Intensive Care Med (2013) 39:165–228DOI 10.1007/s00134-012-2769-8 GUIDELINESR. P. DellingerMitchell M. Levy Surviving Sepsis Campaign: InternationalAndrew Rhodes Guidelines for Management of Severe SepsisDjillali AnnaneHerwig Gerlach and Septic Shock, 2012Steven M. OpalJonathan E. SevranskyCharles L. SprungIvor S. DouglasRoman JaeschkeTiffany M. OsbornMark E. NunnallySean R. TownsendKonrad ReinhartRuth M. KleinpellDerek C. AngusClifford S. DeutschmanFlavia R. MachadoGordon D. RubenfeldSteven WebbRichard J. BealeJean-Louis VincentRui MorenoThe Surviving Sepsis Campaign Guidelines Committeeincluding The Pediatric Subgroup* of Hospital Medicine, Surgical Infection R. P. Dellinger ())Received: 4 June 2012 Society, World Federation of Critical Care Cooper University Hospital,Accepted: 12 November 2012 Nurses, World Federation of PediatricPublished online: 30 January 2013 Camden, NJ, USA Intensive and Critical Care Societies; World e-mail: Dellinger-Phil@CooperHealth.eduÓ SCCM and ESICM 2013 Federation of Societies of Intensive and Critical Care Medicine. Participation andSponsoring organizations: American endorsement: The German Sepsis Society M. M. LevyAssociation of Critical-Care Nurses, and the Latin American Sepsis Institute. Warren Alpert Medical School of BrownAmerican College of Chest Physicians, University, Providence, RI, USAAmerican College of Emergency * Members of the 2012 SSC GuidelinesPhysicians, American Thoracic Society, Committee and Pediatric Subgroup are A. RhodesAsia Paciﬁc Association of Critical Care listed in Appendix 1 at the end of this St. George’s Hospital, London, UKMedicine, Australian and New Zealand article.Intensive Care Society, Brazilian Society of D. AnnaneCritical Care, Canadian Critical Care This article is being simultaneously ˆ ´ Hopital Raymond Poincare,Society, Chinese Society of Critical Care published in Critical Care Medicine andMedicine, Chinese Society of Critical Care Intensive Care Medicine. Garches, FranceMedicine—China Medical Association,Emirates Intensive Care Society, European For additional information regarding this H. GerlachRespiratory Society, European Society of article, contact R.P. Dellinger (Dellinger- ¨ Vivantes-Klinikum Neukolln,Clinical Microbiology and Infectious Phil@CooperHealth.edu). Berlin, GermanyDiseases, European Society of IntensiveCare Medicine, European Society of S. M. OpalPediatric and Neonatal Intensive Care, Memorial Hospital of Rhode Island,Infectious Diseases Society of America, Pawtucket, RI, USAIndian Society of Critical Care Medicine,International Pan Arabian Critical Care J. E. SevranskyMedicine Society, Japanese Association for Emory University Hospital,Acute Medicine, Japanese Society ofIntensive Care Medicine, Pediatric Acute Atlanta, GA, USALung Injury and Sepsis Investigators,Society for Academic Emergency Medicine, C. L. SprungSociety of Critical Care Medicine, Society Hadassah Hebrew University Medical Center, Jerusalem, Israel
166I. S. Douglas Abstract Objective: To provide shock (1C) as the goal of therapy;Denver Health Medical Center, an update to the ‘‘Surviving Sepsis reassessment of antimicrobial therapyDenver, CO, USA daily for de-escalation, when appro- Campaign Guidelines for Manage-R. Jaeschke ment of Severe Sepsis and Septic priate (1B); infection source controlMcMaster University, Shock,’’ last published in 2008. with attention to the balance of risksHamilton, ON, Canada Design: A consensus committee of and beneﬁts of the chosen method 68 international experts representing within 12 h of diagnosis (1C); initialT. M. Osborn 30 international organizations was ﬂuid resuscitation with crystalloidBarnes-Jewish Hospital, convened. Nominal groups were (1B) and consideration of the additionSt. Louis, MO, USA of albumin in patients who continue assembled at key international meet-M. E. Nunnally ings (for those committee members to require substantial amounts ofUniversity of Chicago Medical Center, attending the conference). A formal crystalloid to maintain adequate meanChicago, IL, USA conﬂict of interest policy was devel- arterial pressure (2C) and the avoid- oped at the onset of the process and ance of hetastarch formulations (1B);S. R. Townsend enforced throughout. The entire initial ﬂuid challenge in patients withCalifornia Paciﬁc Medical Center, guidelines process was conducted sepsis-induced tissue hypoperfusionSan Francisco, CA, USA and suspicion of hypovolemia to independent of any industry funding.K. Reinhart A stand-alone meeting was held for achieve a minimum of 30 mL/kg ofFriedrich Schiller University Jena, Jena, all subgroup heads, co- and vice- crystalloids (more rapid administra-Germany chairs, and selected individuals. tion and greater amounts of ﬂuid may Teleconferences and electronic-based be needed in some patients (1C); ﬂuidR. M. Kleinpell discussion among subgroups and challenge technique continued as longRush University Medical Center, among the entire committee served as as hemodynamic improvement isChicago, IL, USA based on either dynamic or static an integral part of the development.D. C. Angus Methods: The authors were advised variables (UG); norepinephrine as theUniversity of Pittsburgh, to follow the principles of the Grad- ﬁrst-choice vasopressor to maintainPittsburgh, PA, USA ing of Recommendations Assessment, mean arterial pressure C65 mmHg Development and Evaluation (1B); epinephrine when an additionalC. S. Deutschman (GRADE) system to guide assessment agent is needed to maintain adequatePerelman School of Medicine at the of quality of evidence from high blood pressure (2B); vasopressinUniversity of Pennsylvania, (0.03 U/min) can be added to nor-Philadelphia, PA, USA (A) to very low (D) and to determine the strength of recommendations as epinephrine to either raise meanF. R. Machado strong (1) or weak (2). The potential arterial pressure to target or toFederal University of Sao Paulo, drawbacks of making strong recom- decrease norepinephrine dose butSao Paulo, Brazil mendations in the presence of low- should not be used as the initial quality evidence were emphasized. vasopressor (UG); dopamine is notG. D. Rubenfeld Recommendations were classiﬁed recommended except in highlySunnybrook Health Sciences Center, selected circumstances (2C); dobuta-Toronto, ON, Canada into three groups: (1) those directly targeting severe sepsis; (2) those tar- mine infusion administered or addedS. Webb geting general care of the critically ill to vasopressor in the presence ofRoyal Perth Hospital, patient and considered high priority in (a) myocardial dysfunction as sug-Perth, Western Australia severe sepsis; and (3) pediatric con- gested by elevated cardiac ﬁlling siderations. Results: Key pressures and low cardiac output, orR. J. Beale recommendations and suggestions, (b) ongoing signs of hypoperfusionGuy’s and St. Thomas’ Hospital Trust, despite achieving adequate intravas-London, UK listed by category, include: early quantitative resuscitation of the septic cular volume and adequate meanJ.-L. Vincent patient during the ﬁrst 6 h after rec- arterial pressure (1C); avoiding use ofErasme University Hospital, ognition (1C); blood cultures before intravenous hydrocortisone in adultBrussels, Belgium antibiotic therapy (1C); imaging septic shock patients if adequate ﬂuid studies performed promptly to con- resuscitation and vasopressor therapyR. Moreno ﬁrm a potential source of infection are able to restore hemodynamic sta- ˜ ´UCINC, Hospital de Sao Jose, Centro (UG); administration of broad-spec- bility (2C); hemoglobin target ofHospitalar de Lisboa Central, E.P.E.,Lisbon, Portugal trum antimicrobials therapy within 7–9 g/dL in the absence of tissue 1 h of the recognition of septic shock hypoperfusion, ischemic coronary (1B) and severe sepsis without septic artery disease, or acute hemorrhage
167(1B); low tidal volume (1A) and blood glucose management com- bolus of 20 mL/kg of crystalloids (orlimitation of inspiratory plateau mencing insulin dosing when two albumin equivalent) over 5–10 minpressure (1B) for acute respiratory consecutive blood glucose levels are (2C); more common use of inotropesdistress syndrome (ARDS); applica- [180 mg/dL, targeting an upper and vasodilators for low cardiac out-tion of at least a minimal amount of blood glucose B180 mg/dL (1A); put septic shock associated withpositive end-expiratory pressure equivalency of continuous veno- elevated systemic vascular resistance(PEEP) in ARDS (1B); higher rather venous hemoﬁltration or intermittent (2C); and use of hydrocortisone onlythan lower level of PEEP for patients hemodialysis (2B); prophylaxis for in children with suspected or provenwith sepsis-induced moderate or deep vein thrombosis (1B); use of ‘‘absolute’’’ adrenal insufﬁciencysevere ARDS (2C); recruitment stress ulcer prophylaxis to prevent (2C). Conclusions: Strong agree-maneuvers in sepsis patients with upper gastrointestinal bleeding in ment existed among a large cohort ofsevere refractory hypoxemia due to patients with bleeding risk factors international experts regarding manyARDS (2C); prone positioning in (1B); oral or enteral (if necessary) level 1 recommendations for the bestsepsis-induced ARDS patients with a feedings, as tolerated, rather than care of patients with severe sepsis.PaO2/FiO2 ratio of B100 mm Hg in either complete fasting or provision Although a signiﬁcant number offacilities that have experience with of only intravenous glucose within aspects of care have relatively weaksuch practices (2C); head-of-bed ele- the ﬁrst 48 h after a diagnosis of support, evidence-based recommen-vation in mechanically ventilated severe sepsis/septic shock (2C); and dations regarding the acutepatients unless contraindicated (1B); addressing goals of care, including management of sepsis and septica conservative ﬂuid strategy for treatment plans and end-of-life plan- shock are the foundation of improvedpatients with established ARDS who ning (as appropriate) (1B), as early as outcomes for this important group ofdo not have evidence of tissue hypo- feasible, but within 72 h of intensive critically ill patients.perfusion (1C); protocols for weaning care unit admission (2C). Recom-and sedation (1A); minimizing use of mendations speciﬁc to pediatric Keywords Sepsis Á Severe sepsis Áeither intermittent bolus sedation or severe sepsis include: therapy with Septic shock Á Sepsis syndrome Ácontinuous infusion sedation target- face mask oxygen, high ﬂow nasal Infection Á Grading ofing speciﬁc titration endpoints (1B); cannula oxygen, or nasopharyngeal Recommendations Assessment,avoidance of neuromuscular blockers continuous PEEP in the presence of Development and Evaluation criteria Áif possible in the septic patient with- respiratory distress and hypoxemia GRADE Á Guidelines Áout ARDS (1C); a short course of (2C), use of physical examination Evidence-based medicine Áneuromuscular blocker (no longer therapeutic endpoints such as capil- Surviving Sepsis Campaign Áthan 48 h) for patients with early lary reﬁll (2C); for septic shock Sepsis bundlesARDS and a PaO2/FIO2 150 mm Hg associated with hypovolemia, the use(2C); a protocolized approach to of crystalloids or albumin to deliver aSepsis is a systemic, deleterious host response to infection making capability when he or she is presented with aleading to severe sepsis (acute organ dysfunction sec- patient’s unique set of clinical variables. Most of theseondary to documented or suspected infection) and septic recommendations are appropriate for the severe sepsisshock (severe sepsis plus hypotension not reversed with patient in the intensive care unit (ICU) and non-ICUﬂuid resuscitation). Severe sepsis and septic shock are settings. In fact, the committee believes that the greatestmajor healthcare problems, affecting millions of people outcome improvement can be made through educationaround the world each year, killing one in four (and often and process change for those caring for severe sepsismore), and increasing in incidence [1–5]. Similar to patients in the non-ICU setting and across the spectrum ofpolytrauma, acute myocardial infarction, or stroke, the acute care. Resource limitations in some institutions andspeed and appropriateness of therapy administered in the countries may prevent physicians from accomplishinginitial hours after severe sepsis develops are likely to particular recommendations. Thus, these recommenda-inﬂuence outcome. tions are intended to be best practice (the committee The recommendations in this document are intended to considers this a goal for clinical practice) and not createdprovide guidance for the clinician caring for a patient with to represent standard of care. The Surviving Sepsissevere sepsis or septic shock. Recommendations from Campaign (SSC) Guidelines Committee hopes that overthese guidelines cannot replace the clinician’s decision- time, particularly through education programs and formal
168audit and feedback performance improvement initiatives, to address content needs for the development process. Fourthe guidelines will inﬂuence bedside healthcare practi- clinicians with experience in the GRADE process applica-tioner behavior that will reduce the burden of sepsis tion (referred to in this document as GRADE group orworldwide. Evidence-Based Medicine [EBM] group) took part in the guidelines development. The guidelines development process began with appointment of group heads and assignment of committee members to groups according to their speciﬁc expertise.Methodology Each group was responsible for drafting the initial update toDeﬁnitions the 2008 edition in their assigned area (with major additional elements of information incorporated into the evolvingSepsis is deﬁned as the presence (probable or documented) manuscript through year-end 2011 and early 2012).of infection together with systemic manifestations of infec- With input from the EBM group, an initial group meet-tion. Severe sepsis is deﬁned as sepsis plus sepsis-induced ing was held to establish procedures for literature review andorgan dysfunction or tissue hypoperfusion (Tables 1, 2) . development of tables for evidence analysis. CommitteesThroughout this manuscript and the performance improve- and their subgroups continued work via phone and thement bundles, which are included, a distinction is made Internet. Several subsequent meetings of subgroups and keybetween deﬁnitions and therapeutic targets or thresholds. individuals occurred at major international meetingsSepsis-induced hypotension is deﬁned as a systolic blood (nominal groups), with work continuing via teleconferencespressure (SBP)90 mmHg or mean arterial pressure (MAP) and electronic-based discussions among subgroups and70 mmHg or a SBP decrease[40 mmHg or less than two members of the entire committee. Ultimately, a meeting ofstandard deviations below normal for age in the absence of all group heads, executive committee members, and otherother causes of hypotension. An example of a therapeutic key committee members was held to ﬁnalize the draft doc-target or typical threshold for the reversal of hypotension is ument for submission to reviewers.seen in the sepsis bundles for the use of vasopressors. In thebundles, the MAP threshold is C65 mmHg. The use of deﬁ-nition versus threshold will be evident throughout this article. Search techniquesSeptic shock is deﬁned as sepsis-induced hypotension per-sisting despite adequate ﬂuid resuscitation. Sepsis-induced A separate literature search was performed for each clearlytissue hypoperfusion is deﬁned as infection-induced hypo- deﬁned question. The committee chairs worked with sub-tension, elevated lactate, or oliguria. group heads to identify pertinent search terms that were to include, at a minimum, sepsis, severe sepsis, septic shock, and sepsis syndrome crossed against the subgroup’s generalHistory of the guidelines topic area, as well as appropriate key words of the speciﬁc question posed. All questions used in the previous guide-These clinical practice guidelines are a revision of the 2008 lines publications were searched, as were pertinent newSSC guidelines for the management of severe sepsis and questions generated by general topic-related searches orseptic shock . The initial SSC guidelines were published recent trials. The authors were speciﬁcally asked to look forin 2004  and incorporated the evidence available through existing meta-analyses related to their question and search athe end of 2003. The 2008 publication analyzed evidence minimum of one general database (i.e., MEDLINE, EM-available through the end of 2007. The most current iteration BASE) and the Cochrane Library [both The Cochraneis based on updated literature search incorporated into the Database of Systematic Reviews (CDSR) and Database ofevolving manuscript through fall 2012. Abstracts of Reviews of Effectiveness (DARE)]. Other databases were optional (ACP Journal Club, Evidence- Based Medicine Journal, Cochrane Registry of ControlledSelection and organization of committee members Clinical Trials, International Standard Randomised Con- trolled Trial Registry (http://www.controlled-trials.com/The selection of committee members was based on interest isrctn/) or metaRegister of Controlled Trials (http://www.and expertise in speciﬁc aspects of sepsis. Co-chairs and controlled-trials.com/mrct/). Where appropriate, availableexecutive committee members were appointed by the evidence was summarized in the form of evidence tables.Society of Critical Care Medicine and European Society ofIntensive Care Medicine governing bodies. Each sponsor-ing organization appointed a representative who had sepsis Grading of recommendationsexpertise. Additional committee members were appointedby the co-chairs and executive committee to create conti- We advised the authors to follow the principles of thenuity with the previous committees’ membership as well as GRADE system to guide assessment of quality of
169Table 1 Diagnostic criteria for sepsisInfection, documented or suspected, and some of the following: General variables Fever ([38.3 °C) Hypothermia (core temperature 36 °C) Heart rate [90 min-1 or more than two SD above the normal value for age Tachypnea Altered mental status Signiﬁcant edema or positive ﬂuid balance ([ 20 mL/kg over 24 h) Hyperglycemia (plasma glucose [140 mg/dL or 7.7 mmol/L) in the absence of diabetes Inﬂammatory variables Leukocytosis (WBC count [12,000 lL-1) Leukopenia (WBC count 4,000 lL-1) Normal WBC count with greater than 10 % immature forms Plasma C-reactive protein more than two SD above the normal value Plasma procalcitonin more than two SD above the normal value Hemodynamic variables Arterial hypotension (SBP 90 mmHg, MAP 70 mmHg, or an SBP decrease [40 mmHg in adults or less than two SD below normal for age) Organ dysfunction variables Arterial hypoxemia (PaO2/FiO2 300) Acute oliguria (urine output 0.5 mL kg-1 h-1 for at least 2 h despite adequate ﬂuid resuscitation) Creatinine increase [0.5 mg/dL or 44.2 lmol/L Coagulation abnormalities (INR [1.5 or aPTT [60 s) Ileus (absent bowel sounds) Thrombocytopenia (platelet count 100,000 lL-1) Hyperbilirubinemia (plasma total bilirubin [4 mg/dL or 70 lmol/L) Tissue perfusion variables Hyperlactatemia ([1 mmol/L) Decreased capillary reﬁll or mottlingSD standard deviation, WBC white blood cell, SBP systolic blood hypothermia (rectal temperature [38.5 or 35 °C), tachycardiapressure, MAP mean arterial pressure, INR international normalized (may be absent in hypothermic patients), and at least one of theratio, aPTT activated partial thromboplastin time following indications of altered organ function: altered mental sta-Diagnostic criteria for sepsis in the pediatric population are signs tus, hypoxemia, increased serum lactate level, or bounding pulsesand symptoms of inﬂammation plus infection with hyper- or Adapted from Table 2 Severe sepsis The GRADE system is based on a sequential assess-Severe sepsis deﬁnition = sepsis-induced tissue hypoperfusion or ment of the quality of evidence, followed by assessment organ dysfunction (any of the following thought to be due to the of the balance between the beneﬁts and risks, burden, and infection) cost, leading to development and grading of a manage- Sepsis-induced hypotension ment recommendation. Keeping the rating of quality of Lactate above upper limits laboratory normal Urine output 0.5 mL kg-1 h-1 for more than 2 h despite evidence and strength of recommendation explicitly sep- adequate ﬂuid resuscitation arate constitutes a crucial and deﬁning feature of the Acute lung injury with PaO2/FiO2 250 in the absence of GRADE approach. This system classiﬁes quality of evi- pneumonia as infection source dence as high (grade A), moderate (grade B), low (grade Acute lung injury with PaO2/FiO2 200 in the presence of pneumonia as infection source C), or very low (grade D). Randomized trials begin as Creatinine [2.0 mg/dL (176.8 lmol/L) high-quality evidence but may be downgraded due to Bilirubin [2 mg/dL (34.2 lmol/L) limitations in implementation, inconsistency, or impreci- Platelet count 100,000 lL sion of the results, indirectness of the evidence, and Coagulopathy (international normalized ratio [1.5) possible reporting bias (Table 3). Examples of indirect-Adapted from  ness of the evidence include population studied, interventions used, outcomes measured, and how theseevidence from high (A) to very low (D) and to determine the relate to the question of interest. Well-done observationalstrength of recommendations (Tables 3, 4) [9–11]. The SSC (nonrandomized) studies begin as low-quality evidence,Steering Committee and individual authors collaborated but the quality level may be upgraded on the basis of awith GRADE representatives to apply the system during the large magnitude of effect. An example of this is theSSC guidelines revision process. The members of the quality of evidence for early administration of antibiotics.GRADE group were directly involved, either in person or References to supplemental digital content appendices ofvia e-mail, in all discussions and deliberations among the GRADEpro Summary of Evidence Tables appear through-guidelines committee members as to grading decisions. out this document.
170Table 3 Determination of the quality of evidence Table 4 Factors determining strong versus weak recommendationUnderlying methodology What should be considered Recommended process A (high) RCTs High or moderate evidence (is The higher the quality of B (moderate) downgraded RCTs or upgraded observational studies there high or moderate quality C (low) well-done observational studies with control RCTs evidence, the more likely a evidence?) D (very low) downgraded controlled studies or expert opinion strong recommendation. based on other evidence Certainty about the balance of The larger the differenceFactors that may decrease the strength of evidence beneﬁts versus harms and between the desirable and burdens (is there certainty?) 1. Poor quality of planning and implementation of available RCTs, undesirable consequences and suggesting high likelihood of bias the certainty around that 2. Inconsistency of results, including problems with subgroup difference, the more likely a analyses strong recommendation. The 3. Indirectness of evidence (differing population, intervention, smaller the net beneﬁt and the control, outcomes, comparison) lower the certainty for that 4. Imprecision of results beneﬁt, the more likely a weak 5. High likelihood of reporting bias recommendation Certainty in or similar values (is The more certainty or similarityMain factors that may increase the strength of evidence there certainty or similarity?) 1. Large magnitude of effect (direct evidence, relative risk [ 2 in values and preferences, the with no plausible confounders) more likely a strong 2. Very large magnitude of effect with relative risk [ 5 and no recommendation threats to validity (by two levels) Resource implications (are The lower the cost of an 3. Dose–response gradient resources worth expected intervention compared to the beneﬁts?) alternative and other costsRCT randomized controlled trial related to the decision–i.e., fewer resources consumed— the more likely a strong The GRADE system classiﬁes recommendations as recommendationstrong (grade 1) or weak (grade 2). The factors inﬂuencingthis determination are presented in Table 4. The assignmentof strong or weak is considered of greater clinical impor- intervention and that most clinicians should use it in mosttance than a difference in letter level of quality of evidence. situations. Circumstances may exist in which a strongThe committee assessed whether the desirable effects of recommendation cannot or should not be followed for anadherence would outweigh the undesirable effects, and the individual because of that patient’s preferences or clinicalstrength of a recommendation reﬂects the group’s degree of characteristics that make the recommendation less appli-conﬁdence in that assessment. Thus, a strong recommen- cable. A strong recommendation does not automaticallydation in favor of an intervention reﬂects the panel’s opinion imply standard of care. For example, the strong recom-that the desirable effects of adherence to a recommendation mendation for administering antibiotics within 1 h of the(beneﬁcial health outcomes; lesser burden on staff and diagnosis of severe sepsis, as well as the recommendationpatients; and cost savings) will clearly outweigh the unde- for achieving a central venous pressure (CVP) ofsirable effects (harm to health; more burden on staff and 8 mmHg and a central venous oxygen saturation (ScvO2)patients; and greater costs). The potential drawbacks of of 70 % in the ﬁrst 6 h of resuscitation of sepsis-inducedmaking strong recommendations in the presence of low- tissue hypoperfusion, although deemed desirable, are notquality evidence were taken into account. A weak recom- yet standards of care as veriﬁed by practice data.mendation in favor of an intervention indicates the judgment Signiﬁcant education of committee members on thethat the desirable effects of adherence to a recommendation GRADE approach built on the process conducted duringprobably will outweigh the undesirable effects, but the panel 2008 efforts. Several members of the committee wereis not conﬁdent about these tradeoffs—either because some trained in the use of GRADEpro software, allowing moreof the evidence is low quality (and thus uncertainty remains formal use of the GRADE system . Rules were dis-regarding the beneﬁts and risks) or the beneﬁts and down- tributed concerning assessing the body of evidence, andsides are closely balanced. A strong recommendation is GRADE representatives were available for adviceworded as ‘‘we recommend’’ and a weak recommendation throughout the process. Subgroups agreed electronicallyas ‘‘we suggest.’’ on draft proposals that were then presented for general Throughout the document are a number of statements discussion among subgroup heads, the SSC Steeringthat either follow graded recommendations or are listed as Committee (two co-chairs, two co-vice chairs, and an at-stand-alone numbered statements followed by ‘‘ungraded’’ large committee member), and several selected keyin parentheses (UG). In the opinion of the committee, committee members who met in July 2011 in Chicago.these recommendations were not conducive for the The results of that discussion were incorporated into theGRADE process. next version of recommendations and again discussed The implications of calling a recommendation strong with the whole group using electronic mail. Draft rec-are that most well-informed patients would accept that ommendations were distributed to the entire committee
171and ﬁnalized during an additional nominal group meeting Management of severe sepsisin Berlin in October 2011. Deliberations and decisionswere then recirculated to the entire committee for Initial resuscitation and infection issues (Table 5)approval. At the discretion of the chairs and following A. Initial resuscitationdiscussion, competing proposals for wording of recom- 1. We recommend the protocolized, quantitative resus-mendations or assigning strength of evidence were citation of patients with sepsis- induced tissueresolved by formal voting within subgroups and at nom- hypoperfusion (deﬁned in this document as hypoten-inal group meetings. The manuscript was edited for style sion persisting after initial ﬂuid challenge or bloodand form by the writing committee with ﬁnal approval by lactate concentration C4 mmol/L). This protocolsubgroup heads and then by the entire committee. To should be initiated as soon as hypoperfusion is rec-satisfy peer review during the ﬁnal stages of manuscript ognized and should not be delayed pending ICUapproval for publication, several recommendations were admission. During the ﬁrst 6 h of resuscitation, theedited with approval of the SSC executive committee goals of initial resuscitation of sepsis-induced hypo-group head for that recommendation and the EBM lead. perfusion should include all of the following as a part of a treatment protocol (grade 1C):Conﬂict of interest policy (a) CVP 8–12 mmHg (b) MAP C65 mmHgSince the inception of the SSC guidelines in 2004, no (c) Urine output C0.5 mL kg h-1members of the committee represented industry; there (d) Superior vena cava oxygenation saturation (ScvO2)was no industry input into guidelines development; and or mixed venous oxygen saturation (SvO2) 70 orno industry representatives were present at any of the 65 %, respectively.meetings. Industry awareness or comment on the recom- 2. We suggest targeting resuscitation to normalize lactatemendations was not allowed. No member of the in patients with elevated lactate levels as a marker ofguidelines committee received honoraria for any role in tissue hypoperfusion (grade 2C).the 2004, 2008, or 2012 guidelines process. A detailed description of the disclosure process and all Rationale. In a randomized, controlled, single-centerauthor disclosures appear in Supplemental Digital Content 1 study, early quantitative resuscitation improved survivalin the supplemental materials to this document. Appendix 2 for emergency department patients presenting with septicshows a ﬂowchart of the COI disclosure process. Committee shock . Resuscitation targeting the physiologic goalsmembers who were judged to have either ﬁnancial or non- expressed in recommendation 1 (above) for the initial 6-hﬁnancial/academic competing interests were recused during period was associated with a 15.9 % absolute reduction inthe closed discussion session and voting session on that 28-day mortality rate. This strategy, termed early goal-topic. Full disclosure and transparency of all committee directed therapy, was evaluated in a multicenter trial ofmembers’ potential conﬂicts were sought. 314 patients with severe sepsis in eight Chinese centers On initial review, 68 ﬁnancial conﬂict of interest . This trial reported a 17.7 % absolute reduction in(COI) disclosures and 54 non-ﬁnancial disclosures were 28-day mortality (survival rates, 75.2 vs. 57.5 %,submitted by committee members. Declared COI disclo- P = 0.001). A large number of other observational stud-sures from 19 members were determined by the COI ies using similar forms of early quantitative resuscitationsubcommittee to be not relevant to the guidelines content in comparable patient populations have shown signiﬁcantprocess. Nine who were determined to have COI (ﬁnan- mortality reduction compared to the institutions’ histori-cial and non-ﬁnancial) were adjudicated by group cal controls (Supplemental Digital Content 2). Phase IIIreassignment and requirement to adhere to SSC COI of the SSC activities, the international performancepolicy regarding discussion or voting at any committee improvement program, showed that the mortality of septicmeetings where content germane to their COI was dis- patients presenting with both hypotension and lactatecussed. Nine were judged as having conﬂicts that could C4 mmol/L was 46.1 %, similar to the 46.6 % mortalitynot be resolved solely by reassignment. One of these found in the ﬁrst trial cited above . As part of per-individuals was asked to step down from the committee. formance improvement programs, some hospitals haveThe other eight were assigned to the groups in which they lowered the lactate threshold for triggering quantitativehad the least COI. They were required to work within resuscitation in the patient with severe sepsis, but thesetheir group with full disclosure when a topic for which thresholds have not been subjected to randomized trials.they had relevant COI was discussed, and they were not The consensus panel judged use of CVP and SvO2 targetsallowed to serve as group head. At the time of ﬁnal to be recommended physiologic targets for resuscitation.approval of the document, an update of the COI statement Although there are limitations to CVP as a marker ofwas required. No additional COI issues were reported that intravascular volume status and response to ﬂuids, a lowrequired further adjudication. CVP generally can be relied upon as supporting positive
172Table 5 Recommendations: initial resuscitation and infection issuesA. Initial resuscitation 1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (deﬁned in this document as hypotension persisting after initial ﬂuid challenge or blood lactate concentration C4 mmol/L). Goals during the ﬁrst 6 h of resuscitation: (a) Central venous pressure 8–12 mmHg (b) Mean arterial pressure (MAP) C 65 mmHg (c) Urine output C 0.5 mL kg-1 h (d) Central venous (superior vena cava) or mixed venous oxygen saturation 70 or 65 %, respectively (grade 1C) 2. In patients with elevated lactate levels targeting resuscitation to normalize lactate as rapidly as possible (grade 2C)B. Screening for sepsis and performance improvement 1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C) 2. Hospital-based performance improvement efforts in severe sepsis (UG)C. Diagnosis 1. Cultures as clinically appropriate before antimicrobial therapy if no signiﬁcant delay ([45 min) in the start of antimicrobial(s) (grade 1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (48 h) inserted (grade 1C) 2. Use of the 1,3 b-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available and invasive candidiasis is in differential diagnosis of cause of infection. 3. Imaging studies performed promptly to conﬁrm a potential source of infection (UG)D. Antimicrobial therapy 1. Administration of effective intravenous antimicrobials within the ﬁrst hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy 2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B) 2b. Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B) 3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C) 4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difﬁcult to treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B). For patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a ﬂuoroquinolone is for P. aeruginosa bacteremia (grade 2B). A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B) 4b. Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility proﬁle is known (grade 2B) 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deﬁciencies, including neutropenia (grade 2C) 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C) 7. Antimicrobial agents should not be used in patients with severe inﬂammatory states determined to be of noninfectious cause (UG)E. Source control 1. A speciﬁc anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the ﬁrst 12 h after the diagnosis is made, if feasible (grade 1C) 2. When infected peripancreatic necrosis is identiﬁed as a potential source of infection, deﬁnitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred (grade 2B) 3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (e.g., percutaneous rather than surgical drainage of an abscess) (UG) 4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established (UG)F. Infection prevention 1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective (grade 2B) 1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B)response to ﬂuid loading. Either intermittent or continuous achieve the ScvO2 or SvO2 goal are options. The strongmeasurements of oxygen saturation were judged to be recommendation for achieving a CVP of 8 mmHg and anacceptable. During the ﬁrst 6 h of resuscitation, if ScvO2 less ScvO2 of 70 % in the ﬁrst 6 h of resuscitation of sepsis-than 70 % or SvO2 equivalent of less than 65 % persists with induced tissue hypoperfusion, although deemed desirable,what is judged to be adequate intravascular volume reple- are not yet the standard of care as veriﬁed by practice data.tion in the presence of persisting tissue hypoperfusion, then The publication of the initial results of the international SSCdobutamine infusion (to a maximum of 20 lg kg-1 min-1) performance improvement program demonstrated thator transfusion of packed red blood cells to achieve a adherence to CVP and ScvO2 targets for initial resuscitationhematocrit of greater than or equal to 30 % in attempts to was low .
173 In mechanically ventilated patients or those with known (n = 30). The second trial included 348 patients with lactatepreexisting decreased ventricular compliance, a higher target levels C3 mmol/L . The strategy in this trial was basedCVP of 12–15 mmHg should be achieved to account for the on a greater than or equal to 20 % decrease in lactate levelsimpediment in ﬁlling . Similar consideration may be per 2 h of the ﬁrst 8 h in addition to ScvO2 target achieve-warranted in circumstances of increased abdominal pressure ment, and was associated with a 9.6 % absolute reduction in. Elevated CVP may also be seen with preexisting clin- mortality (P = 0.067; adjusted hazard ratio, 0.61; 95 % CI,ically signiﬁcant pulmonary artery hypertension, making use 0.43–0.87; P = 0.006).of this variable untenable for judging intravascular volumestatus. Although the cause of tachycardia in septic patientsmay be multifactorial, a decrease in elevated pulse rate with B. Screening for sepsis and performance improvementﬂuid resuscitation is often a useful marker of improving 1. We recommend routine screening of potentiallyintravascular ﬁlling. Published observational studies have infected seriously ill patients for severe sepsis todemonstrated an association between good clinical outcome increase the early identiﬁcation of sepsis and allowin septic shock and MAP C65 mmHg as well as ScvO2 implementation of early sepsis therapy (grade 1C).C70 % (measured in the superior vena cava, either inter-mittently or continuously) . Many studies support the Rationale. The early identiﬁcation of sepsis and imple-value of early protocolized resuscitation in severe sepsis and mentation of early evidence-based therapies have beensepsis-induced tissue hypoperfusion [19–24]. Studies of documented to improve outcomes and decrease sepsis-patients with shock indicate that SvO2 runs 5–7 % lower than related mortality . Reducing the time to diagnosis ofScvO2 . While the committee recognized the controversy severe sepsis is thought to be a critical component ofsurrounding resuscitation targets, an early quantitative reducing mortality from sepsis-related multiple organresuscitation protocol using CVP and venous blood gases dysfunction . Lack of early recognition is a majorcan be readily established in both emergency department and obstacle to sepsis bundle initiation. Sepsis screening toolsICU settings . Recognized limitations to static ventric- have been developed to monitor ICU patients [37–41],ular ﬁlling pressure estimates exist as surrogates for ﬂuid and their implementation has been associated withresuscitation [27, 28], but measurement of CVP is currently decreased sepsis-related mortality .the most readily obtainable target for ﬂuid resuscitation.Targeting dynamic measures of ﬂuid responsiveness during 2. Performance improvement efforts in severe sepsisresuscitation, including ﬂow and possibly volumetric indices should be used to improve patient outcomes (UG).and microcirculatory changes, may have advantages [29–32]. Available technologies allow measurement of ﬂow at Rationale. Performance improvement efforts in sepsisthe bedside [33, 34]; however, the efﬁcacy of these moni- have been associated with improved patient outcomes [19,toring techniques to inﬂuence clinical outcomes from early 42–46]. Improvement in care through increasing compli-sepsis resuscitation remains incomplete and requires further ance with sepsis quality indicators is the goal of a severestudy before endorsement. sepsis performance improvement program . Sepsis The global prevalence of severe sepsis patients initially management requires a multidisciplinary team (physicians,presenting with either hypotension with lactate C4 mmol/L, nurses, pharmacy, respiratory, dieticians, and administra-hypotension alone, or lactate C4 mmol/L alone, is reported tion) and multispecialty collaboration (medicine, surgery,as 16.6, 49.5, and 5.4 %, respectively . The mortality and emergency medicine) to maximize the chance for suc-rate is high in septic patients with both hypotension and cess. Evaluation of process change requires consistentlactate C4 mmol/L (46.1 %) , and is also increased in education, protocol development and implementation, dataseverely septic patients with hypotension alone (36.7 %) collection, measurement of indicators, and feedback toand lactate C4 mmol/L alone (30 %) . If ScvO2 is not facilitate the continuous performance improvement.available, lactate normalization may be a feasible option in Ongoing educational sessions provide feedback on indi-the patient with severe sepsis-induced tissue hypoperfusion. cator compliance and can help identify areas forScvO2 and lactate normalization may also be used as a additional improvement efforts. In addition to traditionalcombined endpoint when both are available. Two multi- continuing medical education efforts to introduce guide-center randomized trials evaluated a resuscitation strategy lines into clinical practice, knowledge translation effortsthat included lactate reduction as a single target or a target have recently been introduced as a means to promote thecombined with ScvO2 normalization [35, 36]. The ﬁrst trial use of high-quality evidence in changing behavior .reported that early quantitative resuscitation based on lactate Protocol implementation associated with education andclearance (decrease by at least 10 %) was noninferior to performance feedback has been shown to change clini-early quantitative resuscitation based on achieving ScvO2 of cian behavior and is associated with improved outcomes70 % or more . The intention-to-treat group contained and cost effectiveness in severe sepsis [19, 23, 24, 49]. In300, but the number of patients actually requiring either partnership with the Institute for Healthcare Improve-ScvO2 normalization or lactate clearance was small ment, phase III of the SSC targeted the implementation of
174a core set (‘‘bundle’’) of recommendations in hospital devices with signs of inﬂammation, catheter dysfunction, orenvironments where change in behavior and clinical indicators of thrombus formation). Obtaining blood culturesimpact were measured . The SSC guidelines and peripherally and through a vascular access device is anbundles can be used as the basis of a sepsis performance important strategy. If the same organism is recovered fromimprovement program. both cultures, the likelihood that the organism is causing the Application of the SSC sepsis bundles led to sustained, severe sepsis is enhanced.continuous quality improvement in sepsis care and was In addition, if equivalent volumes of blood drawn forassociated with reduced mortality . Analysis of the data culture and the vascular access device is positive muchfrom nearly 32,000 patient charts gathered from 239 hospi- earlier than the peripheral blood culture (i.e., more than 2 htals in 17 countries through September 2011 as part of phase earlier), the data support the concept that the vascular accessIII of the campaign informed the revision of the bundles in device is the source of the infection [36, 51, 52]. Quantitativeconjunction with the 2012 guidelines. As a result, for the cultures of catheter and peripheral blood may also be useful2012 version, the management bundle was dropped and the for determining whether the catheter is the source of infec-resuscitation bundle was broken into two parts and modiﬁed tion. The volume of blood drawn with the culture tube shouldas shown in Fig. 1. For performance improvement quality be C10 mL . Quantitative (or semiquantitative) culturesindicators, resuscitation target thresholds are not considered. of respiratory tract secretions are often recommended for theHowever, recommended targets from the guidelines are diagnosis of ventilator-associated pneumonia (VAP) ,included with the bundles for reference purposes. but their diagnostic value remains unclear . The Gram stain can be useful, in particular for respira- tory tract specimens, to determine if inﬂammatory cells areC. Diagnosis present (greater than ﬁve polymorphonuclear leukocytes/1. We recommend obtaining appropriate cultures before high-powered ﬁeld and less than 10 squamous cells/low- antimicrobial therapy is initiated if such cultures do powered ﬁeld) and if culture results will be informative of not cause signiﬁcant delay ([45 min) in the start of lower respiratory pathogens. Rapid inﬂuenza antigen testing antimicrobial(s) administration (grade 1C). To opti- during periods of increased inﬂuenza activity in the com- mize identiﬁcation of causative organisms, we munity is also recommended. A focused history can provide recommend obtaining at least two sets of blood cul- vital information about potential risk factors for infection tures (both aerobic and anaerobic bottles) before and likely pathogens at speciﬁc tissue sites. The potential antimicrobial therapy, with at least one drawn percu- role of biomarkers for diagnosis of infection in patients taneously and one drawn through each vascular access presenting with severe sepsis remains undeﬁned. The utility device, unless the device was recently (48 h) inser- of procalcitonin levels or other biomarkers (such as ted. These blood cultures can be drawn at the same C-reactive protein) to discriminate the acute inﬂammatory time if they are obtained from different sites. Cultures pattern of sepsis from other causes of generalized inﬂam- of other sites (preferably quantitative where appropri- mation (e.g., postoperative, other forms of shock) has not ate), such as urine, cerebrospinal ﬂuid, wounds, been demonstrated. No recommendation can be given for respiratory secretions, or other body ﬂuids that may be the use of these markers to distinguish between severe the source of infection, should also be obtained before infection and other acute inﬂammatory states [56–58]. antimicrobial therapy if doing so does not cause sig- In the near future, rapid, non-culture-based diagnostic niﬁcant delay in antibiotic administration (grade 1C). methods (polymerase chain reaction, mass spectroscopy, microarrays) might be helpful for a quicker identiﬁcation ofRationale. Although sampling should not delay timely pathogens and major antimicrobial resistance determinantsadministration of antimicrobial agents in patients with . These methodologies could be particularly useful forsevere sepsis (e.g., lumbar puncture in suspected meningi- difﬁcult-to-culture pathogens or in clinical situations wheretis), obtaining appropriate cultures before administration of empiric antimicrobial agents have been administered beforeantimicrobials is essential to conﬁrm infection and the culture samples were been obtained. Clinical experienceresponsible pathogens, and to allow de-escalation of anti- remains limited, and more clinical studies are needed beforemicrobial therapy after receipt of the susceptibility proﬁle. recommending these non-culture molecular methods as aSamples can be refrigerated or frozen if processing cannot replacement for standard blood culture methods [60, 61].be performed immediately. Because rapid sterilization ofblood cultures can occur within a few hours after the ﬁrst 2. We suggest the use of the 1,3 b-D-glucan assay (gradeantimicrobial dose, obtaining those cultures before therapy 2B), mannan and anti-mannan antibody assays (gradeis essential if the causative organism is to be identiﬁed. Two 2C), when invasive candidiasis is in the differentialor more blood cultures are recommended . In patients diagnosis of infection.with indwelling catheters (for more than 48 h), at least oneblood culture should be drawn through each lumen of each Rationale. The diagnosis of systemic fungal infectionvascular access device (if feasible, especially for vascular (usually candidiasis) in the critically ill patient can be
175Fig. 1 Surviving sepsiscampaign care bundles SURVIVING SEPSIS CAMPAIGN CARE BUNDLES TO BE COMPLETED WITHIN 3 HOURS: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L TO BE COMPLETED WITHIN 6 HOURS: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L (36 mg/dL): - Measure central venous pressure (CVP)* - Measure central venous oxygen saturation (ScvO2)* 7) Remeasure lactate if initial lactate was elevated* *Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg, ScvO2 of ≥ 70%, and normalization of lactate.challenging, and rapid diagnostic methodologies, such as shock (grade 1C) should be the goal of therapy.antigen and antibody detection assays, can be helpful in Remark: Although the weight of the evidence supportsdetecting candidiasis in the ICU patient. These suggested prompt administration of antibiotics following thetests have shown positive results signiﬁcantly earlier than recognition of severe sepsis and septic shock, thestandard culture methods [62–67], but false-positive feasibility with which clinicians may achieve this idealreactions can occur with colonization alone, and their state has not been scientiﬁcally evaluated.diagnostic utility in managing fungal infection in the ICUneeds additional study . Rationale. Establishing vascular access and initiating aggressive ﬂuid resuscitation are the ﬁrst priorities when3. We recommend that imaging studies be performed managing patients with severe sepsis or septic shock. promptly in attempts to conﬁrm a potential source of Prompt infusion of antimicrobial agents should also be a infection. Potential sources of infection should be sam- priority and may require additional vascular access ports pled as they are identiﬁed and in consideration of patient [68, 69]. In the presence of septic shock, each hour delay risk for transport and invasive procedures (e.g., careful in achieving administration of effective antibiotics is coordination and aggressive monitoring if the decision is associated with a measurable increase in mortality in a made to transport for a computed tomography-guided number of studies [15, 68, 70–72]. Overall, the prepon- needle aspiration). Bedside studies, such as ultrasound, derance of data support giving antibiotics as soon as may avoid patient transport (UG). possible in patients with severe sepsis with or without septic shock [15, 68, 70–77]. The administration of anti-Rationale. Diagnostic studies may identify a source of microbial agents with a spectrum of activity likely to treatinfection that requires removal of a foreign body or drainage the responsible pathogen(s) effectively within 1 h of theto maximize the likelihood of a satisfactory response to diagnosis of severe sepsis and septic shock. Practicaltherapy. Even in the most organized and well-staffed considerations, for example challenges with clinicians’healthcare facilities, however, transport of patients can be early identiﬁcation of patients or operational complexitiesdangerous, as can be placing patients in outside-unit imaging in the drug delivery chain, represent unstudied variablesdevices that are difﬁcult to access and monitor. Balancing that may impact achieving this goal. Future trials shouldrisk and beneﬁt is therefore mandatory in those settings. endeavor to provide an evidence base in this regard. This should be the target goal when managing patients withD. Antimicrobial therapy septic shock, whether they are located within the hospital1. The administration of effective intravenous antimi- ward, the emergency department, or the ICU. The strong crobials within the ﬁrst hour of recognition of septic recommendation for administering antibiotics within 1 h shock (grade 1B) and severe sepsis without septic of the diagnosis of severe sepsis and septic shock,
176although judged to be desirable, is not yet the standard of agents, or if Candida glabrata infection is suspected fromcare as veriﬁed by published practice data . earlier culture data. Knowledge of local resistance pat- If antimicrobial agents cannot be mixed and delivered terns to antifungal agents should guide drug selectionpromptly from the pharmacy, establishing a supply of until fungal susceptibility test results, if available, arepremixed antibiotics for such urgent situations is an performed. Risk factors for candidemia, such as immu-appropriate strategy for ensuring prompt administration. nosuppressed or neutropenic state, prior intense antibioticMany antibiotics will not remain stable if premixed in a therapy, or colonization in multiple sites, should also besolution. This risk must be taken into consideration in considered when choosing initial therapy.institutions that rely on premixed solutions for rapid Because patients with severe sepsis or septic shock haveavailability of antibiotics. In choosing the antimicrobial little margin for error in the choice of therapy, the initialregimen, clinicians should be aware that some antimi- selection of antimicrobial therapy should be broad enoughcrobial agents have the advantage of bolus administration, to cover all likely pathogens. Antibiotic choices should bewhile others require a lengthy infusion. Thus, if vascular guided by local prevalence patterns of bacterial pathogensaccess is limited and many different agents must be and susceptibility data. Ample evidence exists that failure toinfused, bolus drugs may offer an advantage. initiate appropriate therapy (i.e., therapy with activity2a. We recommend that initial empiric anti-infective ther- against the pathogen that is subsequently identiﬁed as the apy include one or more drugs that have activity against causative agent) correlates with increased morbidity and all likely pathogens (bacterial and/or fungal or viral) mortality in patients with severe sepsis or septic shock [68, and that penetrate in adequate concentrations into the 71, 79, 80]. Recent exposure to antimicrobials (within last tissues presumed to be the source of sepsis (grade 1B). 3 months) should be considered in the choice of an empiric antibacterial regimen. Patients with severe sepsis or septicRationale. The choice of empirical antimicrobial therapy shock warrant broad-spectrum therapy until the causativedepends on complex issues related to the patient’s history, organism and its antimicrobial susceptibilities are deﬁned.including drug intolerances, recent receipt of antibiotics Although a global restriction of antibiotics is an important(previous 3 months), underlying disease, the clinical syn- strategy to reduce the development of antimicrobial resis-drome, and susceptibility patterns of pathogens in the tance and to reduce cost, it is not an appropriate strategy incommunity and hospital, and that previously have been the initial therapy for this patient population. However, asdocumented to colonize or infect the patient. The most soon as the causative pathogen has been identiﬁed, de-common pathogens that cause septic shock in hospitalized escalation should be performed by selecting the mostpatients are Gram-positive bacteria, followed by Gram- appropriate antimicrobial agent that covers the pathogennegative and mixed bacterial microorganisms. Candidiasis, and is safe and cost-effective. Collaboration with antimi-toxic shock syndromes, and an array of uncommon patho- crobial stewardship programs, where they exist, isgens should be considered in selected patients. An especially encouraged to ensure appropriate choices and rapid avail-wide range of potential pathogens exists for neutropenic ability of effective antimicrobials for treating septicpatients. Recently used anti-infective agents should gener- patients. All patients should receive a full loading dose ofally be avoided. When choosing empirical therapy, each agent. Patients with sepsis often have abnormal andclinicians should be cognizant of the virulence and growing vacillating renal or hepatic function, or may have abnor-prevalence of oxacillin (methicillin)-resistant Staphylococ- mally high volumes of distribution due to aggressive ﬂuidcus aureus, and resistance to broad-spectrum beta-lactams resuscitation, requiring dose adjustment. Drug serum con-and carbapenem among Gram-negative bacilli in some centration monitoring can be useful in an ICU setting forcommunities and healthcare settings. Within regions in those drugs that can be measured promptly. Signiﬁcantwhich the prevalence of such drug-resistant organisms is expertise is required to ensure that serum concentrationssigniﬁcant, empiric therapy adequate to cover these patho- maximize efﬁcacy and minimize toxicity [81, 82].gens is warranted. Clinicians should also consider whether candidemia is 2b. The antimicrobial regimen should be reassessed dailya likely pathogen when choosing initial therapy. When for potential de-escalation to prevent the develop-deemed warranted, the selection of empirical antifungal ment of resistance, to reduce toxicity, and to reducetherapy (e.g., an echinocandin, triazoles such as ﬂuco- costs (grade 1B).nazole, or a formulation of amphotericin B) should betailored to the local pattern of the most prevalent Candida Rationale. Once the causative pathogen has been iden-species and any recent exposure to antifungal drugs . tiﬁed, the most appropriate antimicrobial agent thatRecent Infectious Diseases Society of America (IDSA) covers the pathogen and is safe and cost-effective shouldguidelines recommend either ﬂuconazole or an echino- be selected. On occasion, continued use of speciﬁccandin. Empiric use of an echinocandin is preferred in combinations of antimicrobials might be indicated evenmost patients with severe illness, especially in those after susceptibility testing is available (e.g., Pseudomonaspatients who have recently been treated with antifungal spp. only susceptible to aminoglycosides; enterococcal
177endocarditis; Acinetobacter spp. infections susceptible only 4b. We suggest that combination therapy, when usedto polymyxins). Decisions on deﬁnitive antibiotic choices empirically in patients with severe sepsis, should notshould be based on the type of pathogen, patient charac- be administered for longer than 3–5 days. De-esca-teristics, and favored hospital treatment regimens. lation to the most appropriate single-agent therapy Narrowing the spectrum of antimicrobial coverage and should be performed as soon as the susceptibilityreducing the duration of antimicrobial therapy will reduce proﬁle is known (grade 2B). Exceptions wouldthe likelihood that the patient will develop superinfection include aminoglycoside monotherapy, which shouldwith other pathogenic or resistant organisms, such as be generally avoided, particularly for P. aeruginosaCandida species, Clostridium difﬁcile, or vancomycin- sepsis, and for selected forms of endocarditis, whereresistant Enterococcus faecium. However, the desire to prolonged courses of combinations of antibiotics areminimize superinfections and other complications should warranted.not take precedence over giving an adequate course oftherapy to cure the infection that caused the severe sepsis Rationale. A propensity-matched analysis, meta-analy-or septic shock. sis, and meta-regression analysis, along with additional observational studies, have demonstrated that combina-3. We suggest the use of low procalcitonin levels or tion therapy produces a superior clinical outcome in similar biomarkers to assist the clinician in the dis- severely ill, septic patients with a high risk of death [86– continuation of empiric antibiotics in patients who 90]. In light of the increasing frequency of resistance to appeared septic, but have no subsequent evidence of antimicrobial agents in many parts of the world, broad- infection (grade 2C). spectrum coverage generally requires the initial use ofRationale. This suggestion is predicated on the prepon- combinations of antimicrobial agents. Combination ther-derance of the published literature relating to the use of apy used in this context connotes at least two differentprocalcitonin as a tool to discontinue unnecessary antimi- classes of antibiotics (usually a beta-lactam agent with acrobials [58, 83]. However, clinical experience with this macrolide, ﬂuoroquinolone, or aminoglycoside for selectstrategy is limited and the potential for harm remains a patients). A controlled trial suggested, however, thatconcern . No evidence demonstrates that this practice when using a carbapenem as empiric therapy in a popu-reduces the prevalence of antimicrobial resistance or the risk lation at low risk for infection with resistantof antibiotic-related diarrhea from C. difﬁcile. One recent microorganisms, the addition of a ﬂuoroquinolone doesstudy failed to show any beneﬁt of daily procalcitonin not improve outcomes of patients . A number of othermeasurement in early antibiotic therapy or survival . recent observational studies and some small, prospective trials support initial combination therapy for selected4a. Empiric therapy should attempt to provide antimi- patients with speciﬁc pathogens (e.g., pneumococcal crobial activity against the most likely pathogens sepsis, multidrug-resistant Gram-negative pathogens) based upon each patient’s presenting illness and local [91–93], but evidence from adequately powered, ran- patterns of infection. We suggest combination empiric domized clinical trials is not available to support therapy for neutropenic patients with severe sepsis combination over monotherapy other than in septic (grade 2B) and for patients with difﬁcult-to- treat, patients at high risk of death. In some clinical scenarios, multidrug-resistant bacterial pathogens such as Acine- combination therapies are biologically plausible and are tobacter and Pseudomonas spp. (grade 2B). For likely clinically useful even if evidence has not demon- selected patients with severe infections associated with strated improved clinical outcome [89, 90, 94, 95]. respiratory failure and septic shock, combination ther- Combination therapy for suspected or known Pseudo- apy with an extended spectrum beta-lactam and either monas aeruginosa or other multiresistant Gram-negative an aminoglycoside or a ﬂuoroquinolone is suggested for pathogens, pending susceptibility results, increases the P. aeruginosa bacteremia (grade 2B). Similarly, a more likelihood that at least 1 drug is effective against that complex combination of beta-lactam and a macrolide is strain and positively affects outcome [88, 96]. suggested for patients with septic shock from bactere- mic Streptococcus pneumoniae infections (grade 2B). 5. We suggest that the duration of therapy typically be 7–10 days if clinically indicated; longer courses mayRationale. Complex combinations might be needed in be appropriate in patients who have a slow clinicalsettings where highly antibiotic-resistant pathogens are response, undrainable foci of infection, bacteremia withprevalent, with such regimens incorporating carbapen- S. aureus; some fungal and viral infections, or immu-ems, colistin, rifampin, or other agents. However, a recent nologic deﬁciencies, including neutropenia (grade 2C).controlled trial suggested that adding a ﬂuoroquinolone toa carbapenem as empiric therapy did not improve out- Rationale. Although patient factors may inﬂuence thecome in a population at low risk for infection with length of antibiotic therapy, in general, a duration of 7–10resistant microorganisms . days (in the absence of source control issues) is adequate.
178Thus, decisions to continue, narrow, or stop antimicrobial infected with an antimicrobial-resistant pathogen or willtherapy must be made on the basis of clinician judgment develop a drug-related adverse effect. Although it isand clinical information. Clinicians should be cognizant important to stop unnecessary antibiotics early, cliniciansof blood cultures being negative in a signiﬁcant percent- should be cognizant that blood cultures will be negative inage of cases of severe sepsis or septic shock, despite the more than 50 % of cases of severe sepsis or septic shockfact that many of these cases are very likely caused by if the patients are receiving empiric antimicrobial therapy;bacteria or fungi. Clinicians should be cognizant that yet many of these cases are very likely caused by bacteriablood cultures will be negative in a signiﬁcant percentage or fungi. Thus, the decisions to continue, narrow, or stopof cases of severe sepsis or septic shock, despite many of antimicrobial therapy must be made on the basis of cli-these cases are very likely caused by bacteria or fungi. nician judgment and clinical information.6. We suggest that antiviral therapy be initiated as early as possible in patients with severe sepsis or septic E. Source control shock of viral origin (grade 2C). 1. We recommend that a speciﬁc anatomical diagnosis ofRationale. Recommendations for antiviral treatment infection requiring consideration for emergent sourceinclude the use of: a) early antiviral treatment of sus- control (e.g., necrotizing soft tissue infection, peritonitis,pected or conﬁrmed inﬂuenza among persons with severe cholangitis, intestinal infarction) be sought and diagnosedinﬂuenza (e.g., those who have severe, complicated, or or excluded as rapidly as possible, and intervention beprogressive illness or who require hospitalization); b) undertaken for source control within the ﬁrst 12 h afterearly antiviral treatment of suspected or conﬁrmed inﬂu- the diagnosis is made, if feasible (grade 1C).enza among persons at higher risk for inﬂuenza 2. We suggest that when infected peripancreatic necrosis iscomplications; and c) therapy with a neuraminidase identiﬁed as a potential source of infection, deﬁnitiveinhibitor (oseltamivir or zanamivir) for persons with intervention is best delayed until adequate demarcationinﬂuenza caused by 2009 H1N1 virus, inﬂuenza A of viable and nonviable tissues has occurred (grade 2B).(H3N2) virus, or inﬂuenza B virus, or when the inﬂuenza 3. When source control in a severely septic patient isvirus type or inﬂuenza A virus subtype is unknown [97, required, the effective intervention associated with the98]. Susceptibility to antivirals is highly variable in a least physiologic insult should be used (e.g., percutane-rapidly evolving virus such as inﬂuenza, and therapeutic ous rather than surgical drainage of an abscess) (UG).decisions must be guided by updated information 4. If intravascular access devices are a possible source ofregarding the most active, strain-speciﬁc, antiviral agents severe sepsis or septic shock, they should be removedduring inﬂuenza epidemics [99, 100]. promptly after other vascular access has been estab- The role of cytomegalovirus (CMV) and other her- lished (UG).pesviruses as signiﬁcant pathogens in septic patients,especially those not known to be severely immunocom- Rationale. The principles of source control in thepromised, remains unclear. Active CMV viremia is management of sepsis include a rapid diagnosis of thecommon (15–35 %) in critically ill patients; the presence speciﬁc site of infection and identiﬁcation of a focus ofof CMV in the bloodstream has been repeatedly found to infection amenable to source control measures (speciﬁ-be a poor prognostic indicator [101, 102]. What is not cally the drainage of an abscess, debridement of infectedknown is whether CMV simply is a marker of disease necrotic tissue, removal of a potentially infected device,severity or if the virus actually contributes to organ injury and deﬁnitive control of a source of ongoing microbialand death in septic patients . No treatment recom- contamination) . Foci of infection readily amenablemendations can be given based on the current level of to source control measures include an intra-abdominalevidence. In those patients with severe primary or gen- abscess or gastrointestinal perforation, cholangitis oreralized varicella-zoster virus infections, and in rare pyelonephritis, intestinal ischemia or necrotizing softpatients with disseminated herpes simplex infections, tissue infection, and other deep space infection, such as anantiviral agents such as acyclovir can be highly effective empyema or septic arthritis. Such infectious foci shouldwhen initiated early in the course of infection . be controlled as soon as possible following successful initial resuscitation [106–108], and intravascular access7. We recommend that antimicrobial agents not be used devices that are potentially the source of severe sepsis or in patients with severe inﬂammatory states determined septic shock should be removed promptly after estab- to be of noninfectious cause (UG). lishing other sites for vascular access [109, 110]. An RCT comparing early to delayed surgical inter-Rationale. When infection is found not to be present, vention for peripancreatic necrosis showed betterantimicrobial therapy should be stopped promptly to outcomes with a delayed approach . Moreover, aminimize the likelihood that the patient will become randomized surgical study found that a minimally
179invasive, step-up approach was better tolerated by debate, despite the recent evidence that the incidence ofpatients and had a lower mortality than open necrosec- antimicrobial resistance does not change appreciably withtomy in necrotizing pancreatitis , although areas of current SDD regimens [119–121]. The grade 2B wasuncertainty exist, such as deﬁnitive documentation of designated for both SOD and CHG as it was felt that riskinfection and appropriate length of delay. The selection of was lower with CHG and the measure better acceptedoptimal source control methods must weigh the beneﬁts despite less published literature than with SOD.and risks of the speciﬁc intervention as well as risks of Supplemental Digital Content 3 shows a GRADEprotransfer . Source control interventions may cause Summary of Evidence Table for the use of topicalfurther complications, such as bleeding, ﬁstulas, or inad- digestive tract antibiotics and CHG for prophylaxisvertent organ injury. Surgical intervention should be against VAP.considered when other interventional approaches areinadequate or when diagnostic uncertainty persists despiteradiologic evaluation. Speciﬁc clinical situations require Hemodynamic support and adjunctive therapyconsideration of available choices, the patient’s prefer- (Table 6)ences, and the clinician’s expertise. G. Fluid therapy of severe sepsis 1. We recommend crystalloids be used as the initial ﬂuidF. Infection prevention of choice in the resuscitation of severe sepsis and1. We suggest that selective oral decontamination (SOD) septic shock (grade 1B). and selective digestive decontamination (SDD) should 2. We recommend against the use of hydroxyethyl be introduced and investigated as a method to reduce starches (HES) for ﬂuid resuscitation of severe sepsis the incidence of VAP; this infection control measure and septic shock (grade 1B). (This recommendation is can then be instituted in healthcare settings and regions based on the results of the VISEP , CRYSTMAS where this methodology is found to be effective (grade , 6S , and CHEST  trials. The results of 2B). the recently completed CRYSTAL trial were not2. We suggest oral chlorhexidine gluconate (CHG) be considered.) used as a form of oropharyngeal decontamination to 3. We suggest the use of albumin in the ﬂuid resuscita- reduce the risk of VAP in ICU patients with severe tion of severe sepsis and septic shock when patients sepsis (grade 2B). require substantial amounts of crystalloids (grade 2C).Rationale. Careful infection control practices (e.g., handwashing, expert nursing care, catheter care, barrier pre-cautions, airway management, elevation of the head of the Rationale. The absence of any clear beneﬁt followingbed, subglottic suctioning) should be instituted during the the administration of colloid solutions compared tocare of septic patients as reviewed in the nursing con- crystalloid solutions, together with the expense associatedsiderations for the SSC . The role of SDD with with colloid solutions, supports a high-grade recommen-systemic antimicrobial prophylaxis and its variants (e.g., dation for the use of crystalloid solutions in the initialSOD, CHG) has been a contentious issue ever since the resuscitation of patients with severe sepsis and septicconcept was ﬁrst developed more than 30 years ago. The shock.notion of limiting the acquisition of opportunistic, often Three recent multicenter RCTs evaluating 6 % HESmultiresistant, healthcare-associated microorganisms has 130/0.4 solutions (tetra starches) have been published.its appeal by promoting ‘‘colonization resistance’’ from The CRYSTMAS study demonstrated no difference inthe resident microbiome existing along mucosal surfaces mortality with HES versus 0.9 % normal saline (31 vs.of the alimentary tract. However, the efﬁcacy of SDD, its 25.3 %, P = 0.37) in the resuscitation of septic shocksafety, propensity to prevent or promote antibiotic resis- patients; however, the study was underpowered to detecttance, and cost-effectiveness remain debatable despite a the 6 % difference in absolute mortality observed .number of favorable meta-analyses and controlled clinical In a sicker patient cohort, a Scandinavian multicentertrials . The data indicate an overall reduction in VAP study in septic patients (6S Trial Group) showedbut no consistent improvement in mortality, except in increased mortality rates with 6 % HES 130/0.42 ﬂuidselected populations in some studies. Most studies do not resuscitation compared to Ringer’s acetate (51 vs. 43 %.speciﬁcally address the efﬁcacy of SDD in patients who P = 0.03) . The CHEST study, conducted in a het-present with sepsis, but some do [116–118]. erogenous population of patients admitted to intensive Oral CHG is relatively easy to administer, decreases care (HES vs. isotonic saline, n = 7000 critically illrisk of nosocomial infection, and reduces the potential patients), showed no difference in 90-day mortalityconcern over promotion of antimicrobial resistance by between resuscitation with 6 % HES with a molecularSDD regimens. This remains a subject of considerable weight of 130 kD/0.40 and isotonic saline (18 vs. 17 %,