Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012

Dellinger, R. Phillip MD1; Levy, Mitchell M. MD2; Rhodes, Andrew MB BS3; Annane, Djillali MD4; Gerlach, Herwig MD, PhD5; Opal, Steven M. MD6; Sevransky, Jonathan E. MD7; Sprung, Charles L. MD8; Douglas, Ivor S. MD9; Jaeschke, Roman MD10; Osborn, Tiffany M. MD, MPH11; Nunnally, Mark E. MD12; Townsend, Sean R. MD13; Reinhart, Konrad MD14; Kleinpell, Ruth M. PhD, RN-CS15; Angus, Derek C. MD, MPH16; Deutschman, Clifford S. MD, MS17; Machado, Flavia R. MD, PhD18; Rubenfeld, Gordon D. MD19; Webb, Steven A. MB BS, PhD20; Beale, Richard J. MB BS21; Vincent, Jean-Louis MD, PhD22; Moreno, Rui MD, PhD23; and the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup

Critical Care Medicine:
doi: 10.1097/CCM.0b013e31827e83af
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Abstract

Objective: To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.

Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.

Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations.

Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”‘ adrenal insufficiency (2C).

Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Author Information

1 Cooper University Hospital, Camden, New Jersey.

2 Warren Alpert Medical School of Brown University, Providence, Rhode Island.

3 St. George’s Hospital, London, United Kingdom.

4 Hôpital Raymond Poincaré, Garches, France.

5 Vivantes-Klinikum Neukölln, Berlin, Germany.

6 Memorial Hospital of Rhode Island, Pawtucket, Rhode Island.

7 Emory University Hospital, Atlanta, Georgia.

8 Hadassah Hebrew University Medical Center, Jerusalem, Israel.

9 Denver Health Medical Center, Denver, Colorado.

10 McMaster University, Hamilton, Ontario, Canada.

11 Barnes-Jewish Hospital, St. Louis, Missouri.

12 University of Chicago Medical Center, Chicago, Illinois.

13 California Pacific Medical Center, San Francisco, California.

14 Friedrich Schiller University Jena, Jena, Germany.

15 Rush University Medical Center, Chicago, Illinois.

16 University of Pittsburgh, Pittsburgh, Pennsylvania.

17 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

18 Federal University of Sao Paulo, Sao Paulo, Brazil.

19 Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.

20 Royal Perth Hospital, Perth, Western Australia.

21 Guy’s and St. Thomas’ Hospital Trust, London, United Kingdom.

22 Erasme University Hospital, Brussels, Belgium.

23 UCINC, Hospital de São José, Centro Hospitalar de Lisboa Central, E.P.E., Lisbon, Portugal.

* Members of the 2012 SSC Guidelines Committee and Pediatric Subgroup are listed in Appendix A at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this on the journal’s Web site (http://journals.lww.com/ccmjournal).

Complete author and committee disclosures are listed in Supplemental Digital Content 1 (http://links.lww.com/CCM/A615).

This article is being simultaneously published in Critical Care Medicine and Intensive Care Medicine.

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

Dr. Dellinger consulted for Biotest (immunoglobulin concentrate available in Europe for potential use in sepsis) and AstraZeneca (anti-TNF compound unsuccessful in recently completed sepsis clinical trial); his institution received consulting income from IKARIA for new product development (IKARIA has inhaled nitric oxide available for off-label use in ARDS) and grant support from Spectral Diagnostics Inc (current endotoxin removal clinical trial), Ferring (vasopressin analog clinical trial-ongoing); as well as serving on speakers bureau for Eisai (anti-endotoxin compound that failed to show benefit in clinical trial).

Dr. Levy received grant support from Eisai (Ocean State Clinical Coordinating Center to fund clinical trial [$500K]), he received honoraria from Eli Lilly (lectures in India $8,000), and he has been involved with the Surviving Sepsis Campaign guideline from its beginning.

Dr. Rhodes consulted for Eli Lilly with monetary compensation paid to himself as well as his institution (Steering Committee for the PROWESS Shock trial) and LiDCO; travel/accommodation reimbursement was received from Eli Lilly and LiDCO; he received income for participation in review activities such as data monitoring boards, statistical analysis from Orion, and for Eli Lilly; he is an author on manuscripts describing early goal-directed therapy, and believes in the concept of minimally invasive hemodynamic monitoring.

Dr. Annane participated on the Fresenius Kabi International Advisory Board (honorarium 2000

). His nonfinancial disclosures include being the principal investigator of a completed investigator-led multicenter randomized controlled trial assessing the early guided benefit to risk of NIRS tissue oxygen saturation; he was the principal investigator of an investigator-led randomized controlled trial of epinephrine vs norepinephrine (CATS study)–Lancet 2007; he also is the principle investigator of an ongoing investigator-led multinational randomized controlled trial of crystalloids vs colloids (Crystal Study).

Dr. Gerlach has disclosed that he has no potential conflicts of interest; he is an author of a review on the use of activated protein C in surgical patients (published in the New England Journal of Medicine, 2009).

Dr. Opal consulted for Genzyme Transgenics (consultant on transgenic antithrombin $1,000), Pfizer (consultant on TLR4 inhibitor project $3,000), British Therapeutics (consultant on polyclonal antibody project $1,000), and Biotest A (consultant on immunoglobul project $2,000). His institution received grant support from Novartis (Clinical Coordinating Center to assist in patient enrollment in a phase III trial with the use of Tissue Factor Pathway Inhibitor [TFPI] in severe community acquired pneumonia [SCAP] $30,000 for 2 years), Eisai ($30,000 for 3 years), Astra Zeneca ($30,000 for 1 year), Aggenix ($30,000 for 1 year), Inimex ($10,000), Eisai ($10,000), Atoxbio ($10,000), Wyeth ($20,000), Sirtris (preclinical research $50,000), and Cellular Bioengineering Inc. ($500). He received honoraria from Novartis (clinical evaluation committee TFPI study for SCAP $20,000) and Eisai ($25,000). He received travel/accommodations reimbursed from Sangart (data and safety monitoring $2,000), Spectral Diagnostics (data and safety monitoring $2,000), Takeda (data and safety monitoring $2,000) and Canadian trials group ROS II oseltamivir study (data and safety monitoring board (no money). He is also on the Data Safety Monitoring Board for Tetraphase (received US $600 in 2012).

Dr. Sevransky received grant support to his institution from Sirius Genomics Inc; he consulted for Idaho Technology ($1,500); he is the co-principal investigator of a multicenter study evaluating the association between intensive care unit organizational and structural factors, including protocols and in-patient mortality. He maintains that protocols serve as useful reminders to busy clinicians to consider certain therapies in patients with sepsis or other life-threatening illness.

Dr. Sprung received grants paid to his institution from Artisan Pharma ($25,000–$50,000), Eisai, Corp ($1,000–$5,000 ACCESS), Ferring Pharmaceuticals A/S ($5,000–$10,000), Hutchinson Technology Incorporated ($1,000–$5,000), Novartis Corp (less than $1,000). His institution receives grant support for patients enrolled in clinical studies from Eisai Corporation (PI. Patients enrolled in the ACCESS study $50,000–$100,000), Takeda (PI. Study terminated before patients enrolled). He received grants paid to his institution and consulting income from Artisan Pharma/Asahi Kasei Pharma America Corp ($25,000–$50,000). He consulted for Eli Lilly (Sabbatical Consulting fee $10,000–$25,000) and received honoraria from Eli Lilly (lecture $1,000–$5,000). He is a member of the Australia and New Zealand Intensive Care Society Clinical Trials Group for the NICE-SUGAR Study (no money received); he is a council member of the International Sepsis Forum (as of Oct. 2010); he has held long time research interests in steroids in sepsis, PI of Corticus study, end-of-life decision making and PI of Ethicus, Ethicatt, and Welpicus studies.

Dr. Douglas received grants paid to his institution from Eli Lilly (PROWESS Shock site), Eisai (study site), National Institutes of Health (ARDS Network), Accelr8 (VAP diagnostics), CCCTG (Oscillate Study), and Hospira (Dexmedetomidine in Alcohol Withdrawal RCT). His institution received an honorarium from the Society of Critical Care Medicine (Paragon ICU Improvement); he consulted for Eli Lilly (PROWESS Shock SC and Sepsis Genomics Study) in accordance with institutional policy; he received payment for providing expert testimony (Smith Moore Leatherwood LLP); travel/accommodations reimbursed by Eli Lilly and Company (PROWESS Shock Steering Committee) and the Society of Critical Care Medicine (Hospital Quality Alliance, Washington DC, four times per year 2009−2011); he received honoraria from Covidien (non-CME lecture 2010, US$500) and the University of Minnesota Center for Excellence in Critical Care CME program (2009, 2010); he has a pending patent for a bed backrest elevation monitor.

Dr. Jaeschke has disclosed that he has no potential conflicts of interest.

Dr. Osborn consulted for Sui Generis Health ($200). Her institution receives grant support from the National Institutes of Health Research, Health Technology Assessment Programme-United Kingdom (trial doctor for sepsis-related RCT). Salary paid through the NIHR government funded (nonindustry) grant. Grant awarded to chief investigator from ICNARC. She is a trial clinician for ProMISe.

Dr. Nunnally received a stipend for a chapter on diabetes mellitus; he is an author of editorials contesting classic tight glucose control.

Dr. Townsend is an advocate for healthcare quality improvement.

Dr. Reinhart consulted for EISAI (Steering Committee member−less then US $10,000); BRAHMS Diagnostics (less than US $10,000); and SIRS-Lab Jena (founding member, less than US $10,000). He received honoraria for lectures including service on the speakers’ bureau from Biosyn Germany (less than

10,000) and Braun Melsungen (less than

10,000). He received royalties from Edwards Life Sciences for sales of central venous oxygen catheters (~$100,000).

Dr. Kleinpell received monetary compensation for providing expert testimony (four depositions and one trial in the past year). Her institution receives grants from the Agency for Healthcare Research and Quality and the Prince Foundation (4-year R01 grant, PI and 3-year foundation grant, Co-l). She received honoraria from the Cleveland Clinic and the American Association of Critical Care Nurses for keynote speeches at conferences; she received royalties from McGraw Hill (co-editor of critical care review book); travel/accommodations reimbursed from the American Academy of Nurse Practitioners, Society of Critical Care Medicine, and American Association of Critical Care Nurses (one night hotel coverage at national conference).

Dr. Angus consulted for Eli Lilly (member of the Data Safety Monitoring Board, Multicenter trial of a PC for septic shock), Eisai Inc (Anti-TLR4 therapy for severe sepsis), and Idaho Technology (sepsis biomarkers); he received grant support (investigator, long-term follow-up of phase III trial of an anti-TLR4 agent in severe sepsis), a consulting income (anti-TRL4 therapy for severe sepsis), and travel/accommodation expense reimbursement from Eisai, Inc; he is the primary investigator for an ongoing National Institutes of Health-funded study comparing early resuscitation strategies for sepsis-induced tissue hypoperfusion.

Dr. Deutschman has nonfinancial involvement as a coauthor of the Society of Critical Care Medicine’s Glycemic Control guidelines.

Dr. Machado reports unrestricted grant support paid to her institution for Surviving Sepsis Campaign implementation in Brazil (Eli Lilly do Brasil); she is the primary investigator for an ongoing study involving vasopressin.

Dr. Rubenfeld received grant support from nonprofit agencies or foundations including National Institutes of Health ($10 million), Robert Wood Johnson Foundation ($500,000), and CIHR ($200,000). His institution received grants from for-profit companies including Advanced Lifeline System ($150,000), Siemens ($50,000), Bayer ($10,000), Byk Gulden ($15,000), AstraZeneca ($10,000), Faron Pharmaceuticals ($5,000), and Cerus Corporation ($11,000). He received honoraria, consulting fees, editorship, royalties, and Data and Safety Monitoring Board membership fees paid to him from Bayer ($500), DHD ($1,000), Eli Lilly ($5,000), Oxford University Press ($10,000), Hospira ($15,000), Cerner ($5,000), Pfizer ($1,000), KCI ($7,500), American Association for Respiratory Care ($10,000), American Thoracic Society ($7,500), BioMed Central ($1,000), National Institutes of Health ($1,500), and the Alberta Heritage Foundation for Medical Research ($250). He has database access or other intellectual (non financial) support from Cerner.

Dr. Webb consulted for AstraZeneca (anti-infectives $1,000−$5,000) and Jansen-Cilag (anti-infectives $1,000-$5,000). He received grant support from a NHMRC project grant (ARISE RECT of EGDT); NHMRC project grant and Fresinius-unrestricted grant (CHEST RCT of voluven vs. saline); RCT of steroid vs. placebo for septic shock); NHMRC project grant (BLISS study of bacteria detection by PRC in septic shock) Intensive Care Foundation-ANZ (BLING pilot RCT of beta-lactam administration by infusion); Hospira (SPICE programme of sedation delirium research); NHMRC Centres for Research Excellent Grant (critical illness microbiology observational studies); Hospira-unrestricted grant (DAHlia RCT of dexmedetomidine for agitated delirium). Travel/accommodations reimbursed by Jansen-Cilag ($5,000–$10,000) and AstraZeneca ($1,000-$5,000); he has a patent for a meningococcal vaccine. He is chair of the ANZICS Clinical Trials Group and is an investigator in trials of EGDT, PCR for determining bacterial load and a steroid in the septic shock trial.

Dr. Beale received compensation for his participation as board member for Eisai, Inc, Applied Physiology, bioMérieux, Covidien, SIRS-Lab, and Novartis; consulting income was paid to his institution from PriceSpective Ltd, Easton Associates (soluble guanylate cyclase activator in acute respiratory distress syndrome/acute lung injury adjunct therapy to supportive care and ventilation strategies), Eisai (eritoran), and Phillips (Respironics); he provided expert testimony for Eli Lilly and Company (paid to his institution); honoraria received (paid to his institution) from Applied Physiology (Applied Physiology PL SAB, Applied Physiology SAB, Brussels, Satellite Symposium at the ISICEM, Brussels), bioMérieux (GeneXpert Focus Group, France), SIRS-Lab (SIRS-LAB SAB Forum, Brussels and SIRS-LAB SAB, Lisbon), Eli Lilly (CHMP Hearing), Eisai (eritoran through leader touch plan in Brussels), Eli Lilly (Lunchtime Symposium, Vienna), Covidien (adult monitoring advisory board meeting, Frankfurt), Covidien (Global Advisory Board CNIBP Boulder USA), Eli Lilly and Company (development of educational presentations including service on speaker’ bureaus (intensive care school hosted in department); travel/accommodations were reimbursed from bioMerieux (GeneXpert Focus Group, France) and LiDCO (Winter Anaesthetic and Critical Care Review Conference), Surviving Sepsis Campaign (Publications Meeting, New York; Care Bundles Conference, Manchester), SSC Publication Committee Meeting and SSC Executive Committee Meeting, Nashville; SSC Meeting, Manchester), Novartis (Advisory Board Meeting, Zurich), Institute of Biomedical Engineering (Hospital of the Future Grand Challenge Kick-Off Meeting, Hospital of the Future Grand Challenge Interviews EPSRC Headquarters, Swindon, Philips (Kick-Off Meeting, Boeblingen, Germany; MET Conference, Cohenhagen), Covidien (Adult Monitoring Advisory Board Meeting, Frankfurt), Eisai (ACCESS Investigators Meeting, Barcelona). His nonfinancial disclosures include authorship of the position statement on fluid resuscitation from the ESICM task force on colloids (yet to be finalized).

Dr. Vincent reports consulting income paid to his institution from Astellas, AstraZeneca, Curacyte, Eli Lilly, Eisai, Ferring, GlaxoSmithKline, Merck, and Pfizer. His institution received honoraria on his behalf from Astellas, AstraZeneca, Curacyte, Eli Lilly, Eisai, Ferring, Merck, and Pfizer. His institution received grant support from Astellas, Curacyte, Eli Lilly, Eisai, Ferring, and Pfizer. His institution received payment for educational presentations from Astellas, AstraZeneca, Curacyte, Eli Lilly, Eisai, Ferring, Merck, and Pfizer.

Dr. Moreno consulted for bioMerieux (expert meeting). He is a coauthor of a paper on corticosteroids in patients with septic shock. He is the author of several manuscripts defining sepsis and stratification of the patient with sepsis. He is also the author of several manuscripts contesting the utility of sepsis bundles.

For additional information regarding this article, contact R.P. Dellinger (Dellinger-Phil@CooperHealth.edu).

© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins