the patient will develop superinfectionwith pathogenic or resistant organisms,such as Candida species, Clostridium diffi-cile, or vancomycin-resistant Enterococcusfaecium. However, the desire to minimizesuperinfections and other complicationsshould not take precedence over the needto give the patient an adequate course oftherapy to cure the infection that causedthe severe sepsis or septic shock.

2c. We suggest combination therapy forpatients with known or suspectedPseudomonas infections as a cause ofsevere sepsis (grade 2D).

2d. We suggest combination empiricaltherapy for neutropenic patients withsevere sepsis (grade 2D).

2e. When used empirically in patientswith severe sepsis, we suggest thatcombination therapy should not beadministered for �3–5 days. De-escalation to the most appropriatesingle therapy should be performedas soon as the susceptibility profile isknown (grade 2D).

Rationale. Although no study or meta-analysis has convincingly demonstratedthat combination therapy produces a supe-rior clinical outcome for individual patho-gens in a particular patient group, combi-nation therapies do produce in vitrosynergy against pathogens in some models(although such synergy is difficult to defineand predict). In some clinical scenarios,such as the two preceding, combinationtherapies are biologically plausible and arelikely clinically useful even if evidence hasnot demonstrated improved clinical out-come (53–56). Combination therapy forsuspected known Pseudomonas pendingsensitivities increases the likelihood that atleast one drug is effective against thatstrain and positively affects outcome (57).

3. We recommend that the duration oftherapy typically be 7–10 days; longercourses may be appropriate in pa-tients who have a slow clinical re-

sponse, undrainable foci of infection,or immunologic deficiencies, includ-ing neutropenia (grade 1D).

4. We recommend that if the presentingclinical syndrome is determined to bedue to a noninfectious cause, antimi-crobial therapy be stopped promptlyto minimize the likelihood that thepatient will become infected with anantibiotic-resistant pathogen or willdevelop a drug-related adverse effect(grade 1D).

Rationale. Clinicians should be cogni-zant that blood cultures will be negativein �50% of cases of severe sepsis or sep-tic shock, yet many of these cases are verylikely caused by bacteria or fungi. Thus,the decisions to continue, narrow, or stopantimicrobial therapy must be made onthe basis of clinician judgment and clin-ical information.

D. Source Control

1a. We recommend that a specific ana-tomical diagnosis of infection requir-ing consideration for emergentsource control (e.g., necrotizing fas-ciitis, diffuse peritonitis, cholangitis,intestinal infarction) be sought anddiagnosed or excluded as rapidly aspossible (grade 1C) and within thefirst 6 hrs following presentation(grade 1D).

1b. We further recommend that all pa-tients presenting with severe sepsisbe evaluated for the presence of afocus on infection amenable tosource control measures, specificallythe drainage of an abscess or localfocus on infection, the debridementof infected necrotic tissue, the re-moval of a potentially infected device,or the definitive control of a sourceof ongoing microbial contamination(grade 1C). (Appendix A provides ex-amples of potential sites needingsource control.)

2. We suggest that when infectedperipancreatic necrosis is identified asa potential source of infection, defini-tive intervention is best delayed untiladequate demarcation of viable andnonviable tissues has occurred (grade2B).

3. We recommend that when source con-trol is required, the effective interventionassociated with the least physiologic in-sult be employed (e.g., percutaneousrather than surgical drainage of anabscess (grade 1D).


4. We recommend that when intravas-cular access devices are a possiblesource of severe sepsis or septicshock, they be promptly removed af-ter other vascular access has beenestablished (grade 1C).

Rationale. The principals of sourcecontrol in the management of sepsis in-clude a rapid diagnosis of the specific siteof infection and identification of a focuson infection amenable to source controlmeasures (specifically the drainage of anabscess, debridement of infected necrotictissue, removal of a potentially infecteddevice, and definitive control of a sourceof ongoing microbial contamination)(58). Foci of infection readily amenable tosource control measures include an in-tra-abdominal abscess or gastrointestinalperforation, cholangitis or pyelonephri-tis, intestinal ischemia or necrotizing softtissue infection, and other deep space in-fection, such as an empyema or septicarthritis. Such infectious foci should becontrolled as soon as possible followingsuccessful initial resuscitation (59), ac-complishing the source control objectivewith the least physiologic upset possible(e.g., percutaneous rather than surgicaldrainage of an abscess [60], endoscopicrather than surgical drainage of biliarytree), and removing intravascular accessdevices that are potentially the source ofsevere sepsis or septic shock promptlyafter establishing other vascular access(61, 62). A randomized, controlled trialcomparing early vs. delayed surgical in-tervention for peripancreatic necrosisshowed better outcomes with a delayedapproach (63). However, areas of uncer-tainty exist, such as definitive docu-mentation of infection and appropriatelength of delay. The selection of optimalsource control methods must weighbenefits and risks of the specific inter-vention as well as risks of transfer (64).Source control interventions may causefurther complications, such as bleed-ing, fistulas, or inadvertent organ in-jury. Surgical intervention should beconsidered when lesser interventionalapproaches are inadequate or when di-agnostic uncertainty persists despite ra-diologic evaluation. Specific clinical sit-uations require consideration ofavailable choices, patient’s preferences,and clinician’s expertise.

E. Fluid Therapy

1. We recommend fluid resuscitationwith either natural/artificial colloids

or crystalloids. There is no evidence-based support for one type of fluidover another (grade 1B).

Rationale. The SAFE study indicatedthat albumin administration was safe andequally as effective as crystalloid (65). Therewas an insignificant decrease in mortalityrates with the use of colloid in a subsetanalysis of septic patients (p � .09). Previ-ous meta-analyses of small studies of ICUpatients had demonstrated no differencebetween crystalloid and colloid fluid resus-citation (66–68). Although administrationof hydroxyethyl starch may increase therisk of acute renal failure in patients withsepsis, variable findings preclude definitiverecommendations (69, 70). As the volumeof distribution is much larger for crystal-loids than for colloids, resuscitation withcrystalloids requires more fluid to achievethe same end points and results in moreedema. Crystalloids are less expensive.

2. We recommend that fluid resuscita-tion initially target a central venouspressure of �8 mm Hg (12 mm Hg inmechanically ventilated patients).Further fluid therapy is often re-quired (grade 1C).

3a. We recommend that a fluid challengetechnique be applied wherein fluidadministration is continued as longas the hemodynamic improvement(e.g., arterial pressure, heart rate,urine output) continues (grade 1D).

3b. We recommend that fluid challengein patients with suspected hypovole-mia be started with �1000 mL ofcrystalloids or 300–500 mL of col-loids over 30 mins. More rapid ad-ministration and greater amounts offluid may be needed in patients withsepsis-induced tissue hypoperfusion(see Initial Resuscitation recommen-dations) (grade 1D).

3c. We recommend that the rate of fluidadministration be reduced substan-tially when cardiac filling pressures(central venous pressure or pulmo-nary artery balloon-occluded pres-sure) increase without concurrenthemodynamic improvement (grade1D).

Rationale. Fluid challenge must beclearly separated from simple fluid ad-ministration; it is a technique in whichlarge amounts of fluids are administeredover a limited period of time under closemonitoring to evaluate the patient’s re-sponse and avoid the development of pul-monary edema. The degree of intravascular

volume deficit in patients with severe sepsisvaries. With venodilation and ongoing cap-illary leak, most patients require continu-ing aggressive fluid resuscitation duringthe first 24 hrs of management. Input istypically much greater than output, andinput/output ratio is of no utility to judgefluid resuscitation needs during this timeperiod.

F. Vasopressors

1. We recommend that mean arterialpressure (MAP) be maintained �65mm Hg (grade 1C).

Rationale. Vasopressor therapy is re-quired to sustain life and maintain perfu-sion in the face of life-threatening hypo-tension, even when hypovolemia has notyet been resolved. Below a certain meanarterial pressure, autoregulation in vari-ous vascular beds can be lost, and perfu-sion can become linearly dependent onpressure. Thus, some patients may re-quire vasopressor therapy to achieve aminimal perfusion pressure and maintainadequate flow (71, 72). The titration ofnorepinephrine to as low as MAP 65 mmHg has been shown to preserve tissueperfusion (72). In addition, preexistingcomorbidities should be considered as tomost appropriate MAP target. For exam-ple, a MAP of 65 mm Hg might be too lowin a patient with severe uncontrolled hy-pertension, and in a young previouslynormotensive, a lower MAP might beadequate. Supplementing end points,such as blood pressure, with assess-ment of regional and global perfusion,such as blood lactate concentrationsand urine output, is important. Ade-quate fluid resuscitation is a fundamen-tal aspect of the hemodynamic manage-ment of patients with septic shock andshould ideally be achieved before vaso-pressors and inotropes are used, butusing vasopressors early as an emer-gency measure in patients with severeshock is frequently necessary. Whenthat occurs, great effort should be di-rected to weaning vasopressors withcontinuing fluid resuscitation.

2. We recommend either norepineph-rine or dopamine as the first choicevasopressor agent to correct hypo-tension in septic shock (administeredthrough a central catheter as soon asone is available) (grade 1C).

3a. We suggest that epinephrine, phenyl-ephrine, or vasopressin should not beadministered as the initial vasopres-


sor in septic shock (grade 2C). Vaso-pressin 0.03 units/min may be addedto norepinephrine subsequently withanticipation of an effect equivalent tothat of norepinephrine alone.

3b. We suggest that epinephrine be thefirst chosen alternative agent in sep-tic shock that is poorly responsive tonorepinephrine or dopamine (grade2B).

Rationale. There is no high-qualityprimary evidence to recommend one cat-echolamine over another. Much litera-ture exists that contrasts the physiologiceffects of choice of vasopressor and com-bined inotrope/vasopressors in septicshock (73–85). Human and animal stud-ies suggest some advantages of norepi-nephrine and dopamine over epinephrine(the latter with the potential for tachy-cardia as well as disadvantageous effectson splanchnic circulation and hyper-lactemia) and phenylephrine (decrease instroke volume). There is, however, noclinical evidence that epinephrine resultsin worse outcomes, and it should be thefirst chosen alternative to dopamine ornorepinephrine. Phenylephrine is the ad-renergic agent least likely to producetachycardia but as a pure vasopressorwould be expected to decrease stroke vol-ume. Dopamine increases mean arterialpressure and cardiac output, primarilydue to an increase in stroke volume andheart rate. Norepinephrine increasesmean arterial pressure due to its vasocon-strictive effects, with little change inheart rate and less increase in stroke vol-ume compared with dopamine. Eithermay be used as a first-line agent to correcthypotension in sepsis. Norepinephrine ismore potent than dopamine and may bemore effective at reversing hypotension inpatients with septic shock. Dopamine maybe particularly useful in patients with com-promised systolic function but causes moretachycardia and may be more arrhythmo-genic (86). It may also influence the endo-crine response via the hypothalamic-pituitary axis and have immunosuppressiveeffects.

Vasopressin levels in septic shock havebeen reported to be lower than antici-pated for a shock state (87). Low doses ofvasopressin may be effective in raisingblood pressure in patients refractory toother vasopressors and may have otherpotential physiologic benefits (88 –93).Terlipressin has similar effects but is longlasting (94). Studies show that vasopres-sin concentrations are elevated in early

septic shock, but with continued shockthe concentration decreases to normalrange in the majority of patients between24 and 48 hrs (95). This has been calledrelative vasopressin deficiency because inthe presence of hypotension, vasopressinwould be expected to be elevated. Thesignificance of this finding is unknown.The recent VASST trial, a randomized,controlled trial comparing norepineph-rine alone to norepinephrine plus vaso-pressin at 0.03 units/min, showed no dif-ference in outcome in the intent to treatpopulation. An a priori defined subgroupanalysis showed that the survival of pa-tients receiving �15 �g/min norepineph-rine at the time of randomization wasbetter with vasopressin. However, thepretrial rationale for this stratificationwas based on exploring potential benefitin the �15 �g norepinephrine require-ment population. Higher doses of vaso-pressin have been associated with car-diac, digital, and splanchnic ischemia andshould be reserved for situations wherealternative vasopressors have failed (96).Cardiac output measurement to allowmaintenance of a normal or elevated flowis desirable when these pure vasopressorsare instituted.

5. We recommend that low-dose dopa-mine not be used for renal protection(grade 1A).

Rationale. A large randomized trialand meta-analysis comparing low-dosedopamine to placebo found no differencein either primary outcomes (peak serumcreatinine, need for renal replacement,urine output, time to recovery of normalrenal function) or secondary outcomes(survival to either ICU or hospital dis-charge, ICU stay, hospital stay, arrhyth-mias) (97, 98). Thus, the available data donot support administration of low dosesof dopamine solely to maintain renalfunction.

6. We recommend that all patients re-quiring vasopressors have an arterialcatheter placed as soon as practical ifresources are available (grade 1D).

Rationale. In shock states, estimationof blood pressure using a cuff is com-monly inaccurate; use of an arterial can-nula provides a more appropriate and re-producible measurement of arterialpressure. These catheters also allow con-tinuous analysis so that decisions regard-ing therapy can be based on immediateand reproducible blood pressure informa-tion.

G. Inotropic Therapy

1. We recommend that a dobutamine in-fusion be administered in the presenceof myocardial dysfunction as sug-gested by elevated cardiac filling pres-sures and low cardiac output (grade1C).

2. We recommend against the use of astrategy to increase cardiac index topredetermined supranormal levels(grade 1B).

Rationale. Dobutamine is the first-choice inotrope for patients with mea-sured or suspected low cardiac output inthe presence of adequate left ventricularfilling pressure (or clinical assessment ofadequate fluid resuscitation) and ade-quate mean arterial pressure. Septic pa-tients who remain hypotensive after fluidresuscitation may have low, normal, orincreased cardiac outputs. Therefore,treatment with a combined inotrope/vasopressor, such as norepinephrine ordopamine, is recommended if cardiacoutput is not measured. When the capa-bility exists for monitoring cardiac out-put in addition to blood pressure, a vaso-pressor, such as norepinephrine, may beused separately to target specific levels ofmean arterial pressure and cardiac out-put. Two large prospective clinical trialsthat included critically ill ICU patientswho had severe sepsis failed to demon-strate benefit from increasing oxygen de-livery to supranormal targets by use ofdobutamine (99, 100). These studies didnot specifically target patients with se-vere sepsis and did not target the first 6hrs of resuscitation. The first 6 hrs ofresuscitation of sepsis-induced hypoper-fusion need to be treated separately fromthe later stages of severe sepsis (see Ini-tial Resuscitation recommendations).

H. Corticosteroids

1. We suggest that intravenous hydro-cortisone be given only to adult septicshock patients after it has been con-firmed that their blood pressure ispoorly responsive to fluid resuscita-tion and vasopressor therapy (grade2C).

Rationale. One French multicenter,randomized controlled trial (RCT) of pa-tients in vasopressor-unresponsive septicshock (hypotension despite fluid resuscita-tion and vasopressors) showed a significantshock reversal and reduction of mortalityrate in patients with relative adrenal insuf-


ficiency (defined as postadrenocortico-tropic hormone [ACTH] cortisol increase�9 �g/dL) (101). Two additional smallerRCTs also showed significant effects onshock reversal with steroid therapy (102,103). However, a recent large, Europeanmulticenter trial (CORTICUS), which hasbeen presented in abstract form but not yetpublished, failed to show a mortality benefitwith steroid therapy of septic shock (104).CORTICUS did show a faster resolution ofseptic shock in patients who received ste-roids. The use of the ACTH test (respondersand nonresponders) did not predict thefaster resolution of shock. Importantly, un-like the French trial, which only enrolledshock patients with blood pressure unre-sponsive to vasopressor therapy, the COR-TICUS study included patients with septicshock, regardless of how the blood pressureresponded to vasopressors. Although corti-costeroids do appear to promote shock re-versal, the lack of a clear improvement inmortality—coupled with known side ef-fects of steroids, such as increased risk ofinfection and myopathy—generally tem-pered enthusiasm for their broad use. Thus,there was broad agreement that the recom-mendation should be downgraded from theprevious guidelines (Appendix B). Therewas considerable discussion and consider-ation by the committee on the option ofencouraging use in those patients whoseblood pressure was unresponsive to fluidsand vasopressors, while strongly discourag-ing use in subjects whose shock respondedwell to fluids and pressors. However, thismore complex set of recommendations wasrejected in favor of the preceding singlerecommendation (Appendix B).

2. We suggest that the ACTH stimulationtest not be used to identify the subsetof adults with septic shock who shouldreceive hydrocortisone (grade 2B).

Rationale. Although one study sug-gested those who did not respond toACTH with a brisk surge in cortisol (fail-ure to achieve or �9 �g/dL increase incortisol 30–60 mins after ACTH admin-istration) were more likely to benefitfrom steroids than those who did re-spond, the overall trial population ap-peared to benefit regardless of ACTH re-sult, and the observation of a potentialinteraction between steroid use andACTH test was not statistically significant(101). Furthermore, there was no evi-dence of this distinction between re-sponders and nonresponders in a recentmulticenter trial (104). Commonly usedcortisol immunoassays measure total

cortisol (protein-bound and free) whilefree cortisol is the pertinent measure-ment. The relationship between free andtotal cortisol varies with serum proteinconcentration. When compared with areference method (mass spectrometry),cortisol immunoassays may over- or un-derestimate the actual cortisol level, af-fecting the assignment of patients to re-sponders or nonresponders (105).Although the clinical significance is notclear, it is now recognized that etomi-date, when used for induction for intuba-tion, will suppress the hypothalamic-pituitary-adrenal axis (106).

3. We suggest that patients with septicshock should not receive dexametha-sone if hydrocortisone is available(grade 2B).

Rationale. Although often proposedfor use until an ACTH stimulation testcan be administered, we no longer sug-gest an ACTH test in this clinical situa-tion (see the preceding point 3). Further-more, dexamethasone can lead toimmediate and prolonged suppression ofthe hypothalamic-pituitary-adrenal axisafter administration (107).

4. We suggest the daily addition of oralfludrocortisone (50 �g) if hydrocorti-sone is not available and the steroidthat is substituted has no significantmineralocorticoid activity. Fludrocor-tisone is considered optional if hydro-cortisone is used (grade 2C).

Rationale. One study added 50 �g offludrocortisone orally (101). Since hydro-cortisone has intrinsic mineralocorticoidactivity, there is controversy as towhether fludrocortisone should be added.

5. We suggest that clinicians wean thepatient from steroid therapy when va-sopressors are no longer required(grade 2D).

Rationale. There has been no compar-ative study between a fixed-duration andclinically guided regimen or between ta-pering and abrupt cessation of steroids.Three RCTs used a fixed-duration proto-col for treatment (101, 103, 104), and intwo RCTs, therapy was decreased aftershock resolution (102, 108). In four RCTssteroids were tapered over several days(102–104, 108), and in two RCTs (101,109) steroids were withdrawn abruptly.One crossover study showed hemody-namic and immunologic rebound effectsafter abrupt cessation of corticosteroids

(110). It remains uncertain whether out-come is affected by tapering of steroids.

6. We recommend that doses of cortico-steroids comparable to �300 mg ofhydrocortisone daily not be used insevere sepsis or septic shock for thepurpose of treating septic shock(grade 1A).

Rationale. Two randomized prospec-tive clinical trials and a meta-analysesconcluded that for therapy of severe sep-sis or septic shock, high-dose corticoste-roid therapy is ineffective or harmful(111–113). Reasons to maintain higherdoses of corticosteroid for medical condi-tions other than septic shock may exist.

7. We recommend that corticosteroidsnot be administered for the treatmentof sepsis in the absence of shock.There is, however, no contraindicationto continuing maintenance steroidtherapy or to using stress-dose ste-roids if the patient’s endocrine or cor-ticosteroid administration historywarrants (grade 1D).

Rationale. No studies exist that specif-ically target severe sepsis in the absence ofshock and offer support for use of stressdoses of steroids in this patient population.Steroids may be indicated in the presenceof a history of steroid therapy or adrenaldysfunction. A recent preliminary study ofstress-dose level steroids in community-acquired pneumonia is encouraging butneeds confirmation (114).

I. Recombinant HumanActivated Protein C (rhAPC)

1. We suggest that adult patients with sep-sis-induced organ dysfunction associ-ated with a clinical assessment of highrisk of death, most of whom will haveAcute Physiology and Chronic HealthEvaluation (APACHE) II �25 or multi-ple organ failure, receive rhAPC if thereare no contraindications (grade 2B ex-cept for patients within 30 days of sur-gery, for whom it is grade 2C). Relativecontraindications should also be consid-ered in decision making.

2. We recommend that adult patientswith severe sepsis and low risk ofdeath, most of whom will haveAPACHE II �20 or one organ failure,do not receive rhAPC (grade 1A).

Rationale. The evidence concerninguse of rhAPC in adults is primarily based ontwo RCTs: PROWESS (1,690 adult patients,stopped early for efficacy) (115) and AD-


DRESS (stopped early for futility) (116).Additional safety information comes froman open-label observational study, EN-HANCE (117). The ENHANCE trial alsosuggested that early administration ofrhAPC was associated with better out-comes.

PROWESS involved 1,690 patients anddocumented 6.1% in absolute total mor-tality reduction with a relative risk reduc-tion of 19.4%, 95% confidence interval6.6–30.5%, and number needed to treat16 (115). Controversy associated with theresults focused on a number of subgroupanalyses. Subgroup analyses have the po-tential to mislead due to the absence ofan intent to treat, sampling bias, andselection error (118). The analyses sug-gested increasing absolute and relativerisk reduction with greater risk of deathusing both higher APACHE II scores andgreater number of organ failures (119).This led to drug approval for patientswith high risk of death (such as APACHEII �25) and more than one organ failurein Europe.

The ADDRESS trial involved 2,613 pa-tients judged to have a low risk of deathat the time of enrollment. The 28-daymortality rate from all causes was 17% onplacebo vs. 18.5% on APC, relative risk1.08, 95% confidence interval 0.92–1.28(116). Again, debate focused on subgroupanalyses; analyses were restricted tosmall subgroups of patients withAPACHE II score �25 or more than oneorgan failure, which failed to show bene-fit. However, these patient groups alsohad a lower mortality than in PROWESS.

Relative risk reduction of death wasnumerically lower in the subgroup of pa-tients with recent surgery (n � 502) inthe PROWESS trial (30.7% placebo vs.27.8% APC) (119) when compared withthe overall study population (30.8% pla-cebo vs. 24.7% APC) (115). In the AD-DRESS trial, patients with recent surgeryand single organ dysfunction who re-ceived APC had significantly higher 28-day mortality rates (20.7% vs. 14.1%, p �.03, n � 635) (116).

Serious adverse events did not differ inthe studies (115–117) with the exceptionof serious bleeding, which occurred moreoften in the patients treated with APC:2% vs. 3.5% (PROWESS; p � .06) (115);2.2% vs. 3.9% (ADDRESS; p � .01) (116);6.5% (ENHANCE, open label) (117). Thepediatric trial and implications are dis-cussed in the pediatric consideration sec-tion of this article. (Appendix C providesabsolute contraindications to use of

rhAPC and prescribing information forrelative contraindications.)

Intracranial hemorrhage (ICH) oc-curred in the PROWESS trial in 0.1%(placebo) and 0.2% (APC) (not signifi-cant) (106); in the ADDRESS trial 0.4%(placebo) vs. 0.5 % (APC) (not significant)(116); and in ENHANCE 1.5% (108). Reg-istry studies of rhAPC report higherbleeding rates than randomized con-trolled trials, suggesting that the risk ofbleeding in actual practice may be greaterthan reported in PROWESS and AD-DRESS (120, 121).

The two RCTs in adult patients weremethodologically strong and precise andprovided direct evidence regarding deathrates. The conclusions are limited, how-ever, by inconsistency that is not ade-quately resolved by subgroup analyses(thus the designation of moderate-qualityevidence). Results, however, consistentlyfail to show benefit for the subgroup ofpatients at lower risk of death and con-sistently show increases in serious bleed-ing. The RCT in pediatric severe sepsisfailed to show benefit and has no impor-tant limitations. Thus, for low-risk andpediatric patients, we rate the evidence ashigh quality.

For adult use there is probable mor-tality reduction in patients with clinicalassessment of high risk of death, most ofwhom will have APACHE II �25 or mul-tiple organ failure. There is likely no ben-efit in patients with low risk of death,most of whom will have APACHE II �20or single organ dysfunction. The effectsin patients with more than one organfailure but APACHE II �25 are unclear,and in that circumstance one may useclinical assessment of the risk of deathand number of organ failures to supportdecision. There is a certain increasedrisk of bleeding with administration ofrhAPC, which may be higher in surgicalpatients and in the context of invasiveprocedures. Decision on utilization de-pends on assessing likelihood of mor-tality reduction vs. increases in bleed-ing and cost. (Appendix D provides thenominal committee vote on recommen-dation for rhAPC.) A European regula-tory mandated RCT of rhAPC vs. pla-cebo in patients with septic shock isnow ongoing (122).

J. Blood Product Administration

1. Once tissue hypoperfusion has resolvedand in the absence of extenuating cir-cumstances, such as myocardial isch-

emia, severe hypoxemia, acute hemor-rhage, cyanotic heart disease, or lacticacidosis (see recommendations for ini-tial resuscitation), we recommend thatred blood cell transfusion occur whenhemoglobin decreases to �7.0 g/dL(�70 g/L) to target a hemoglobin of7.0–9.0 g/dL (70–90 g/L) in adults(grade 1B).

Rationale. Although the optimum he-moglobin for patients with severe sepsishas not been specifically investigated, theTransfusion Requirements in CriticalCare trial suggested that a hemoglobin of7–9 g/dL (70–90 g/L) when comparedwith 10–12 g/dL (100–200 g/L) was notassociated with increased mortality inadults (123). Red blood cell transfusion inseptic patients increases oxygen deliverybut does not usually increase oxygen con-sumption (124 –126). This transfusionthreshold of 7 g/dL (70 g/L) contrastswith the early goal-directed resuscitationprotocol that uses a target hematocrit of30% in patients with low ScvO2 (mea-sured in superior vena cava) during thefirst 6 hrs of resuscitation of septic shock.

2. We recommend that erythropoietinnot be used as a specific treatment ofanemia associated with severe sepsisbut may be used when septic patientshave other accepted reasons for ad-ministration of erythropoietin, such asrenal failure-induced compromise ofred blood cell production (grade 1B).

Rationale. No specific information re-garding erythropoietin use in septic pa-tients is available, but clinical trials incritically ill patients show some decreasein red cell transfusion requirement withno effect on clinical outcome (127, 128).The effect of erythropoietin in severe sep-sis and septic shock would not be ex-pected to be more beneficial than in othercritical conditions. Patients with severesepsis and septic shock may have coexist-ing conditions that do warrant use oferythropoietin.

3. We suggest that fresh frozen plasmanot be used to correct laboratory clot-ting abnormalities in the absence ofbleeding or planned invasive proce-dures (grade 2D).

Rationale. Although clinical studieshave not assessed the impact of transfu-sion of fresh frozen plasma on outcomesin critically ill patients, professional or-ganizations have recommended fresh fro-zen plasma for coagulopathy when thereis a documented deficiency of coagulation


factors (increased prothrombin time, in-ternational normalized ratio, or partialthromboplastin time) and the presence ofactive bleeding or before surgical or in-vasive procedures (129–131). In addition,transfusion of fresh frozen plasma innonbleeding patients with mild abnor-malities of prothrombin time usually failsto correct the prothrombin time (132).There are no studies to suggest that cor-rection of more severe coagulation ab-normalities benefits patients who are notbleeding.

4. We recommend against antithrombinadministration for the treatment of se-vere sepsis and septic shock (grade 1B).

Rationale. A phase III clinical trial ofhigh-dose antithrombin did not demon-strate any beneficial effect on 28-day all-cause mortality in adults with severe sepsisand septic shock. High-dose antithrombinwas associated with an increased risk ofbleeding when administered with heparin(133). Although a post hoc subgroup anal-ysis of patients with severe sepsis and highrisk of death showed better survival in pa-tients receiving antithrombin, antithrom-bin cannot be recommended until furtherclinical trials are performed (134).

5. In patients with severe sepsis, we sug-gest that platelets be administeredwhen counts are �5000/mm3 (5 �109/L) regardless of apparent bleeding.Platelet transfusion may be consideredwhen counts are 5000–30,000/mm3

(5–30 � 109/L) and there is a signifi-cant risk of bleeding. Higher plateletcounts (�50,000/mm3 [50 � 109/L])are typically required for surgery orinvasive procedures (grade 2D).

Rationale. Guidelines for transfusionof platelets are derived from consensusopinion and experience in patients under-going chemotherapy. Recommendationstake into account the etiology of throm-bocytopenia, platelet dysfunction, risk ofbleeding, and presence of concomitantdisorders (129, 131).

II. SUPPORTIVE THERAPY OFSEVERE SEPSIS

A. Mechanical Ventilation ofSepsis-Induced Acute LungInjury (ALI)/Acute RespiratoryDistress Syndrome (ARDS)

1. We recommend that clinicians targeta tidal volume of 6 mL/kg (predicted)body weight in patients with ALI/ARDS (grade 1B).

2. We recommend that plateau pressuresbe measured in patients with ALI/ARDS and that the initial upper limitgoal for plateau pressures in a pas-sively inflated patient be �30 cm H2O.Chest wall compliance should be con-sidered in the assessment of plateaupressure (grade 1C).

Rationale. Over the past 10 yrs, sev-eral multicenter randomized trials havebeen performed to evaluate the effects oflimiting inspiratory pressure throughmoderation of tidal volume (135–139).These studies showed differing resultsthat may have been caused by differencesbetween airway pressures in the treat-ment and control groups (135, 140). Thelargest trial of a volume- and pressure-limited strategy showed a 9% decrease ofall-cause mortality in patients with ALI orARDS ventilated with tidal volumes of 6mL/kg of predicted body weight (PBW),as opposed to 12 mL/kg, and aiming for aplateau pressure �30 cm H2O (135). Theuse of lung-protective strategies for pa-tients with ALI is supported by clinicaltrials and has been widely accepted, butthe precise choice of tidal volume for anindividual patient with ALI may requireadjustment for such factors as the plateaupressure achieved, the level of positiveend-expiratory pressure chosen, the com-pliance of the thoracoabdominal com-partment, and the vigor of the patient’sbreathing effort. Some clinicians believeit may be safe to ventilate with tidal vol-umes �6 mL/kg PBW as long as the pla-teau pressure can be maintained �30 cmH2O (141, 142). The validity of this ceil-ing value will depend on breathing effort,as those who are actively inspiring gen-erate higher transalveolar pressures for agiven plateau pressure than those whoare passively inflated. Conversely, pa-tients with very stiff chest walls may re-quire plateau pressures �30 cm H2O tomeet vital clinical objectives. One retro-spective study suggested that tidal vol-umes should be lowered even with pla-teau pressures �30 cm H2O (143). Anadditional observational study suggestedthat knowledge of the plateau pressureswas associated with lower plateau pres-sures; however, in that trial plateau pres-sure was not independently associatedwith mortality rates across a wide rangeof plateau pressures that bracketed 30 cmH2O (144). The largest clinical trial em-ploying a lung-protective strategy cou-pled limited pressure with limited tidal

volumes to demonstrate a mortality ben-efit (135).

High tidal volumes that are coupledwith high plateau pressures should beavoided in ALI/ARDS. Clinicians should useas a starting point the objective of reducingtidal volume over 1–2 hrs from its initialvalue toward the goal of a “low” tidal vol-ume (�6 mL/kg PBW) achieved in con-junction with an end-inspiratory plateaupressure �30 cm H2O. If plateau pressureremains �30 after reduction of tidal vol-ume to 6 mL/kg PBW, tidal volume shouldbe reduced further to as low as 4 mL/kgPBW. (Appendix E provides ARDSNet ven-tilator management and formulas to calcu-late predicted body weight.)

No single mode of ventilation (pres-sure control, volume control, airwaypressure release ventilation, high-fre-quency ventilation) has been consistentlyshown advantageous when comparedwith any other that respects the sameprinciples of lung protection.

3. We recommend that hypercapnia (al-lowing PaCO2 to increase above its pre-morbid baseline, so-called permissivehypercapnia) be allowed in patientswith ALI/ARDS if needed to minimizeplateau pressures and tidal volumes(grade 1C).

Rationale. An acutely elevated PaCO2

may have physiologic consequences thatinclude vasodilation as well as an in-creased heart rate, blood pressure, andcardiac output. Allowing modest hyper-capnia in conjunction with limiting tidalvolume and minute ventilation has beendemonstrated to be safe in small, nonran-domized series (145, 146). Patientstreated in larger trials that have the goalof limiting tidal volumes and airway pres-sures have demonstrated improved out-comes, but permissive hypercapnia wasnot a primary treatment goal in these stud-ies (135). The use of hypercapnia is limitedin patients with preexisting metabolic aci-dosis and is contraindicated in patientswith increased intracranial pressure. So-dium bicarbonate or tromethamine(THAM) infusion may be considered in se-lected patients to facilitate use of permis-sive hypercarbia (147, 148).

4. We recommend that positive end-expiratory pressure (PEEP) be set soas to avoid extensive lung collapse atend-expiration (grade 1C).

Rationale. Raising PEEP in ALI/ARDSkeeps lung units open to participate ingas exchange. This will increase PaO2


when PEEP is applied through either anendotracheal tube or a face mask (149–151). In animal experiments, avoidance ofend-expiratory alveolar collapse helpsminimize ventilator-induced lung injurywhen relatively high plateau pressuresare in use. One large multicenter trial ofthe protocol-driven use of higher PEEPin conjunction with low tidal volumes didnot show benefit or harm when comparedwith lower PEEP levels (152). Neither thecontrol nor experimental group in thatstudy, however, was clearly exposed tohazardous plateau pressures. A recentmulticenter Spanish trial compared ahigh PEEP, low-moderate tidal volumeapproach to one that used conventionaltidal volumes and the least PEEP achiev-ing adequate oxygenation. A marked sur-vival advantage favored the former ap-proach in high-acuity patients with ARDS(153). Two options are recommended forPEEP titration. One option is to titratePEEP (and tidal volume) according tobedside measurements of thoracopulmo-nary compliance with the objective of ob-taining the best compliance, reflecting afavorable balance of lung recruitmentand overdistension (154). The second op-tion is to titrate PEEP based on severityof oxygenation deficit and guided by theFIO2 required to maintain adequate oxy-genation (135) (Appendix D). Whicheverthe indicator— compliance or oxygen-ation—recruiting maneuvers are reason-able to employ in the process of PEEPselection. Blood pressure and oxygen-ation should be monitored and recruit-ment discontinued if deterioration inthese variables is observed. A PEEP �5cm H20 is usually required to avoid lungcollapse (155).

5. We suggest prone positioning in ARDSpatients requiring potentially injuriouslevels of FIO2 or plateau pressure whoare not at high risk for adverse conse-quences of positional changes in facili-ties that have experience with suchpractices (grade 2C).

Rationale. Several small studies andone larger study have shown that a ma-jority of patients with ALI/ARDS respondto the prone position with improved ox-ygenation (156–159). One large multi-center trial of prone positioning for approx-imately 7 hrs/day did not showimprovement in mortality rates in patientswith ALI/ARDS; however, a post hoc anal-ysis suggested improvement in those pa-tients with the most severe hypoxemia byPaO2/FIO2 ratio, in those exposed to high

tidal volumes, and in those who improvedCO2 exchange as a result of proning (159).A second large trial of prone positioning,conducted for an average of approximately8 hrs/day for 4 days in adults with hypox-emic respiratory failure of low-moderateacuity, confirmed improvement in oxygen-ation but also failed to show a survival ad-vantage (160). However, a randomizedstudy that extended the length of time forproning each day to a mean of 17 hrs for amean of 10 days supported benefit of pron-ing, with randomization to supine positionan independent risk factor for mortality bymultivariate analysis (161). Prone position-ing may be associated with potentially life-threatening complications, including acci-dental dislodgment of the endotrachealtube and central venous catheters, butthese complications can usually be avoidedwith proper precautions.

6a. Unless contraindicated, we recom-mend that mechanically ventilatedpatients be maintained with the headof the bed elevated to limit aspirationrisk and to prevent the developmentof ventilator-associated pneumonia(grade 1B).

6b. We suggest that the head of bed beelevated approximately 30 – 45°(grade 2C).

Rationale. The semirecumbent posi-tion has been demonstrated to decreasethe incidence of ventilator-associatedpneumonia (VAP) (162). Enteral feedingincreased the risk of developing VAP;50% of the patients who were fed enter-ally in the supine position developed VAP(163). However, the bed position was onlymonitored once a day, and patients whodid not achieve the desired bed elevationwere not included in the analysis (163). Arecent study did not show a difference inincidence of VAP between patients main-tained in supine and semirecumbent po-sitions (164). In this study, patients in thesemirecumbent position did not consis-tently achieve the desired head of the bedelevation, and the head of bed elevationin the supine group approached that ofthe semirecumbent group by day 7 (164).When necessary, patients may be laid flatfor procedures, hemodynamic measure-ments, and during episodes of hypoten-sion. Patients should not be fed enterallywith the head of the bed at 0°.

7. We suggest that noninvasive maskventilation (NIV) only be considered inthat minority of ALI/ARDS patientswith mild-moderate hypoxemic respi-

ratory failure (responsive to relativelylow levels of pressure support andPEEP) with stable hemodynamics whocan be made comfortable and are eas-ily arousable; who are able to protectthe airway and spontaneously clearthe airway of secretions; and who areanticipated to recover rapidly from theprecipitating insult. A low thresholdfor airway intubation should be main-tained (grade 2B).

Rationale. Obviating the need for air-way intubation confers multiple advan-tages: better communication, lower inci-dence of infection, reduced requirementsfor sedation. Two RCTs demonstrate im-proved outcome with the use of NIV whenit can be employed successfully (162,165). Unfortunately, only a small percent-age of patients with life-threatening hy-poxemia can be managed in this way.

8. We recommend that a weaning proto-col be in place and that mechanicallyventilated patients with severe sepsisundergo spontaneous breathing trialsregularly to evaluate the ability to dis-continue mechanical ventilation whenthey satisfy the following criteria: a)They are arousable; b) they are hemo-dynamically stable (without vasopres-sor agents); c) they have no new po-tentially serious conditions; d) theyhave low ventilatory and end-expira-tory pressure requirements; and e)their FIO2 requirements could besafely delivered with a face mask ornasal cannula. If the spontaneousbreathing trial is successful, consider-ation should be given for extubation(Appendix E). Spontaneous breathingtrial options include a low level ofpressure support, continuous positiveairway pressure (�5 cm H2O), or aT-piece (grade 1A).

Rationale. Recent studies demon-strate that daily spontaneous breathingtrials in appropriately selected patientsreduce the duration of mechanical venti-lation (166–169). Successful completionof spontaneous breathing trials leads to ahigh likelihood of successful discontinu-ation of mechanical ventilation.

9. We recommend against the routineuse of the pulmonary artery catheterfor patients with ALI/ARDS (grade1A).

Rationale. While insertion of a pulmo-nary artery catheter may provide usefulinformation on a patient’s volume status


and cardiac function, potential benefits ofsuch information may be confounded bydifferences in interpretation of results(170–172), lack of correlation of pulmo-nary artery occlusion pressures with clin-ical response (173), and absence of aproven strategy to use catheter results toimprove patient outcomes (174). Twomulticenter randomized trials, one in pa-tients with shock or acute lung injury(175) and one in patients with acute lunginjury (176), failed to show benefit withthe routine use of pulmonary artery cath-eters in patients with acute lung injury.In addition, other studies in differenttypes of critically ill patients have failedto show definitive benefit with routineuse of the pulmonary artery catheter(177–179). Well-selected patients remainappropriate candidates for pulmonary ar-tery catheter insertion when the answersto important management decisions de-pend on information only obtainablefrom direct measurements made withinthe pulmonary artery.

10. To decrease days of mechanical ven-tilation and ICU length of stay werecommend a conservative fluidstrategy for patients with establishedacute lung injury who do not haveevidence of tissue hypoperfusion(grade 1C).

Rationale. Mechanisms for the devel-opment of pulmonary edema in patientswith acute lung injury include increasedcapillary permeability, increased hydro-static pressure, and decreased oncoticpressure (180, 181). Small prospectivestudies in patients with critical illnessand acute lung injury have suggested thatless weight gain is associated with im-proved oxygenation (182) and fewer daysof mechanical ventilation (183, 184). Useof a fluid-conservative strategy directed atminimizing fluid infusion and weightgain in patients with acute lung injurybased on either a central venous catheteror a pulmonary artery catheter alongwith clinical variables to guide treatmentstrategies led to fewer days of mechanicalventilation and reduced length of ICUstay without altering the incidence of re-nal failure or mortality rates (185). Ofnote, this strategy was only used in pa-tients with established acute lung injury,some of whom had shock present. Activeattempts to reduce fluid volume wereconducted only during periods free fromshock.

B. Sedation, Analgesia, andNeuromuscular Blockade inSepsis

1. We recommend sedation protocolswith a sedation goal when sedation ofcritically ill mechanically ventilatedpatients with sepsis is required (grade1B).

Rationale. A growing body of evidenceindicates that the use of protocols forsedation of critically ill ventilated pa-tients can reduce the duration of me-chanical ventilation and ICU and hospitallength of stay (186–188). A randomized,controlled clinical trial found that proto-col use reduced duration of mechanicalventilation, lengths of stay, and tracheos-tomy rates (186).

A report describing the implementa-tion of protocols, including sedation andanalgesia, using a short-cycle improve-ment methodology in the management ofcritically ill patients demonstrated a de-crease in the cost per patient-day and adecrease of ICU length of stay (187). Fur-thermore, a prospective before-and-afterstudy on the implementation of a seda-tion protocol demonstrated enhancedquality of sedation with reduced drugcosts. Although this protocol also mayhave contributed to a longer duration ofmechanical ventilation, ICU dischargewas not delayed (188). Despite the lack ofevidence regarding the use of subjectivemethods of evaluation of sedation in sep-tic patients, the use of a sedation goal hasbeen shown to decrease the duration ofmechanical ventilation in critically ill pa-tients (186). Several subjective sedationscales have been described in the medicalliterature. Currently, however, there isnot a clearly superior sedation evaluationmethodology against which these seda-tion scales can be evaluated (189). Thebenefits of sedation protocols appear tooutweigh the risks.

2. We recommend intermittent bolus se-dation or continuous infusion seda-tion to predetermined end points (e.g.,sedation scales) with daily interrup-tion/lightening of continuous infusionsedation with awakening and retitra-tion if necessary for sedation adminis-tration to septic mechanically venti-lated patients (grade 1B).

Rationale. Although not specificallystudied in patients with sepsis, the ad-ministration of intermittent sedation,daily interruption, and retitration or sys-temic titration to a predefined end point

have been demonstrated to decrease theduration of mechanical ventilation (186,189, 190). Patients receiving neuromus-cular blocking agents (NMBAs) must beindividually assessed regarding discontin-uation of sedative drugs because neuro-muscular blocking drugs must also bediscontinued in that situation. The use ofintermittent vs. continuous methods forthe delivery of sedation in critically illpatients has been examined. An observa-tional study of mechanically ventilatedpatients showed that patients receivingcontinuous sedation had significantlylonger durations of mechanical ventila-tion and ICU and hospital length of stay(191).

Similarly, a prospective, controlledstudy in 128 mechanically ventilatedadults receiving continuous intravenoussedation demonstrated that a daily inter-ruption in the continuous sedative infu-sion until the patient was awake de-creased the duration of mechanicalventilation and ICU length of stay (192).Although the patients did receive contin-uous sedative infusions in this study, thedaily interruption and awakening allowedfor titration of sedation, in effect makingthe dosing intermittent. Systematic (pro-tocolized) titration to a predefined endpoint has also been shown to alter out-come (186). Additionally, a randomizedprospective blinded observational studydemonstrated that although myocardialischemia is common in critically ill ven-tilated patients, daily sedative interrup-tion is not associated with an increasedoccurrence of myocardial ischemia (193).Thus, the benefits of daily interruption ofsedation appear to outweigh the risks.These benefits include potentially shorterduration of mechanical ventilation andICU stay, better assessment of neurologicfunction, and reduced costs.

3. We recommend that NMBAs beavoided if possible in the septic patientdue to the risk of prolonged neuro-muscular blockade following discon-tinuation. If NMBAs must be main-tained, either intermittent bolus asrequired or continuous infusion withmonitoring the depth of blockade withtrain-of-four monitoring should beused (grade 1B).

Rationale. Although NMBAs are oftenadministered to critically ill patients,their role in the ICU is not well defined.No evidence exists that maintaining neu-romuscular blockade in this patient pop-ulation reduces mortality or major mor-


bidity. In addition, no studies have beenpublished that specifically address the useof NMBAs in septic patients.

The most common indication forNMBA use in the ICU is to facilitate me-chanical ventilation (194). When appro-priately used, NMBAs may improve chestwall compliance, prevent respiratory dys-synchrony, and reduce peak airway pres-sures (195). Muscle paralysis may alsoreduce oxygen consumption by decreas-ing the work of breathing and respiratorymuscle blood flow (196). However, a ran-domized, placebo-controlled clinical trialin patients with severe sepsis demon-strated that oxygen delivery, oxygen con-sumption, and gastric intramucosal pHwere not improved during profound neu-romuscular blockade (197).

An association between NMBA use andmyopathies and neuropathies has beensuggested by case studies and prospectiveobservational studies in the critical carepopulation (195, 198–201). The mecha-nisms by which NMBAs produced or con-tribute to myopathies and neuropathiesin critically ill patients are presently un-known. There appears to be an addedassociation with the concurrent use ofNMBAs and steroids. Although no studiesexist specific to the septic patient popu-lation, it seems clinically prudent basedon existent knowledge that NMBAs not beadministered unless there is a clear indi-cation for neuromuscular blockade thatcannot be safely achieved with appropri-ate sedation and analgesia (195).

Only one prospective, randomizedclinical trial has evaluated peripheralnerve stimulation vs. standard clinical as-sessment in ICU patients. Rudis et al.(202) randomized 77 critically ill patientsrequiring neuromuscular blockade in theICU to receive dosing of vecuroniumbased on train-of-four stimulation orclinical assessment (control). The periph-eral nerve stimulation group received lessdrug and recovered neuromuscular func-tion and spontaneous ventilation fasterthan the control group. Nonrandomizedobservational studies have suggested thatperipheral nerve monitoring reduces orhas no effect on clinical recovery fromNMBAs in the ICU (203, 204).

Benefits to neuromuscular monitor-ing, including faster recovery of neuro-muscular function and shorter intuba-tion times, appear to exist. A potential forcost savings (reduced total dose ofNMBAs and shorter intubation times)also may exist, although this has not beenstudied formally.

C. Glucose Control

1. We recommend that following initialstabilization, patients with severe sep-sis and hyperglycemia who are admit-ted to the ICU receive intravenous in-sulin therapy to reduce blood glucoselevels (grade 1B).

2. We suggest use of a validated protocolfor insulin dose adjustments and tar-geting glucose levels to the �150mg/dL range (grade 2C).

3. We recommend that all patients re-ceiving intravenous insulin receive aglucose calorie source and thatblood glucose values be monitoredevery 1–2 hrs until glucose valuesand insulin infusion rates are stableand then every 4 hrs thereafter(grade 1C).

4. We recommend that low glucose lev-els obtained with point-of-care testingof capillary blood be interpreted withcaution, as such measurements mayoverestimate arterial blood or plasmaglucose values (grade 1B).

Rationale. The consensus on glucosecontrol in severe sepsis was achieved atthe first committee meeting and subse-quently approved by the entire commit-tee. (Appendix G presents the committeevote.) One large randomized single-center trial in a predominantly cardiacsurgical ICU demonstrated a reduction inICU mortality with intensive intravenousinsulin (Leuven protocol) targeting bloodglucose to 80–110 mg/dL (for all pa-tients, a relative 43% and absolute 3.4%mortality reduction; for those with �5days in the ICU, a 48% relative and 9.6%absolute mortality reduction) (205). A re-duction in organ dysfunction and ICUlength of stay (LOS) (from a median of 15to 12 days) was also observed in the sub-set with ICU LOS �5 days. A second ran-domized trial of intensive insulin therapyusing the Leuven protocol enrolled med-ical ICU patients with an anticipated ICULOS of �3 days in three medical ICUs(206). Overall mortality was not reduced,but ICU and hospital LOS were reducedassociated with earlier weaning from me-chanical ventilation and less acute kidneyinjury. In patients with a medical ICULOS �3 days, hospital mortality was re-duced with intensive insulin therapy(43% vs. 52.5%; p � .009). However, in-vestigators were unsuccessful in predict-ing ICU LOS, and 433 patients (36%) hadan ICU LOS of �3 days. Furthermore, useof the Leuven protocol in the medical ICUresulted in a nearly three-fold higher rate

of hypoglycemia than in the original ex-perience (18% vs. 6.2% of patients) (205,206).

One large before-and-after observa-tional trial showed a 29% relative and6.1% absolute reduction in mortality anda 10.8% reduction in median ICU LOS(207). In a subgroup of 53 patients withseptic shock, there was an absolute mor-tality reduction of 27% and a relativereduction of 45% (p � .02). Two addi-tional observational studies reported anassociation of mean glucose levels withreductions in mortality, polyneuropathy,acute renal failure, nosocomial bactere-mia, and number of transfusions, andthey suggested that a glucose thresholdfor improved mortality lies somewherebetween 145 and 180 mg/dL (208, 209).However, a large observational study(n � 7,049) suggested that both a lowermean glucose and less variation of bloodglucose may be important (210). A meta-analysis of 35 trials on insulin therapy incritically ill patients, including 12 ran-domized trials, demonstrated a 15% re-duction in short-term mortality (relativerisk 0.85, 95% confidence interval 0.75–0.97) but did not include any studies ofinsulin therapy in medical ICUs (211).

Two additional multicenter RCTs ofintensive insulin therapy, one focusingon patients with severe sepsis (VISEP)and the second on medical and surgicalICU patients, failed to demonstrate im-provement in mortality but are not yetpublished (212, 213). Both were stoppedearlier than planned because of high ratesof hypoglycemia and adverse events inthe intensive insulin groups. A large RCTthat is planned to compare targeting 80–110 mg/dL (4.5–6.0 mmol/L) vs. 140–180mg/dL (8 –10 mmol/L) and recruit�6,000 patients (Normoglycemia in In-tensive Care Evaluation and Survival Us-ing Glucose Algorithm Regulation, orNICE-SUGAR) is ongoing (214).

Several factors may affect the accuracyand reproducibility of point-of-care test-ing of blood capillary blood glucose, in-cluding the type and model of the deviceused, user expertise, and patient factors,including hematocrit (false elevationwith anemia), PaO2, and drugs (215). Onereport showed overestimation of arterialplasma glucose values by capillary point-of-care testing sufficient to result in dif-ferent protocol-specified insulin dose ti-tration. The disagreement betweenprotocol-recommended insulin doses waslargest when glucose values were low(216). A recent review of 12 published


insulin infusion protocols for critically illpatients showed wide variability in insu-lin dose recommendations and variableglucose control during simulation (217).This lack of consensus about optimal dos-ing of intravenous insulin may reflectvariability in patient factors (severity ofillness, surgical vs. medical settings) orpractice patterns (e.g., approaches tofeeding, intravenous dextrose) in the en-vironments in which these protocolswere developed and tested. Alternatively,some protocols may be more effectivethan others. This conclusion is supportedby the wide variability in hypoglycemiarates reported with protocols (205–207,212, 213). Thus, the use of a validated andsafe intensive insulin protocol is impor-tant not only for clinical care but also forthe conduct of clinical trials to avoid hy-poglycemia, adverse events, and prema-ture termination of these trials before theefficacy signal, if any, can be determined.

The finding of reduced morbidity andmortality within the longer ICU length ofstay subsets along with acceptable costweighed heavily on our recommendationto attempt glucose control after initialstabilization of the patient with hypergly-cemia and severe sepsis. However, themortality benefit and safety of intensiveinsulin therapy (goal to normalize bloodglucose) have been questioned by two re-cent trials, and we recommend maintain-ing glucose levels �150 mg/dL until re-cent and ongoing trials are published orcompleted. Further study of protocolsthat have been validated to be safe andeffective for controlling blood glucoseconcentrations and blood glucose varia-tion in the severe sepsis population isneeded.

D. Renal Replacement

1. We suggest that continuous renal re-placement therapies and intermittenthemodialysis are equivalent in pa-tients with severe sepsis and acute re-nal failure (grade 2B).

2. We suggest the use of continuoustherapies to facilitate management offluid balance in hemodynamically un-stable septic patients (grade 2D).

Rationale. Although numerous non-randomized studies have reported a non-significant trend toward improved sur-vival using continuous methods (218–225), two meta-analyses (226, 227)reported the absence of significant differ-ence in hospital mortality between pa-tients who receive continuous and inter-

mittent renal replacement therapies. Thisabsence of apparent benefit of one modal-ity over the other persists even when theanalysis is restricted to only randomizedstudies (227). To date, five prospectiverandomized studies have been published(228–232). Four of them found no signif-icant difference in mortality (229–232).One study found significantly highermortality in the continuous treatmentgroup (228), but imbalanced randomiza-tion had led to a higher baseline severityof illness in this group. When a multiva-riable model was used to adjust for sever-ity of illness, no difference in mortalitywas apparent between the groups (228).Most studies comparing modes of renalreplacement in the critically ill have in-cluded a small number of patients andsome major weaknesses (randomizationfailure, modifications of therapeutic pro-tocol during the study period, combina-tion of different types of continuous renalreplacement therapies, small number ofheterogenous groups of patients en-rolled). The most recent and largest ran-domized study (232) enrolled 360 pa-tients and found no significant differencein survival between the two groups.Moreover, there is no current evidence tosupport the use of continuous therapiesin sepsis independent of renal replace-ment needs.

Concerning the hemodynamic toler-ance of each method, no current evidenceexists to support a better tolerance withcontinuous treatments. Only two pro-spective studies (230, 233) have reporteda better hemodynamic tolerance withcontinuous treatment, with no improve-ment in regional perfusion (233) and nosurvival benefit (230). Four other pro-spective studies did not find any signifi-cant difference in mean arterial pressureor drop in systolic pressure between thetwo methods (229, 231, 232, 234). Con-cerning fluid balance management, twostudies reported a significant improve-ment in goal achievement with continu-ous methods (228, 230). In summary,current evidence is insufficient to drawstrong conclusions regarding the mode ofreplacement therapy for acute renal fail-ure in septic patients.

Four randomized controlled trialshave addressed whether the dose of con-tinuous renal replacement affects out-comes in patients with acute renal failure(235–238). Three found improved mor-tality in patients receiving higher doses ofrenal replacement (235, 237, 238), whileone (236) did not. None of these trials

was conducted specifically in patientswith sepsis. Although the weight of cur-rent evidence suggests that higher dosesof renal replacement may be associatedwith improved outcomes, these resultsmay not be easily generalizable. The re-sults of two very large multicenter ran-domized trials comparing the dose of re-nal replacement (ATN in the UnitedStates and RENAL in Australia and NewZealand) will be available in 2008 and willgreatly inform practice.

E. Bicarbonate Therapy

1. We recommend against the use of so-dium bicarbonate therapy for the pur-pose of improving hemodynamics orreducing vasopressor requirements inpatients with hypoperfusion-inducedlactic acidemia with pH �7.15 (grade1B).

Rationale. No evidence supports theuse of bicarbonate therapy in the treat-ment of hypoperfusion-induced lactic aci-demia associated with sepsis. Two ran-domized, blinded, crossover studies thatcompared equimolar saline and bicarbon-ate in patients with lactic acidosis failedto reveal any difference in hemodynamicvariables or vasopressor requirements(239, 240). The number of patients withpH �7.15 in these studies was small.Bicarbonate administration has been as-sociated with sodium and fluid overload,an increase in lactate and PCO2, and adecrease in serum ionized calcium, butthe relevance of these variables to out-come is uncertain. The effect of bicarbon-ate administration on hemodynamics andvasopressor requirements at lower pH aswell as the effect on clinical outcomes atany pH is unknown. No studies have ex-amined the effect of bicarbonate admin-istration on outcomes.

F. Deep Vein ThrombosisProphylaxis

1. We recommend that patients with se-vere sepsis receive deep vein thrombosis(DVT) prophylaxis with either a) low-dose unfractionated heparin (UFH) ad-ministered twice or three times per day;or b) daily low-molecular weight hepa-rin (LMWH) unless there are contrain-dications (i.e., thrombocytopenia, severecoagulopathy, active bleeding, recent in-tracerebral hemorrhage) (grade 1A).

2. We recommend that septic patientswho have a contraindication for hepa-rin use receive mechanical prophylac-


tic device, such as graduated compres-sion stockings or intermittentcompression devices, unless contrain-dicated (grade 1A).

3. We suggest that in very high-risk pa-tients, such as those who have severesepsis and history of DVT, trauma, ororthopedic surgery, a combination ofpharmacologic and mechanical ther-apy be used unless contraindicated ornot practical (grade 2C).

4. We suggest that in patients at veryhigh risk, LMWH be used rather thanUFH as LMWH is proven superior inother high-risk patients (grade 2C).

Rationale. ICU patients are at risk forDVT (241). Significant evidence exists forbenefit of DVT prophylaxis in ICU pa-tients in general. No reasons suggest thatsevere sepsis patients would be differentfrom the general patient population.

Nine randomized placebo-controlledclinical trials of DVT prophylaxis in gen-eral populations of acutely ill patients ex-ist (242–250). All nine trials showed re-duction in DVT or pulmonary embolism.The prevalence of infection/sepsis was17% in all studies in which this was as-certainable, with a 52% prevalence of in-fection/sepsis patients in the study thatincluded ICU patients only. Benefit ofDVT prophylaxis is also supported bymeta-analyses (251, 252). With that inmind, DVT prophylaxis would appear tohave a high grade for quality of evidence(A). Because the risk of administration tothe patient is small, the gravity of thepotential result of not administering isgreat, and the cost is low, the grading ofthe strength of the recommendation isstrong. The evidence supports equiva-lency of LMWH and UFH in general med-ical populations. A recent meta-analysiscomparing UFH twice daily and threetimes daily demonstrated that UFH threetimes daily produced better efficacy andtwice daily produced less bleeding (253).Practitioners should use underlying riskfor VTE and bleeding to individualizechoice of twice daily vs. three times daily.

The cost of LMWH is greater and thefrequency of injection is less. UFH is pre-ferred over LMWH in patients with mod-erate to severe renal dysfunction.

Mechanical methods (intermittent com-pression devices and graduated compres-sion stockings) are recommended when an-ticoagulation is contraindicated or as anadjunct to anticoagulation in very high-riskpatients (254–256). In very high-risk pa-tients, LMWH is preferred over UFH (257–

259). Patients receiving heparin should bemonitored for development of heparin-induced thrombocytopenia.

G. Stress Ulcer Prophylaxis

1. We recommend that stress ulcer pro-phylaxis using H2 blocker (grade 1A)or proton pump inhibitor (grade 1B)be given to patients with severe sepsisto prevent upper gastrointestinal (GI)bleed. The benefit of prevention of up-per GI bleed must be weighed againstthe potential effect of an increasedstomach pH on development of venti-lator-associated pneumonia.

Rationale. Although no study has beenperformed specifically in patients with se-vere sepsis, trials confirming the benefitof stress ulcer prophylaxis in reducingupper GI bleeds in general ICU popula-tions would suggest that 20% to 25% ofpatients enrolled in these types of trialshave sepsis (260 –263). This benefitshould be applicable to patients with se-vere sepsis and septic shock. In addition,the conditions shown to benefit fromstress ulcer prophylaxis (coagulopathy,mechanical ventilation, hypotension) arefrequently present in patients with severesepsis and septic shock (264, 265).

Although there are individual trialsthat have not shown benefit from stressulcer prophylaxis, numerous trials and ameta-analysis show reduction in clini-cally significant upper GI bleeding, whichwe consider significant even in the ab-sence of proven mortality benefit (266–269). The benefit of prevention of upperGI bleed must be weighed against thepotential effect of increased stomach pHon greater incidence of ventilator-associated pneumonia (270). Those se-vere sepsis patients with the greatest riskof upper GI bleeding are likely to benefitmost from stress ulcer prophylaxis. Therationale for preferring suppression ofacid production over sulcrafate was basedon the study of 1,200 patients by Cook etal. (271, 272) comparing H2 blockers andsulcrafate and a meta-analysis. Two stud-ies support equivalency between H2blockers and proton pump inhibitors.One study included very ill ICU patients;the second study was larger and demon-strated noninferiority of omeprazole sus-pension for clinically significant stress ul-cer bleeding (273, 274). No data relatingto utility of enteral feeding in stress ulcerprophylaxis exist. Patients should be pe-riodically evaluated for continued needfor prophylaxis.

H. Selective Digestive TractDecontamination (SDD)

The guidelines group was evenly spliton the issue of SDD, with equal numbersweakly in favor and against recommend-ing the use of SDD (Appendix H). Thecommittee therefore chose not to make arecommendation for the use of SDD spe-cifically in severe sepsis at this time. Thefinal consensus on use of SDD in severesepsis was achieved at the last nominalcommittee meeting and subsequently ap-proved by the entire committee (Appen-dix H provides the committee vote).

Rationale. The cumulative conclusionfrom the literature demonstrates thatprophylactic use of SDD (enteral nonab-sorbable antimicrobials and short-courseintravenous antibiotics) reduces infec-tions, mainly pneumonia, and mortalityin the general population of critically illand trauma patients (275–286) withoutpromoting emergence of resistant Gram-negative bacteria. Post hoc subgroupanalyses (287, 288) of two prospectiveblinded studies (289, 290) suggest thatSDD reduces nosocomial (secondary) in-fections in ICU patients admitted withprimary infections (268) and may reducemortality (288). No studies of SDD spe-cifically focused on patients with severesepsis or septic shock. The use of SDD insevere sepsis patients would be targetedtoward preventing secondary infection.As the main effect of SDD is in preventingventilator-associated pneumonia (VAP),studies comparing SDD with nonantimi-crobial interventions, such as ventilatorbundles for reducing VAP, are needed.Further investigation is required to de-termine the comparative efficacy of thesetwo interventions, separately or in com-bination. Although studies incorporatingenteral vancomycin in the regimen ap-pear to be safe (291–293), concerns per-sist about the potential for emergence ofresistant Gram-positive infections.

I. Consideration for Limitationof Support

1. We recommend that advance careplanning, including the communica-tion of likely outcomes and realisticgoals of treatment, be discussed withpatients and families (grade 1D).

Rationale. Decisions for less aggres-sive support or withdrawal of supportmay be in the patient’s best interest(294 –296). Too frequently, inadequate


physician/family communication charac-terizes end-of-life care in the ICU. Thelevel of life support given to ICU patientsmay not be consistent with their wishes.Early and frequent caregiver discussionswith patients who face death in the ICUand with their loved ones may facilitateappropriate application and withdrawal oflife-sustaining therapies. A recent RCTdemonstrated reduction of anxiety anddepression in family members when end-of-life meetings were carefully plannedand conducted, included advance careplanning, and provided relevant informa-tion about diagnosis, prognosis, andtreatment (297).

III. Pediatric Considerations inSevere Sepsis

While sepsis in children is a majorcause of mortality, the overall mortalityfrom severe sepsis in children is muchlower that that in adults, estimated atabout 10% (298). The definitions for se-vere sepsis and septic shock in childrenare similar but not identical to the defi-nitions in adults (299). In addition toage-appropriate differences in vital signs,the definition of systemic inflammatoryresponse syndrome requires the presenceof either temperature or leukocyte abnor-malities. The presence of severe sepsisrequires sepsis plus cardiovascular dys-function or ARDS or two or more otherorgan dysfunctions (299).

A. Antibiotics

1. We recommend that antibiotics be ad-ministered within 1 hr of the identifi-cation of severe sepsis, after appropri-ate cultures have been obtained (grade1D).

Early antibiotic therapy is as criticalfor children with severe sepsis as it is foradults.

B. Mechanical Ventilation

No graded recommendations.Due to low functional residual capac-

ity, young infants and neonates with se-vere sepsis may require early intubation(300). Drugs used for intubation have im-portant side effects in these patients; forexample, concerns have been raisedabout the safety of using etomidate inchildren with meningococcal sepsis be-cause of adrenal suppression effect (301).The principles of lung-protective strategiesare applied to children as they are to adults.

C. Fluid Resuscitation

1. We suggest that initial resuscitationbegin with infusion of crystalloidswith boluses of 20 mL/kg over 5–10mins, titrated to clinical monitors ofcardiac output, including heart rate,urine output, capillary refill, and levelof consciousness (grade 2C).

Intravenous access for fluid resuscita-tion and inotrope/vasopressor infusion ismore difficult to attain in children thanin adults. The American Heart Associa-tion and the American Academy of Pedi-atrics have developed pediatric advancedlife support guidelines for emergency es-tablishment of intravascular support en-couraging early intraosseous access(302). On the basis of a number of stud-ies, it is accepted that aggressive fluidresuscitation with crystalloids or colloidsis of fundamental importance to survivalof septic shock in children (303–308).Three randomized controlled trials com-pared the use of colloid to crystalloidresuscitation in children with dengueshock (303, 307, 308). No difference inmortality between colloid or crystalloidresuscitation was shown.

Children normally have a lower bloodpressure than adults, and fall in bloodpressure can be prevented by vasocon-striction and increasing heart rate.Therefore, blood pressure by itself is not areliable end point for assessing the ade-quacy of resuscitation. However, once hy-potension occurs, cardiovascular collapsemay soon follow. Hepatomegaly occurs inchildren who are fluid overloaded and canbe a helpful sign of adequacy of fluidresuscitation. Large fluid deficits typi-cally exist, and initial volume resuscita-tion usually requires 40–60 mL/kg butcan be much higher (304–308). However,the rate of fluid administration should bereduced substantially when there are(clinical) signs of adequate cardiac fillingwithout hemodynamic improvement.

D. Vasopressors/Inotropes(Should Be Used inVolume-Loaded Patients WithFluid Refractory Shock)

1. We suggest dopamine as the firstchoice of support for the pediatric pa-tient with hypotension refractory tofluid resuscitation (grade 2C).

In the initial resuscitation phase, va-sopressor therapy may be required to sus-tain perfusion pressure, even when hypo-

volemia has not yet been resolved.Children with severe sepsis can presentwith low cardiac output and high sys-temic vascular resistance, high cardiacoutput and low systemic vascular resis-tance, or low cardiac output and low sys-temic vascular resistance shock. At vari-ous stages of sepsis or the treatmentthereof, a child may move from one he-modynamic state to another. Vasopressoror inotrope therapy should be used ac-cording to the clinical state of the child.

Dopamine-refractory shock may re-verse with epinephrine or norepinephrineinfusion (309).

2. We suggest that patients with lowcardiac output and elevated systemicvascular resistance states (cool ex-tremities, prolonged capillary refill,decreased urine output but normalblood pressure following fluid resus-citation) be given dobutamine (grade2C).

The choice of vasoactive agent is de-termined by the clinical examination. Forthe child with a persistent low cardiacoutput state with high systemic vascularresistance despite fluid resuscitation andinotropic support, vasodilator therapymay reverse shock (310). When pediatricpatients remain in a normotensive lowcardiac output and high vascular resis-tance state despite epinephrine and vaso-dilator therapy, the use of a phosphodies-terase inhibitor may be considered (311–313). In the case of extremely lowsystemic vascular resistance despite theuse of norepinephrine, vasopressin usehas been described in a number of casereports. There is no clear evidence for theuse of vasopressin in pediatric sepsis(314, 315).

E. Therapeutic End Points

1. We suggest that the therapeutic endpoints of resuscitation of septic shockbe normalization of the heart rate, cap-illary refill of �2 secs, normal pulseswith no differential between peripheraland central pulses, warm extremities,urine output �1 mL·kg�1·hr�1, andnormal mental status (290) (grade 2C).

Capillary refill may be less reliable in acold environment. Other end points thathave been widely used in adults and maylogically apply to children include de-creased lactate and improved base deficit,ScvO2 �70% or SV̄O2 �65%, central ve-nous pressure of 8–12 mm Hg, or othermethods to analyze cardiac filling. Opti-


mizing preload optimizes cardiac index.In terms of identifying acceptable cardiacoutput in children with systemic arterialhypoxemia, such as cyanotic congenitalheart disease or severe pulmonary dis-ease, arterial-venous oxygen content dif-ference is a better marker than mixedvenous hemoglobin saturation with oxy-gen. As noted previously, blood pressureby itself is not a reliable end point forresuscitation. If a thermodilution catheter isused, therapeutic end points are cardiac index�3.3 and �6.0 L·min�1·m�2 with normalcoronary perfusion pressure (mean arterialpressure minus central venous pressure) forage (290). Using clinical end points, such asreversal of hypotension and restoration ofcapillary refill, for initial resuscitation at thecommunity hospital level before transfer to atertiary center was associated with signifi-cantly improved survival rates in childrenwith septic shock (305). Development of atransport system including publicizing to lo-cal hospitals and transport with mobile inten-sive care services significantly decreased thecase fatality rate from meningococcal diseasein the United Kingdom (316).

F. Approach to Pediatric SepticShock

Figure 1 shows a flow diagram sum-marizing an approach to pediatric septicshock (317).

G. Steroids

1. We suggest that hydrocortisone ther-apy be reserved for use in childrenwith catecholamine resistance andsuspected or proven adrenal insuffi-ciency (grade 2C).

Patients at risk for adrenal insuffi-ciency include children with severe septicshock and purpura (318, 319), childrenwho have previously received steroidtherapies for chronic illness, and childrenwith pituitary or adrenal abnormalities.Children who have clear risk factors foradrenal insufficiency should be treatedwith stress-dose steroids (hydrocortisone50 mg/m2/24 hrs).

Adrenal insufficiency in pediatric se-vere sepsis is associated with a poor prog-nosis (320). No strict definitions exist,but absolute adrenal insufficiency in thecase of catecholamine-resistant septicshock is assumed at a random total cor-tisol concentration �18 �g/dL (496nmol/L). A post 30- or 60-min ACTHstimulation test increase in cortisol of �9�g/dL (248 mmol/L) has been used to

define relative adrenal insufficiency. Thetreatment of relative adrenal insuffi-ciency in children with septic shock iscontroversial. A retrospective study froma large administrative database recentlyreported that the use of any corticoste-roids in children with severe sepsis wasassociated with increased mortality (oddsratio 1.9, 95% confidence interval 1.7–2.2) (321). While steroids may have beengiven preferentially to more severely illchildren, the use of steroids was an inde-pendent predictor of mortality in multi-variable analysis (321). Given the lack ofdata in children and potential risk, ste-roids should not be used in children who

do not meet minimal criteria for adrenalinsufficiency. A randomized, controlledtrial in children with septic shock is verymuch needed.

H. Protein C and ActivatedProtein C

1. We recommend against the use rhAPCin children (grade 1B).

Protein C concentrations in childrenreach adult values at the age of 3 yrs. Thismight indicate that the importance ofprotein C supplementation either as pro-tein C concentrate or as rhAPC is even

Figure 1. Approach to pediatric shock. *Normalization of blood pressure and tissue perfusion;**hypotension, abnormal capillary refill or extremity coolness. PALS, Pediatric Advanced Life Support;PICU, pediatric intensive care unit; CI, cardiac index; ECMO, extracorporeal membrane oxygenation.


greater in young children than in adults(322). There has been one dose-finding,randomized, placebo-controlled studyperformed using protein C concentrate.This study was not powered to show aneffect on mortality rate but did show apositive effect on sepsis-induced coagula-tion disturbances (323). An RCT of rhAPCin pediatric severe sepsis patients wasstopped by recommendation of the DataMonitoring Committee for futility afterenrollment of 399 patients: 28-day allcause mortality was 18% placebo groupvs. 17% APC group. Major amputationsoccurred in 3% of the placebo group vs.2% in the APC group (324). Due to theincreased risk of bleeding (7% vs. 6% inthe pediatric trial) and lack of proof ofefficacy, rhAPC is not recommended foruse in children.

I. DVT Prophylaxis

1. We suggest the use of DVT prophylaxisin postpubertal children with severesepsis (grade 2C).

Most DVTs in young children are as-sociated with central venous catheters.Femoral venous catheters are commonlyused in children, and central venouscatheter-associated DVTs occur in ap-proximately 25% of children with a fem-oral central venous catheter. Heparin-bonded catheters may decrease the risk ofcatheter-associated DVT and should beconsidered for use in children with severesepsis (325, 326). No data on the efficacyof UFH or LMWH prophylaxis to preventcatheter-related DVT in children in theICU exist.

J. Stress Ulcer Prophylaxis

No graded recommendations.Studies have shown that the rate of

clinically important gastrointestinalbleeding in children occurs at rates sim-ilar to adults (327, 328). As in adults,coagulopathy and mechanical ventilationare risk factors for clinically importantgastrointestinal bleeding. Stress ulcerprophylaxis strategy is commonly used inmechanically ventilated children, usuallywith H2 blockers. Its effect is not known.

K. Renal Replacement Therapy

No graded recommendations.Continuous veno-venous hemofiltration

(CVVH) may be clinically useful in childrenwith anuria/severe oliguria and fluid over-load, but no large RCTs have been per-

formed comparing CVVH with intermittentdialysis. A retrospective study of 113 criti-cally ill children reported that childrenwith less fluid overload before CVVH hadbetter survival, especially in those childrenwith dysfunction of three or more organs(329). CVVH or other renal replacementtherapy should be instituted in childrenwith anuria/severe oliguria before signifi-cant fluid overload occurs.

L. Glycemic Control

No graded recommendations.In general, infants are at risk for de-

veloping hypoglycemia when they dependon intravenous fluids. This means that aglucose intake of 4–6 mg·kg�1·min�1 ormaintenance fluid intake with glucose10%/NaCl-containing solution is advised.Associations have been reported betweenhyperglycemia and an increased risk ofdeath and longer length of stay (330). Arecent retrospective pediatric ICU studyreported associations of hyperglycemia,hypoglycemia, and glucose variabilitywith length of stay and mortality rates(331). No studies in pediatric patients(without diabetes mellitus) analyzing theeffect of strict glycemic control using in-sulin exist. In adults, the recommenda-tion is to maintain serum glucose �150mg/dL. Insulin therapy to avoid long pe-riods of hyperglycemia seems sensible inchildren as well, but the optimal goalglucose is not known. However, continu-ous insulin therapy should only be con-ducted with frequent glucose monitoringin view of the risks for hypoglycemia.

M. Sedation/Analgesia

1. We recommend sedation protocolswith a sedation goal when sedation ofcritically ill mechanically ventilatedpatients with sepsis is required (grade1D).

Appropriate sedation and analgesia arethe standard of care for children who aremechanically ventilated. Although thereare no data supporting any particulardrugs or regimens, it should be notedthat propofol should not be used for long-term sedation in children because of thereported association with fatal metabolicacidosis (332, 333).

N. Blood Products

No graded recommendations.The optimal hemoglobin for a criti-

cally ill child with severe sepsis is not

known. A recent multicenter trial re-ported similar outcomes in stable criti-cally ill children managed with a transfu-sion threshold of 7 g/dL compared withthose managed with a transfusion thresh-old of 9.5 g/dL (334). Whether a lowertransfusion trigger is safe or appropriatein the initial resuscitation of septic shockhas not been determined.

O. Intravenous Immunoglobulin

1. We suggest that immunoglobulin beconsidered in children with severesepsis (grade 2C).

Administration of polyclonal intrave-nous immunoglobulin has been reportedto reduce mortality rate and is a promis-ing adjuvant in the treatment of sepsisand septic shock in neonates. A recentrandomized controlled study of poly-clonal immunoglobulin in pediatric sep-sis syndrome patients (n � 100) showed asignificant reduction in mortality andLOS and less progress to complications,especially disseminated intravascular co-agulation (335).

P. Extracorporeal MembraneOxygenation (ECMO)

1. We suggest that use of ECMO be lim-ited to refractory pediatric septicshock and/or respiratory failure thatcannot be supported by conventionaltherapies (grade 2C).

ECMO has been used in septic shockin children, but its impact is not clear.Survival from refractory shock or respi-ratory failure associated with sepsis is80% in neonates and 50% in children. Inone study analyzing 12 patients with me-ningococcal sepsis in ECMO, eight of the12 patients survived, with six leadingfunctionally normal lives at a median of 1yr (range, 4 months to 4 yrs) of follow-up.Children with sepsis on ECMO do notperform worse than children without sep-sis at long-term follow-up (336, 337).

Although the pediatric considerationssection of this article offers importantinformation to the practicing pediatricclinician for the management of criticallyill children with sepsis, the reader is re-ferred to the reference list for more in-depth descriptions of appropriate man-agement of pediatric septic patients.

SUMMARY AND FUTUREDIRECTIONS

Although this document is static, theoptimum treatment of severe sepsis and


septic shock is a dynamic and evolvingprocess. New interventions will be provenand, as stated in the current recommen-dations, established interventions mayneed modification. This publication rep-resents an ongoing process. The Surviv-ing Sepsis Campaign and the consensuscommittee members are committed toupdating the guidelines regularly as newinterventions are tested and published.

Although evidence-based recommen-dations have been published frequently inthe medical literature, documentation ofimpact on patient outcome is limited(338). However, there is growing evi-dence that protocol implementation as-sociated with education and performancefeedback does change clinician behaviorand may improve outcomes and reducecosts in severe sepsis (20, 24, 25). PhaseIII of the Surviving Sepsis Campaign tar-gets the implementation of a core set ofthe previous recommendations in hospi-tal environments where change in behav-ior and clinical impact are being mea-sured. The sepsis bundles were developedin collaboration with the Institute ofHealthcare Improvement (339). Concur-rent or retrospective chart review willidentify and track changes in practice andclinical outcome. Software and softwaresupport are available at no cost in sevenlanguages, allowing bedside data entryand allowing creation of regular reportsfor performance feedback. The SSC alsooffers significant program support andeducational materials at no cost to theuser (www.survivingsepsis.org).

Engendering evidence-based changein clinical practice through multifacetedstrategies while auditing practice andproviding feedback to healthcare practi-tioners is the key to improving outcomesin severe sepsis. Nowhere is this moreevident than in the worldwide enthusi-asm for phase III of the SSC, a perfor-mance improvement program using SSCguideline-based sepsis bundles. Using theguidelines as the basis, the bundles haveestablished a global best practice for themanagement of critically ill patients withsevere sepsis. As of November 2007,nearly 12,000 patients had been enteredinto the SSC central database, represent-ing efforts of 239 hospitals in 17 coun-tries. Changes in practice and potentialeffects on survival are being measured.

ACKNOWLEDGMENTS

As mentioned previously, the Surviv-ing Sepsis Campaign (SSC) is partially

funded by unrestricted educational in-dustry grants, including those from Ed-wards LifeSciences, Eli Lilly and Com-pany, and Philips Medical Systems. TheSSC also received funding from the Coa-lition for Critical Care Excellence of theSociety of Critical Care Medicine. Thegreat majority of industry funding hascome from Eli Lilly and Company.

Current industry funding for the Sur-viving Sepsis Campaign is directed to theperformance improvement initiative. Noindustry funding was used for committeemeetings. No honoraria were provided tocommittee members. The revision pro-cess was funded primarily by the Societyof Critical Care Medicine, with the spon-soring professional organizations provid-ing travel expenses for their designateddelegate to the guidelines revision meet-ing where needed.

OTHER ACKNOWLEDGMENTS

In addition, we acknowledge ToniPiper and Rae McMorrow for their assis-tance in bringing the manuscripts to-gether; and Gordon Guyatt and HenryMasur, MD, for their guidance on gradingof evidence and antibiotic recommenda-tions, respectively.

Nine of the 11 organizations thatsponsored the first guidelines are spon-sors of the revision. Four additional na-tional organizations (Canadian CriticalCare Society, Japanese Association forAcute Medicine, Japanese Society of In-tensive Care Medicine, and Society ofHospital Medicine), the World Federationof Intensive and Critical Care Societies,and two sepsis organizations (GermanSepsis Society and the Latin AmericanSepsis Institute) have also come on boardas sponsors. Two organizations thatsponsored the first guidelines (AmericanThoracic Society and Australian and NewZealand Intensive Care Society) electednot to sponsor the revision.

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APPENDIX A

Source Control

Source ControlTechnique Examples

Drainage Intra-abdominal abscessThoracic empyemaSeptic arthritis

Debridement Pyelonephritis, cholangitisInfected pancreatic

necrosisIntestinal infarctionMediastinitis

Device removal Infected vascular catheterUrinary catheterInfected intrauterine

contraceptive deviceDefinitive control Sigmoid resection for

diverticulitisCholecystectomy for

gangrenouscholecystitis

Amputation for clostridialmyonecrosis

APPENDIX B

Steroids

Considerable difference of opinion ex-isted among committee members as tothe best option for the style of the rec-ommendations for steroid use in septicshock. Some committee members arguedfor two recommendations and pointed tothe two distinct patient populations ofthe French Trial (enrollment early in sep-tic shock and blood pressure unrespon-sive to vasopressors) and the CORTICUStrial (enrollment allowed up to 72 hrs anddid not target patients with blood pres-sure unresponsive to vasopressin), lead-ing to two distinct results. Furthermore,

a single recommendation suggested tosome that this approach might lead toexcessive use of steroids and increasedincidence of superinfections, citing thesepsis and septic shock adverse events inthe steroid-treated patients in theCORTICUS trial. Those who argued forone recommendation pointed to prob-lems with two different recommenda-tions that would require the bedside cli-nician to choose a time point forclassification of one or the other as wellas a distinct blood pressure cutoff withthe potential for the blood pressure tovary over time. In addition, there are in-adequate data to provide standardizationof how much fluids and vasopressorsshould be in place to call the blood pres-sure unresponsive or poorly responsive.These members also pointed to the factthat the increased superinfection/sepsis/septic shock adverse events in CORTICUSare contrary to the results of other stress-dose steroid trials, such as early ARDS(lower incidence of infections) (341), lateARDS (decreased development of septicshock), and community-acquired pneu-monia (decreased development of septicshock) (114). Based on GRADE adjudica-tion guidelines, a secret ballot vote wasconducted to resolve the issue.

The two options put to vote were:

Two-Recommendation Option

1. We suggest that intravenous hydro-cortisone be given to adult septicshock patients if blood pressure is in-adequate with appropriate fluid resus-citation and vasopressor therapy(grade 2B).

2. We suggest intravenous hydrocorti-sone not be given to adult septic shockpatients if blood pressure is adequatewith appropriate fluid resuscitationand vasopressor therapy (grade 2B).

One-Recommendation Option

1. We suggest that intravenous hydrocor-tisone be given only to adult septicshock patients with blood pressurepoorly responsive to fluid resuscitationand vasopressor therapy (grade 2C).

The committee vote that determinedthe current recommendation was:

Favor two-recommendation op-tion—19Favor one-recommendation op-tion—31Abstain—1


APPENDIX C

Contraindications to Use ofRecombinant Human ActivatedProtein C (rhAPC)

rhAPC increases the risk of bleedingand is contraindicated in patients withthe following clinical situations in whichbleeding could be associated with a highrisk of death or significant morbidity:

Active internal bleedingRecent (within 3 months) hemor-rhagic strokeRecent (within 2 months) intracra-nial or intraspinal surgery, or severehead traumaTrauma with an increased risk of life-threatening bleedingPresence of an epidural catheterIntracranial neoplasm or mass lesionor evidence of cerebral herniationKnown hypersensitivity to rhAPC orany component of the product

See labeling instructions for relativecontraindications. The committee rec-ommends that platelet count be main-tained at �30,000 during infusion ofrhAPC. (Physicians’ Desk Reference, 61stEdition. Montvale, NJ, Thompson PDR,2007, p 1829).

APPENDIX D

Recombinant Activated ProteinC Nominal Group Vote

Strong for use, 6Weak for use, 15Neutral, 1Weak for not using, 0Strong for not using, 0

APPENDIX E

ARDSNet VentilatorManagement

Assist control mode—volume venti-lation (96)Reduce tidal volume to 6 mL/kg leanbody weightKeep inspiratory plateau pressure(Pplat) �30 cm H2OReduce tidal volume as low as 4 mL/kgpredicted body weight to limit PplatMaintain arterial oxygen saturation/pulse oximetry oxyhemoglobin satu-ration (SpO2) 88% to 95%

Anticipated PEEP settings at variousFIO2 requirementsFIO2 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, 1.0PEEP 5, 5, 8, 8, 10, 10, 10, 12, 14, 14,14, 16, 18, 20–24

Predicted Body Weight CalculationMale—50 � 2.3 (height [inches] �60) or 50 � 0.91 (height [cm] �152.4)Female— 45.5 � 2.3 (height[inches] � 60) or 45.5 � 0.91(height [cm] � 152.4)

APPENDIX G

Glycemic Control Committee Vote

Glycemic control—90%Total votes � 51Agree—34Too conservative, but accept—4Too liberal, but accept—8Disapprove, too conservative—0Disapprove, too liberal—5Disapprove, other—0

APPENDIX F


APPENDIX I

2008 SSC Guidelines Committee

R. Phillip Dellinger (Chair), TomAhrens,a Naoki Aikawa,b Derek Angus,Djillali Annane, Richard Beale, Gordon R.Bernard, Julian Bion,c Christian Brun-Buisson, Thierry Calandra, Joseph Carcillo,Jean Carlet, Terry Clemmer, JonathanCohen, Edwin A. Deitch,d Jean-FrancoisDhainaut, Mitchell Fink, Satoshi Gando,b

Herwig Gerlach, Gordon Guyatt,e MaureneHarvey, Jan Hazelzet, Hiroyuki Hirasawa,f

Steven M. Hollenberg, Michael Howell, Ro-man Jaeschke,e Robert Kacmarek, DidierKeh, Mitchell M. Levy,g Jeffrey Lipman,John J. Marini, John Marshall, Claude Mar-tin, Henry Masur, Steven Opal, Tiffany M.Osborn,h Giuseppe Pagliarello,i MargaretParker, Joseph Parrillo, Graham Ramsay,Adrienne Randolph, Marco Ranieri, RobertC. Read,j Konrad Reinhart,k AndrewRhodes, Emmanuel Rivers,h GordonRubenfeld, Jonathan Sevransky, Eliezer Sil-va,l Charles L. Sprung, B. Taylor Thomp-son, Sean R. Townsend, Jeffery Vender,m

Jean-Louis Vincent,n Tobias Welte,o JaniceZimmerman.

aAmerican Association of Critical-Care Nurses; bJapanese Association forAcute Medicine; cEuropean Society ofIntensive Care Medicine; dSurgical In-fection Society; eGrades of Recommen-dation, Assessment, Development andEvaluation (GRADE) Group; fJapaneseSociety of Intensive Care Medicine;gSociety of Critical Care Medicine;hAmerican College of Emergency Phy-sicians; iCanadian Critical Care Society;jEuropean Society of Clinical Micro-biology and Infectious Diseases; kGer-man Sepsis Society; lLatin AmericanSepsis Institute; mAmerican College

of Chest Physicians; nInternationalSepsis Forum; oEuropean RespiratorySociety.

APPENDIX J

Author Disclosure Information2006–2007

Dr. Dellinger has consulted for Astra-Zeneca, Talecris, and B Braun. He has re-ceived honoraria from Eli Lilly (2), Brahms(2), INO Therapeutics (1), Pulsion (1), andbioMerieux (1). He has also received grantsupport from AstraZeneca and Artisan.

Dr. Levy has received honoraria fromEli Lilly and Edwards Lifesciences. Hehas also received grant support fromPhilips Medical Systems, Edwards Life-sciences, Philips Medical Systems, Novar-tis, Biosite, and Eisai.

Dr. Carlet has consulted for Forrest,Wyeth, Chiron, bioMerieux, and Glaxo-SmithKline. He has also received hono-raria from Eli Lilly, Becton Dickinson,Jansen, Cook, AstraZeneca, Hutchinson,Bayer, Gilead, MSD, and Targanta.

Dr. Bion has not disclosed any poten-tial conflicts of interest.

Dr. Parker has consulted for Johnson& Johnson.

Dr. Jaeschke has received honorariafrom AstraZeneca, Boehringer, Eli Lilly,GlaxoSmithKline, and MSD.

Dr. Reinhart has consulted for Eli Lillyand Edwards Lifesciences. He has alsoreceived honoraria from B Braun androyalties from Edwards Lifesciences.

Dr. Angus has consulted for or re-ceived speaking fees from AstraZeneca,BrahmsDiagnostica,Eisai,EliLilly,Glaxo-SmithKline, OrthoBiotech, Takeda, andWyeth-Ayerst. He has also received grant

support from GlaxoSmithKline, Ortho-Biotech, and Amgen.

Dr. Brun-Buisson has not disclosedany potential conflicts of interest.

Dr. Beale has received honoraria fromEisai and speaking fees (paid to university)from Lilly UK, Philips, Lidco, and Chiron.

Dr. Calandra has consulted for Baxter,received honoraria from Roche Diagnos-tics, and received grant support fromBaxter and Roche Diagnostics. He alsoserved on the advisory board for Biosite.

Dr. Dhainaut has consulted for EliLilly and Novartis. He has also receivedhonoraria from Eli Lilly.

Dr. Gerlach has not disclosed any po-tential conflicts of interest.

Ms. Harvey has not disclosed any po-tential conflicts of interest.

Dr. Marini has consulted for KCI andreceived honoraria from Maquet.

Dr. Marshall has consulted for BectonDickinson, Takeda, Pfizer, Spectral Diagnos-tics, Eisai, and Leo-Pharma. He has also re-ceived honoraria from Spectral Diagnostics.

Dr. Ranieri has served on the advisoryboard for Maquet and received supportfor a sponsored trial from Eli Lilly. Hehas also received grant support fromTyco, Draeger, and Hamilton.

Dr. Ramsay has consulted for EdwardsLifesciences and Respironics.

Dr. Sevransky has not disclosed anypotential conflicts of interest.

Dr. Thompson has consulted for EliLilly, Abbott, and AstraZeneca. He has alsoreceived grant support from the NIH for astudy on computerized glucose control.

Dr. Townsend has not disclosed anypotential conflicts of interest.

Dr. Vender has consulted and receivedhonoraria from Eli Lilly.

Dr. Zimmerman has not disclosed anypotential conflicts of interest.

Dr. Vincent has consulted for Astra-Zeneca, Biosite, bioMerieux, Edwards Life-sciences, Eli Lilly, Eisai, Ferring, Glaxo-SmithKline, Intercell, Merck, Novartis,NovoNordisk, Organon, Pfizer, PhilipsMedical Systems, Roche Diagnostics, Spec-tral Diagnostics, Takeda, and Wyeth-Lederle. He has also received honorariafrom Eli Lilly, Edwards Lifesciences, Eisai,GlaxoSmithKline, Novartis, NovoNordisk,and Pfizer.

Appendix H. Selective Digestive Decontamination Nominal Group Vote

AntibioticsStrongfor Use

Weakfor Use Neutral

Weakfor Not Using

Strongfor Not Using

Systemicand oral

— 9 4 8 1

Systemicalone

— 2 7 5 3


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