POINT: Should the Surviving Sepsis Campaign Guidelines Be Retired? Yes

      Abbreviations:

      COI (conflict of interest), ESICM (European Society of Intensive Care Medicine), IDSA (Infectious Disease Society of America), IHI (Institute for Healthcare Improvement), ISF (International Sepsis Forum), RCT (randomized controlled trial), SSC (Surviving Sepsis Campaign), SCCM (Society of Critical Care Medicine)
      Concern regarding the Surviving Sepsis Campaign (SSC) guidelines dates to their inception. Guideline development was sponsored by Eli Lilly and Edwards Life Sciences as part of a commercial marketing campaign.
      • Eichacker P.Q.
      • Natanson C.
      • Danner R.L.
      Surviving sepsis - practice guidelines, marketing campaigns and Eli Lilly.
      Throughout its history, the SSC has a track record of making strong recommendations based on weak evidence and being poorly responsive to new evidence.
      • Finfer S.
      The Surviving Sepsis Campaign: robust evaluation and high-quality primary research is still needed.
      • Salluh J.I.
      • Bozza P.T.
      • Bozza F.A.
      Surviving sepsis campaign: a critical reappraisal.
      • Hicks P.
      • Cooper D.J.
      • Webb S.
      • et al.
      The surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. An assessment by the Australian and New Zealand Intensive Care Society.
      The original backbone of the guidelines was a single-center trial by Rivers et al
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      defining a protocol for early goal-directed therapy. Even after key elements of the Rivers protocol were disproven (eg, targeting a central venous oxygen saturation >70%, blood transfusions for hemoglobin >7 g/dL), the SSC continued to recommend them.
      The cornerstone of the SSC guidelines has always been completion of specific bundles of treatment within specific periods; however, it has become increasingly clear that these bundles are not evidence-based. Apart from the timely administration of antibiotics, multiple studies have demonstrated that all the other elements of the 3- and 6-h resuscitation bundle are devoid of supporting scientific evidence and do not positively influence patient outcomes.
      • Finfer S.
      The Surviving Sepsis Campaign: robust evaluation and high-quality primary research is still needed.
      • Salluh J.I.
      • Bozza P.T.
      • Bozza F.A.
      Surviving sepsis campaign: a critical reappraisal.
      • Hicks P.
      • Cooper D.J.
      • Webb S.
      • et al.
      The surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. An assessment by the Australian and New Zealand Intensive Care Society.
      • Barochia A.V.
      • Cui X.
      • Vitberg D.
      • et al.
      Bundled care for septic shock: an analysis of clinical trials.
      • Rhee C.
      • Filbin M.
      • Massaro A.F.
      • et al.
      Compliance with the National SEP-1 quality measure and association with sepsis outcomes: a multicenter retrospective cohort study.
      Indeed, the 30 mL/kg fluid bolus mandate is likely harmful.
      • Andrews B.
      • Semler M.W.
      • Muchemwa L.
      • et al.
      Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension. A randomized clinical trial.
      • Marik P.E.
      • Malbrain M.L.
      The SEP-1 quality mandate may be harmful: how to drown a patient with 30 ml per kg fluid!.
      Measurement of serum lactate within 3 h and repeated measurement after 6 h is the most common reason for noncompliance with the “bundle”
      • Rhee C.
      • Filbin M.
      • Massaro A.F.
      • et al.
      Compliance with the National SEP-1 quality measure and association with sepsis outcomes: a multicenter retrospective cohort study.
      ; yet, it is unproven that measurement of blood lactate will improve patient outcomes.
      • Marik P.E.
      SEP-1: the lactate myth and other fairytales.
      Despite waning evidence to support these bundles, the 2018 SSC guidelines have doubled down, by combining the 3- and 6- h bundles into a single 1-h bundle (Table 1).
      • Levy M.M.
      • Evans L.E.
      • Rhodes A.
      The Surviving Sepsis Campaign Bundle: 2018 update.
      This would require obtaining blood cultures, administering antibiotics, initiating 30 mL/kg fluid, and initiating vasopressors for ongoing hypotension: all within an hour of triage. This major policy shift has been made despite the lack of any prospective evidence that supports it.
      Table 1Bundle Elements With Strength of Recommendations
      Reprinted with permission from Levy et al.
      • Levy M.M.
      • Evans L.E.
      • Rhodes A.
      The Surviving Sepsis Campaign Bundle: 2018 update.
      Bundle ElementGrade of Recommendation and Level of Evidence
      Measure lactate level. Remeasure if initial lactate >2 mmol/LWeak recommendation; low-quality evidence
      Obtain blood cultures before administration of antibioticsBest practice statement
      Administer broad-spectrum antibioticsStrong recommendation, moderate quality of evidence
      Rapidly administer 30ml/kg crystalloid for hypotension or lactate ≥4 mmol/LStrong recommendation, low quality of evidence
      Apply vasopressors if patient is hypotensiveStrong recommendation, moderate quality of during or after fluid resuscitation to maintain evidence
      Mean arterial pressure ≥65 mm Hg
      Well-intentioned policies may inadvertently cause harm. One example of this is the 2002 Centers for Medicare & Medicaid Services’ quality measure mandating that all patients admitted for pneumonia must receive blood cultures and antibiotics within 4 h of ED triage.
      • Schuur J.D.
      • Hsia R.Y.
      • Burstin H.
      • et al.
      Quality measurement in the emergency department: past and future.
      As with the 2018 SSC guidelines, this initiative was based on retrospective data correlating rapid treatment with better outcomes. Pressure to comply with this metric caused harm by promoting premature diagnoses and the liberal use of antibiotics. Eventually, it was recognized that forcing ED to work faster actually worsened patient care, prompting the removal of the 4-h mandate.
      Compared with the 4-h pneumonia mandate, a 1-h sepsis mandate would cause much greater harm. Achieving the 3-h treatment bundle is challenging enough for most EDs.
      • Deis A.S.
      • Whiles B.B.
      • Brown A.R.
      • et al.
      Three-hour bundle compliance and outcomes in patients with undiagnosed severe sepsis.
      Complying with a 1-h bundle would require diagnosing any ill patient with possible infection as septic, which would immediately trigger fluid and antibiotic administration.
      • Venkatesh A.K.
      • Slesinger T.
      • Whittle J.
      • et al.
      Preliminary performance on the new CMS Sepsis-1 National Quality Measure: early insights from the Emergency Quality Network (E-QUAL).
      Such issues with overdiagnosis have previously been documented, even with less demanding sepsis protocols.
      • Durston W.
      Does adoption of a regional sepsis protocol reduce mortality?.
      For example, this would expose many nonseptic patients to iatrogenic volume overload, the risk of Clostridium difficile infection, and promote bacterial resistance. The Infectious Disease Society of America (IDSA) chose not to endorse the 2016 guidelines largely because of concerns regarding excessive antibiotic use and overly rigid timelines for antibiotic initiation: problems that would be dramatically exacerbated by the new 2018 guidelines.
      Infectious Disease Society of America (IDSA)
      Position Statement: why IDSA did not endorse the Surviving Sepsis Campaign Guidelines.
      Additional collateral damage would potentially result from attention being diverted from other patients in the ED with high-acuity illness of noninfectious etiology.
      The SSC has long assumed that protocolized care is superior to individualized treatment guided by the bedside clinician. This hypothesis has its roots in the original trial of Early Goal-Directed Therapy by Rivers et al.
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      This protocol has subsequently been shown to be no better than usual care in three large randomized controlled studies.
      Early, goal-directed therapy for septic shock- a patient-level meta-analysis.
      Although guidelines should summarize evidence and provide evidence-based recommendations, the SSC recommends prescribing a rigid set of bundles that mandate specific interventions within fixed time frames
      • Rhodes A.
      • Evans L.
      • Alhazzani W.
      • et al.
      Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2016.
      ; these recommendations are mostly unsupported by evidence. Nonetheless, they have been adopted by the Centers for Medicare & Medicaid Services as a core quality measure (Severe Sepsis/Septic Shock Early Management Bundle). This pressures physicians to administer treatments despite their best medical judgment. It is noteworthy that in response to the publication of the 2016 SSC guidelines, Timothy Buchman and Elie Azoulay, the Editors of Critical Care Medicine and Intensive Care Medicine, respectively, stated that “As clinicians, we are bound to deviate from guidelines when such deviation is reasonably expected to improve an individual patient outcome… We therefore caution against any quality metric or reimbursement policy that mandates slavish adherence to a particular recommendation.”
      • Buchman T.G.
      • Azoulay E.
      Practice guidelines as implementation science: the Journal Editors' perspective.
      This statement is clearly at odds with the stated goals of the 2016 and 2018 SSC guidelines.
      • Levy M.M.
      • Evans L.E.
      • Rhodes A.
      The Surviving Sepsis Campaign Bundle: 2018 update.
      • Rhodes A.
      • Evans L.
      • Alhazzani W.
      • et al.
      Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2016.
      For example, these guidelines slavishly mandate a fluid bolus to all patients with sepsis-induced hypotension or a lactate >4 mmol/L regardless of the patients clinical status.
      • Levy M.M.
      • Evans L.E.
      • Rhodes A.
      The Surviving Sepsis Campaign Bundle: 2018 update.
      • Rhodes A.
      • Evans L.
      • Alhazzani W.
      • et al.
      Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2016.
      Indeed, the 2016 SSC guidelines advocate that patients with pneumonia or acute lung injury be intubated specifically so that they can receive the 30 mL/kg fluid bolus.
      • Dellinger R.P.
      • Schorr C.A.
      • Levy M.M.
      A users guide to the 2016 Surviving Sepsis Guidelines.
      Early antibiotic therapy is sensible; however, a recent randomized controlled trial of prehospital administration of antibiotics did not demonstrate an improvement in patient outcomes with the earlier administration of antibiotics.
      • Alam N.
      • Oskam E.
      • Stassen P.M.
      • et al.
      Prehospital antibiotics in the ambulance for sepsis: a multicentre, opn label, randomised trial.
      We therefore do not agree with mandating antibiotic initiation within an hour of triage, because in most instances this is unlikely to improve patient outcomes, and in many instances this may be logistically impossible. Instead, we endorse the concept as expressed by the IDSA that “each antibiotic ordered should be initiated promptly, with health care systems working to reduce that time to as short a duration as feasible.”
      Infectious Disease Society of America (IDSA)
      Position Statement: why IDSA did not endorse the Surviving Sepsis Campaign Guidelines.
      Remarkably, the authors of the 2016 SSC guidelines have stated that the…recommendation for antibiotic administration within an hour of diagnosis of sepsis is a lofty goal of care… Despite the best intentions of the healthcare team, antibiotic administration within one hour from time of diagnosis may be difficult due to the complexity of the hospital environment and essential care being delivered to other patients during the same time period by the same healthcare practitioners and health system.
      • Dellinger R.P.
      • Schorr C.A.
      • Levy M.M.
      A users guide to the 2016 Surviving Sepsis Guidelines.
      This statement undermines the very core of the 2018 SSC guideline that requires that antibiotics be administered within an hour of triage.
      • Levy M.M.
      • Evans L.E.
      • Rhodes A.
      The Surviving Sepsis Campaign Bundle: 2018 update.
      We have waited patiently for years in hope that the guidelines would improve, but they have not. The 2018 SSC update appears to have deviated from evidence-based medicine more than the 2016 version. These recommendations will likely cause hasty management decisions, inappropriate fluid administration, and indiscriminate use of broad-spectrum antibiotics, which are impediments to providing the best possible care to our septic patients. We believe therefore that the SSC guidelines should be retired. In its place, we suggest that trustworthy evidence-based sepsis guidelines be developed and based upon high-quality systematic reviews conducted by a global group of stakeholder societies.

      Acknowledgments

      *Collaborating authors: Scott Aberegg, MD, MPH, University of Utah, UT; Jennifer Beck-Esmay, MD, Mount Sinai Saint Luke’s-West; Steven Carroll, DO, MEd, Emory University School of Medicine, GA; Jon-Emile Kenny, MD; Alex Koyfman, MD, FACEP, FAAEM, UT Southwestern Medical Center, TX; Michelle Lin, MD, University of California, CA; Brit Long, MD, Brooke Army Medical Center, TX; Manu Malbrain, MD, PhD, Brussels University Hospital (UZB), Belgium; Justin Morgenstern, MD, University of Toronto, Canada; Segun Olusanya, MD, St Bartholomew’s Hospital, UK; Salim Rezaie, MD, Greater San Antonio Emergency Physicians, TX; Philippe Rola, MD, Montreal Canada; Manpreet Singh, MD, Harbor-UCLA Medical Center, CA; Reuben Strayer, MD, Anand Swaminathan, MD; and Adam Thomas, MD, FRCPC, University of British Columbia, Canada.

      Supplementary Data

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