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Final 08 SSC Guidelines

Final 08 SSC Guidelines

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Published by: Abraham Ceseña Pérez on Jul 05, 2012
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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
*The correct citation for this article is as follows.Dellinger RP, Levy MM, Carlet, JM, et al: SurvivingSepsis Campaign: International guidelines for manage-ment of severe sepsis and septic shock: 2008 [pub-lished correction appears in
Crit Care Med 
2008; 36:1394–1396].
Crit Care Med 
2008; 36:296–327.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);McMasterUniversity,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 Universitaire Vaudois, 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);RhodeIslandHospital,Providence,RI(ST); Evanston Northwestern Healthcare, Evanston, IL (JSV);TheMethodistHospital,Houston,TX(JLZ);ErasmeUniversityHospital, Brussels, Belgium (JLV).Sponsoring organizations: American Association ofCritical-Care Nurses,* American College of Chest Physi-cians,* American College of Emergency Physicians,* Ca-nadian Critical Care Society, European Society of ClinicalMicrobiology and Infectious Diseases,* European Societyof Intensive Care Medicine,* European Respiratory Soci-ety,* Indian Society of Critical Care Medicine,** Interna-tional Sepsis Forum,* Japanese Association for AcuteMedicine, Japanese Society of Intensive Care Medicine;Society of Critical Care Medicine,* Society of HospitalMedicine,** Surgical Infection Society,* World Federationof Critical Care Nurses,** World Federation of Societies ofIntensive and Critical Care Medicine.** Participation andendorsement by the German Sepsis Society and the Latin American Sepsis Institute. *Sponsor of 2004 guidelines.**Sponsors of 2008 guidelines who did not participateformally in revision process. Members of the 2008 SSCGuidelines Committee are listed in Appendix I. Appendix Jprovides author disclosure information. Also published in
Intensive Care Medicine 
(January2008).For information regarding this article, E-mail:Dellinger-Phil@CooperHealth.eduCopyright © 2007 by the Society of Critical CareMedicine
DOI: 10.1097/01.CCM.0000298158.12101.41
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.
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.
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. Weak recommendations (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.
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-sortherapy(1C);stress-dosesteroidtherapygivenonlyinsepticshockafterbloodpressure 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).
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.
: 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
1Crit Care Med 2008 Reprint
evere 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 of individuals 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 of the 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 of these 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.
Sepsis is defined as infection plus sys-temic manifestations of infection(Scheme 1) (12). Severe sepsis is definedas sepsis plus sepsis-induced organ dys-function or tissue hypoperfusion. Thethreshold for this dysfunction has variedsomewhat from one severe sepsis researchstudy to another. An example of typicalthresholds identification of severe sepsis isshown in Scheme 2 (12, 13). Sepsis-induced hypotension is defined as a systolicblood pressure (SBP)
90 mm Hg or meanarterial pressure
70 mm Hg or a SBPdecrease
40 mm Hg or
below nor-mal for age in the absence of other causesof hypotension. Septic shock is defined assepsis-induced hypotension persisting de-
Scheme 1.
Diagnostic criteria for sepsisInfection, documented or suspected, and some of the following:General variablesFever (
38.3°C)Hypothermia (core temperature
36°C)Heart rate
90 min
above the normal value for ageTachypnea Altered mental statusSignificant edema or positive fluid balance (
20 mL/kg over 24 hrs)Hyperglycemia (plasma glucose
140 mg/dL or 7.7 mmol/L) in the absence of diabetesInflammatory variablesLeukocytosis (WBC count
)Leukopenia (WBC count
)Normal WBC count with
10% immature formsPlasma C-reactive protein
above the normal valuePlasma procalcitonin
above the normal valueHemodynamic variables Arterial hypotension (SBP
90 mm Hg; MAP
70 mm Hg; or an SBP decrease
40 mm Hgin adults or
below normal for age)Organ dysfunction variables Arterial hypoxemia (Pa
300) Acute oliguria (urine output
0.5 mL/Kg hr or 45 mmol/L for at least 2 hrs, despite adequatefluid resuscitation)Creatinine increase
0.5 mg/dL or 44.2
mol/LCoagulation abnormalities (INR
1.5 or a PTT
60 secs)Ileus (absent bowel sounds)Thrombocytopenia (platelet count,
)Hyperbilirubinemia (plasma total bilirubin
4 mg/dL or 70
mol/L)Tissue perfusion variablesHyperlactatemia (
upper limit of lab normal)Decreased capillary refill or mottlingDiagnostic criteria for sepsis in the pediatric population are signs and symptoms of inflammationplus infection with hyper- or hypothermia (rectal temperature
38.5°C or
35°C),tachycardia (may be absent in hypothermic patients), and at least one of the followingindications of altered organ function: altered mental status, hypoxemia, increased serumlactate level, or bounding pulses. WBC, white blood cell; SBP, systolic blood pressure; MAP, mean arterial blood pressure; INR,international normalized ratio; a PTT, activated partial thromboplastin time. Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS Interna-tional Sepsis Definitions Conference.
Crit Care Med 
2003; 31:1250–1256
Scheme 2.
Severe sepsis
sepsis-induced tissue hypoperfusion or organ dysfunction (any of the followingthought to be due to the infection)Sepsis-induced hypotensionLactate greater than the upper limits of normal laboratory resultsUrine output
0.5 mL/kg hr for
2 hrs, despite adequate fluid resuscitation ALI with Pa
250 in the absence of pneumonia as infection source ALI with Pa
200 in the presence of pneumonia as infection sourceCreatinine
2.0 mg/dL (176.8
2 mg/dL (34.2
mol/L)Platelet count
100,000Coagulopathy (INR
1.5) ALI, acute lung injury; INR, international normalized ratio. Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS Interna-tional Sepsis Definitions Conference.
Crit Care Med 
2003; 31:1250–1256. ACCP/SCCM ConsensusConference Committee: American College of Chest Physicians/Society of Critical Care MedicineConsensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovativetherapies in sepsis.
Crit Care Med 
1992; 20:864–874
2 Crit Care Med 2008 Reprint
spite adequate fluid resuscitation. Sepsis-induced tissue hypoperfusion is defined aseither septic shock, an elevated lactate, oroliguria.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-datedsearchinto2007(seefollowingmeth-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 of Critical 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 funding was 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 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 areas where 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 memberspotentialconflicts 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 of the entire committee, and two follow-upnominal group meetings in 2007.Subgroups were formed, each charged with 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 chair worked 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 of the subgroup as well as pertinent key words 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 performed via e-mail before the first committeemeeting and at the first meeting. Rules were distributed concerning assessingthe body of evidence, and GRADE experts were 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 first American 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, inall 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 of recommendation explicitly separate consti-tutes a crucial and defining feature of theGRADE approach. This system classifiesquality of evidence as high (grade A), mod-
3Crit Care Med 2008 Reprint

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