Surviving Sepsis Campaign

It was the turn of the millennium. For most, sepsis was an obscure entity of importance only to intensivists, clinical academics, and basic science investigators. The molecular biology was beginning to be unraveled and industry was increasingly hopeful that sepsis might be treated with innovative biologic therapies. Consensus definitions had been created a decade earlier but had received little attention outside of clinical trialists.

Then, in short order, came a series of randomized controlled trials (RCTs) supporting successful treatment of sepsis with protocolized early resuscitation, anticoagulant therapy, and steroids (^1–3). This caught the attention of the frontline clinical community caring for sepsis patients as signaled by the intense interest in these trial results at scientific meetings. The stage was now set for engaging these enthused clinicians as to how sepsis might be diagnosed sooner and treated more effectively to improve outcomes. Sepsis outcomes based on analysis of control group clinical trial data were at this time disappointing (^1–3).

THE ORIGINS OF THE SURVIVING SEPSIS CAMPAIGN

The Surviving Sepsis Campaign (SSC) was introduced at the 2002 European Society of Intensive Care Medicine (ESICM) annual meeting in Barcelona with the “Barcelona Declaration” (⁴). Mitchell Levy, Phil Dellinger, and Graham Ramsay presented the concept to the leadership of three professional organizations (the ESICM, the Society of Critical Care Medicine [SCCM], and the International Sepsis Forum [ISF]). The SSC was initially administered by these three organizations. The “Barcelona Declaration” committed the three organizations to strive to reduce mortality of sepsis by 25% within 5 years by improving recognition and treatment. In addition, the “Barcelona Declaration” urged governments and healthcare providers to recognize the growing burden of sepsis and to commit to providing adequate resources to combat it. A 5-point action plan was developed:

• Diagnosis—Facilitate early and accurate diagnosis through the adoption of one, single, clear definition of sepsis.
• Treatment—Ensure appropriate and timely use of treatments and interventions via consistent clinical protocols.
• Referral—Recognize universally acceptable referral guidelines in all countries of the world.
• Education—Provide leadership, support, and information to clinicians about sepsis management.
• Counseling—Provide a framework for improving and accelerating access to continuing post-ICU care and counseling for patients.

The plan was for the SSC to be rolled out in three phases: 1) The initial declaration and commitment; 2) The development of evidence-based guidelines for sepsis management; and 3) A performance improvement initiative (on a global scale) to implement the guidelines and reduce sepsis mortality.

DEVELOPMENT AND EVOLUTION OF THE GUIDELINES OVER THE YEARS

The first set of SSC guidelines was published in 2004 (⁵). Since then, updates have been published on a roughly 4-year cycle (2008, 2012, 2016, and 2021) (^6–9) (Fig. 1). Each edition has seen an evolution of the methodology for the data analysis and an evolution in the clinical guidance for optimal management. The field of sepsis management was evolving quickly and the SSC was a major driver in identifying problems and promoting advances. In consideration of the worldwide impact of the COVID-19 pandemic leading to hospitals and ICUs filled with critically ill COVID-19 patients, the SSC published separate guidelines on management of the critically ill COVID patient (¹⁰).

Figure 1.: Surviving Sepsis Campaign (SSC) guidelines publication timeline and metrics. Guideline mastheads are displayed from original 2004 publication through the 2021 revision. The timeline displays and contrasts page numbers and numbers of references. To the left is the original SSC logo (2004 and 2008 editions) and the revised logo (2012 and forward).

Innovative and dedicated leadership has been key to the success of the SSC. A broad coalition of sponsoring organizations has been built over the years, beginning with 11 in 2004 and with 21 in 2021 (Table 1).

TABLE 1. - Organizations Endorsing the 2021 Surviving Sepsis Guidelines

Society of Critical Care Medicine

European Society of Intensive Care Medicine

American Association of Critical Care Nurses

American College of Chest Physicians

American College of Emergency Physicians

American Thoracic Society

African Sepsis Alliance

Asia and Pacific Sepsis Alliance

Association De Medicina Intensiva Brasileira

Australian and New Zealand Intensive Care Society

Canadian Critical Care Society

Chinese Society of Critical Care Medicine

European Respiratory Society

European Society of Clinical Microbiology and Infectious Diseases

Indian Society of Critical Care Medicine

Infectious Diseases Society of North America

Japanese Society of Intensive Care Medicine

Latin American Sepsis Institute

Society for Academic Emergency Medicine

Scandinavian Critical Care Trials Group

Key areas where the guidelines have evolved include funding streams, the management of potential conflicts of interest (COI), the evidence-based methodology, ensuring adequate panel diversity, authorship issues, and the decision that the guidelines need to be relevant to the entire world including children. In addition, the last two sets of guidelines have introduced the public/patient voice into the process to ensure that they are relevant for our patients, who may receive care directed by them.

CONFLICTS OF INTEREST

From the outset, the guidelines’ leadership recognized the importance of potential COI. At no point has the panel had any members from industry and industry has had no input into the guidelines development process. In addition, no member of the guidelines panel has received any reimbursement or honoraria for their work in relation to these activities. All panelists complete a COI declaration, which has been actively managed, either through the guideline’s leadership group or, since 2012, through an independent panel made up of very senior past officers of ESICM and SCCM. In recent iterations, there has been additional focus directed toward academic (nonfinancial) COI. Based on COI, guideline panelists have been asked either to abstain from voting on recommendations with potential conflict or in certain circumstances asked not to participate in the evidence synthesis process.

PANEL SELECTION/DIVERSITY

Since 2012, there has been greater recognition that the panel needs to adequately represent the populations of healthcare patients and providers it serves with greater race and gender balance as well as national, geographical, and income-setting representation. The process has matured but remains a work in progress. For example, the number of women on the guidelines committee over the five renditions of the guidelines (2004, 2008, 2012, 2016, and 2021) are 4 (10%), 5 (9%), 13 (19%), 11 (19%), and 17 (28%). Another example is geographical representation outside of North America and Europe which has progressed over the five renditions of the guidelines: 2 (5%), 5 (9%), 11 (16%), 10 (17%), and 15 (25%). In addition, with the last two iterations, a target was established of at least 33% panel turnover from the previous version. It was felt that this would adequately maintain the organizational memory of the process while allowing new thinking to emerge that did not leave the product stale and old.

AUTHORSHIP

While initial versions of the guideline (2004–2008) had a mast head author writing committee that drafted the article for subsequent sign-off by the entire committee, since 2012, all panelists have been asked to sign the paper as a named author. This gave greater transparency over who and what was behind the development processes and gave authors more sense of responsibility for the content of the entire document.

PEDIATRICS

From the beginning of the development of the SSC guidelines, it was recognized that children should be considered separately from adults. The first guidelines, in 2004, as well as the updates in 2008 and 2012, included a section called “Pediatric Considerations” pointing out important differences between children and adults. The critical care community, however, recognized the limitations of this approach, and the SSC leadership formed a task force with broad international representation to develop SSC guidelines for children, first co-published in Pediatric Critical Care Medicine and Intensive Care Medicine in 2020 (¹¹).

LOW- AND MIDDLE-INCOME COUNTRIES

Recent versions of the guideline have put more focus on optimizing recommendations relevancy for different parts of the world. This goal was facilitated by ensuring that low- and middle-income country (LMIC) settings are represented in each working group of the panel. The SSC guidelines have several recommendations as to therapies or tools that should not be used, which is relevant to set priorities in resource-limited settings. Other recommendations highly relevant for LMICs include the prompt administration of antibiotics with adequate dosage and de-escalation strategies. However, recommendations for lower-income countries remain challenging due to scant LMIC-specific data. Limited resources for organ support may also bear on optimal therapy, for example, aggressiveness of fluid resuscitation. The work of the SSC Sepsis in Resource-Limited Nations Workgroup includes publication of a before and after feasibility trial of increasing evidence based interventions in LMIC (¹²).

EVOLUTION OF SSC GUIDELINE METHODOLOGY

A trustworthy guideline results from rigorous methodology that minimizes personal biases, allows transparent assessment of the total body of evidence, and incorporates all essential variables to formulate recommendations.

The first iteration of the SSC guideline was completed before significant advancement in guideline development methodology. The panel used an evaluation system developed by Sackett (¹³), classifying evidence according to study design and precision (grades A, B, and C). During that period, most guideline developers used a modified Delphi process to formulate recommendations. Guideline development methodology at that time lacked a systematic summary of the evidence, comprehensive assessment of the quality of evidence, a structured framework to transition from evidence to recommendation, and did not assign strength to recommendations. From 2008, the SSC guideline structured the questions in the Population, Intervention, Control, and Outcome (PICO) format, which provided explicit criteria for study selection and allowed judgment of the quality of the evidence at an outcome level (⁶).

As the methodology of guideline development evolved, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach emerged as a comprehensive, rigorous, and transparent methodology (¹⁴). Therefore, the SSC leadership adopted the GRADE approach with GRADE experts represented on the guidelines committee and charged to guide the methodology of the process. Unlike traditional approaches, the GRADE approach allowed assessment of the quality of evidence considering crucial factors that went beyond basic study design, such as inconsistency, indirectness, imprecision, and publication bias. In addition, it allowed the panel to develop recommendations considering not only quality of evidence but also balance of benefit and harm, patients’ values, cost, equity, and feasibility. The panel assigned a strength (strong vs weak) to each recommendation which reflected the confidence in the overall balance between desirable and undesirable consequences.

In 2016, best practice statements were included in the guidelines. Best practice statements are recommendations the committee feels are important but not amenable for formal recommendations because the evidence is difficult to summarize or assess using GRADE methodology. These recommendations represent ungraded strong recommendations that are typically used when the benefit or harm is unequivocal.

In the 2021 guidelines, the structure expanded to include librarians, systematic review experts, methodologists, and public members that collaborated with the panel. Professional medical librarians facilitated the electronic searches tailored to each PICO question. The systematic review team assisted the panel to identify and summarize the relevant evidence. Working with the methodology team, the quality of evidence was assessed and the evidence-to-decision framework was used to support the panel in formulating recommendations (¹⁵). Public members provided input on patients’ values and preferences.

Table 2 shows the evolution of methodology over the five renditions of the guidelines.

TABLE 2. - Surviving Sepsis Campaign Guideline Methodology

Category	SSC 2004	SSC 2008	SSC 2012	SSC 2016	SSC 2021
Panela	44 members	55 members	68 members	55 members	60 members
Number of recommendations	46 recommendations	78 recommendations	84 recommendations	71 recommendations	75 recommendations
				18 BPS	15 BPS
COI managementb	Financial COIs	Financial COIs	Financial COIs	Financial COIs	Financial and academic COIs
Topic prioritizationc	Panel discussion	Panel discussion	Panel discussion	Panel discussion	Multifaceted approachd
Structured Patient/Problem, Intervention, Comparison, and Outcome questions	No	Yes	Yes	Yes	Yes
Outcome prioritizatione	Not formally done	Not formally done	Not formally done	Not formally done	Yes
Search strategyf	Panel members	Panel members	Panel members	A professional medical librarian with input from panel	A team of professional medical librarians with input from panel
Source of evidenceg	Medline database	Medline database	At least one electronic database	At least two electronic databases	At least two electronic databases
Assessment of the quality of evidenceh	Approach by Sackett (13)	GRADE approach	GRADE approach	GRADE approach	GRADE approach
Involvement of patients	No	No	No	No	11 public members were involvedi
Formulating recommendation	Modified Delphi approach	GRADE approach	GRADE approach	GRADE approach	GRADE approach and evidence to decision frameworkj
Types of recommendations and statements	Recommendations with no distinction of strength	Level 1k	Level 1k	Strong recommendation	Strong recommendation
		Level 2	Level 2	Weak recommendation	Weak recommendation
			Ungraded statements	BPSl	BPSl
Implications of  recommendationsm	No	Yes	Yes	Yes	Yes

BPS = best practice statement, COI = conflicts of interest, GRADE = Grading of Recommendations, Assessment, Development, and Evaluation, SSC = Surviving Sepsis Campaign.

^aThe total number of panel members that participated in the guideline.

^bTypes of COI that were adjudicated and managed in each guideline.

^cUsing a systematic approach to select topics of high priority to address in the guideline.

^dUsing a framework based on practice variability (based on surveying 800 intensivists globally), awareness of new evidence, and panel ranking.

^eUsing a systematic approach to identify outcomes that are relevant most to patients for each recommendation.

^fThis category outlines who performed the electronic literature searches for relevant evidence.

^gElectronic databases that were searched for relevant studies.

^hAlso known as confidence or certainty in the evidence.

ⁱPublic members provided input on outcomes importance, patients’ values, and reviewed the final list of recommendations especially for the long-term outcomes subgroup.

^jEvidence to decision framework asks the panel to consider the following factors when formulating the recommendation: priority of topic, magnitude of benefit and harm, balance of effect, patent values, cost and resources, acceptability, and feasibility.

^kLevel 1 recommendation corresponds to a strong recommendation, while level 2 corresponds to a weak recommendation.

^lAll BPSs followed strict criteria, a BPS is an ungraded strong recommendation.

^mThis step involves clearly stating the implications of recommendations for stakeholders including patients, healthcare providers, and policymakers.

EVOLUTION OF SPECIFIC GUIDELINE RECOMMENDATIONS OVER THE YEARS

High-quality studies, adequately designed and powered to assess patient-centered outcomes, have facilitated updates of guidelines’ recommendations over time. Earlier editions of the guidelines included recommendations supported by publications reporting positive results with the testing of promising science-based interventions in sepsis (^1,2). Progress, however, is often not linear. Confirmatory trials are needed and these confirmatory trials, even when they are negative, still move the field forward.

The first study published (2001) that appeared to show a significant impact of a specific treatment of sepsis was that of “early goal-directed therapy (EGDT),” which supported resuscitation of sepsis-induced tissue hypoperfusion targeting first central venous pressure (CVP) and then superior vena cava oxygen saturation (Scvo₂) measured with catheter insertion into the superior vena cava (¹). The 2004, 2008, and 2012 SSC guidelines recommended these two EGDT targets. However, after three multicenter and multinational studies failed to confirm improved outcomes with CVP and Scvo₂ targets, the 2016 guidelines no longer recommended them (^16–18). Nonetheless, SSC maintained the principles of early resuscitation with clear statements that sepsis and septic shock are medical emergencies and individualized resuscitation targets remain important.

Similarly, recommendations for choice of resuscitation fluids have changed throughout the years. In 2004, results of a meta-analysis in general critically ill patients supported a weak recommendation to use either crystalloids or colloids as first-line fluids for sepsis resuscitation (¹⁹). Subsequent large RCTs demonstrated worse outcomes with artificial starch colloids (^20–23). In 2012, the SSC guidelines recommended the use of crystalloids as first-line fluids and recommended against the use of starches (²⁴). Albumin was recommended in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. The 2016 guidelines supported either balanced solutions or saline for crystalloid resuscitation. This recommendation was revisited in 2021 based on the Saline against Lactated Ringer’s or Plasma-Lyte and Isotonic Solutions and Major Adverse Renal Events Trial trials and modified to preferential use of balanced crystalloid solutions (^25,26).

Following publication of the 2021 guidelines, two large randomized trials and a meta-analysis comparing normal saline and balanced crystalloids were published (^27–29). The subgroup of septic patients in the meta-analysis including these two new studies was reported to have an estimated effect on mortality using balanced crystalloids that ranged from a 14% relative reduction to a 1% relative increase in mortality. This new evidence should be taken into consideration in the next interaction of the SSC guidelines.

After a single study showed a large reduction in mortality with the use of low dose (200 mg/d) IV hydrocortisone, the 2004 SSC guideline issued a recommendation to use corticosteroids in patients with septic shock (³). However, a subsequent study in septic patients with less severe shock failed to show improved outcome and the 2008 guidelines suggested corticosteroids be given only to adults with septic shock after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy (³⁰). The wording of the recommendation changed subtly in 2012 and 2016 to suggest against IV hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy were able to restore hemodynamic stability. Two major RCTs published in 2018, Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock and Activated Protein C and Corticosteroids for Human Septic Shock, led to a weak recommendation in the 2021 guidelines in favor of corticosteroids in patients with ongoing shock following fluid resuscitation. The committee follows this recommendation with a remark that supports a specific threshold vasopressor dose for triggering administration, with steroids commenced when the dose of norepinephrine or epinephrine is greater than or equal to 0.25 µg/kg/min at least 4 hours after vasopressor initiation (^31,32). Using steroids as an example, the timeline depicted in Figure 2 gives a sense of how clinical trial results of corticosteroids in septic shock influenced guidelines recommendations between 2002 and 2021.

Figure 2.: Timeline of interaction of clinical trial results of corticosteroids in septic shock on guidelines recommendations between 2002 and 2021. 1 - 2004 Surviving Sepsis Campaign (SSC) - recommends IV hydrocortisone for septic shock. 2 - 2008 SSC suggests IV hydrocortisone only when blood pressure is poorly responsive to fluids and vasopressors. 3 - 2012, 2016 SSC suggests against IV hydrocortisone if fluids and vasopressors restore hemodynamic stability. 4 - 2021 SSC suggests IV hydrocortisone use with ongoing requirement for higher vasopressor therapy. ADRENAL = Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock, APROCCHSS = Activated Protein C and Corticosteroids for Human Septic Shock, JAMA = Journal American Medical Association, NEJM = New England Journal of Medicine.

SURVIVING SEPSIS CAMPAIGN GUIDELINES INFLUENCE

Five sets of SSC guidelines were published in the journals Critical Care Medicine and Intensive Care Medicine, totaling 10 source publications. In Scopus, the guidelines have been cited 21,158 times in over 7,000 publications, 25 non-English languages, representing authors from over 125 countries.

The influence of the SSC guidelines on sepsis thinking is demonstrated through two Scopus citation metrics: the Field Weighted Citation Impact (FWCI) and the Citation Benchmark. The FWCI demonstrates how well cited a publication is compared with similar publications. A FWCI greater than 1.00 signifies greater citations than expected according to the average. A FWCI of 1.48 means 48% more citations accrued than expected.

The SSC guideline publication FWCI ranged from 19 to 186.51 (Table 3). The Citation Benchmark demonstrates how citations compare with the average for similar publications. Every SSC published guideline since the inaugural publication in 2004 is in the 99th percentile indicating all SSC guidelines ranked in the top 1% globally for the number of generated citations.

TABLE 3. - Surviving Sepsis Campaign Guideline Publication Impact by Scopus and Year

Guidelines Year	Journal Title	Publication Date	Metric Dates	Citations (n)	Field Weighted Citation Index	Citation Benchmark Percentile
2004	CCM	2004	2004–2019	2,562	72.93	99th
2004	ICM	2004	2004–2019	671	19	99th
2008	CCM	2008	2008–2022	3,909	119	99th
2008	ICM	2008	2008–2022	1,358	37.62	99th
2012	CCM	2013	2012–2022	4,327	186.51	99th
2012	ICM	2013	2012–2022	3,172	120.03	99th
2016	CCM	2017	2016–2022	1,755	71.31	99th
2016	ICM	2017	2016–2022	3,214	181.2	99th
2020a	CCM	2020	2020–2022	430	51.63	99th
2020a	ICM	2020	2020–2022	980	119.87	99th
2021	CCM	2021	2021–2022	75	30.27	99th
2021	ICM	2021	2021–2022	115	45.19	99th

CCM = Critical Care Medicine, ICM = Intensive Care Medicine.

^aSurviving Sepsis Campaign COVID Guidelines.

Guidelines year is the year during which work was completed. Publication year is the year the document was published. Scopus allows for 15 yr of continuous data from publication date. Field Weighted Citation Impact demonstrates how well cited an article is compared with like publications. It considers the year of publication, document type, and disciplines associated with its source. It is the ratio of the publication’s citations to the average number of citations received by all similar publications over a 3-yr window. An FWCI > 1 means the output is more cited than expected according to the global average (Field Weighted Citation Impact of 1.48 mean 48% more cited than expected). The Citation Benchmark demonstrates how citations received by a publication compare with the average for similar publications in an 18-mo window. It accounts for the publication year, document type, and source disciplines. The 99th percentile is high and indicates a publication is in the top 1% globally for the number of citations. Scopus access date: June 5, 2022.

The Altmetric Attention Score indicates the amount of attention the work received through additional outlets such as news, blogs, and social media. All SSC guidelines publications scored in the top 5% of all research outputs ever tracked by Altmetric. When comparing articles of a similar publication period, the SSC guidelines ranked higher than 97% to 99% of its contemporaries (Table 4). Additional impact is demonstrated through several domains including related nursing publications (^33,34) and a nursing complement to the SSC guidelines, which ranked in the 85th percentile for citations compared with like articles in Scopus with a FWCI of 1.82 (³⁴).

TABLE 4. - Surviving Sepsis Campaign Guideline Publication Impact by Altmetric Attention Score and Year

Guidelines Year	Journal Title	Publication Date	Altmetrics: Attention Score	Altmetrics Attention Score: Percentile of All Research Outputs Ever Tracked by Altmetric	Altmetrics High Attention Score: Percentile Compared With Articles of Similar Age
2004	CCM	2004	37	96	97
2004	ICM	2004	ND	ND	ND
2008	CCM	2008	47	96	98
2008	ICM	2008	38	96	97
2012	CCM	2013	120	98	99
2012	ICM	2013	62	97	98
2016	CCM	2017	381	99	99
2016	ICM	2017	694	66	99
2020a	CCM	2020	456	99	99
2020a	ICM	2020	591	99	99
2021	CCM	2021	638	99	99
2021	ICM	2021	1,284	99	99

CCM = Critical Care Medicine, ICM = Intensive Care Medicine, ND = no data.

^aSurviving Sepsis Campaign COVID Guidelines.

Guidelines year is the year during which work was completed. Publication year is the year the document was published. The Altmetric Attention Score functions as an indicator of the amount of attention the work received through additional outlets such as news, blogs, and social media. All the Surviving Sepsis Campaign (SSC) guidelines publications scored in the top 5% of all research outputs ever tracked by Altmetric. When comparing articles of a similar publication period, the SSC guidelines ranked higher than 97% to 99% of its contemporaries. Altmetric data accessed from source journals, access date: June 5, 2022.

SSC PERFORMANCE IMPROVEMENT PROGRAM

After publication of the 2004 guidelines, the SSC set about creating an international quality improvement program that would facilitate hospitals in implementing evidence-based interventions. The SSC approached the Institute for Healthcare Improvement (IHI) (Boston, MA) to collaborate on designing this approach (³⁵). The IHI had been pioneering the use of “bundle technology,” groupings of evidence-based interventions in disease management that when performed reliably have been shown to improve outcomes (³⁶) in management of other diseases. The key to bundles is two-fold: first that bundle elements should be easy to measure and second, that elements should be linked in time. Working with IHI’s critical care leaders, the 6- and 24-hour sepsis bundles, based on the new guidelines, were developed.

Other improvement strategies gleaned from IHI included the importance of measuring the change in clinical care that is associated with bundle implementation—“How do you know if the changes you are making are leading to improvement?” (³⁷) and developing collaborative communities who learn from each other as they improve care (³⁷). Novel at the time, the SSC commissioned the design of a database with a graphic user interface to screen patients, collect data, provide results of that data to bedside practitioners and produce improvement reports that demonstrated progress over time. The local version of the database, installed at hospitals worldwide, captured patient-level information related to sepsis bundle interventions and transmitted data back to a master database at the SCCM. To encourage site participation, a downloadable version of the database translated into seven languages was deployed in 2006.

Between 2005 and 2012, the SSC conducted a number of learning collaboratives with global reach. In the United States, individual collaboratives were sponsored on the East Coast, Midwest, and West Coast comprising 59 hospitals. Similarly, successful sepsis performance improvement collaboratives were also conducted in other countries including England, Spain, and Brazil (^38–40). These efforts, plus SSC list serve and website promotion, were sufficient to catalyze substantial participation in the SSC performance improvement campaign. In 2010, analyzing 15,022 patients’ data from 165 sites worldwide, Levy et al (⁴¹) reported that the adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 years (95% CI, 2.5–8.4 yr). By 2015, data from 29,470 patients were available for analysis demonstrating that each 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality (⁴²).

As the evidence base supporting sepsis interventions evolved, the SSC revised the sepsis bundles to reflect changes in guidelines, recommendations and contemporary practice. Following studies challenging the efficacy of tight glucose control in the medical ICU, administration of hydrocortisone for shock and use of recombinant activated protein C, the 6- and 24-hour bundles were replaced with the 3- and 6-hour bundle in 2012 (^30,43,44). With these changes, the SSC conducted the International Multicentre Prevalence Study on Sepsis, studying data from 1,794 patients and 62 countries and finding that although compliance with all of the evidence-based bundle metrics was not high (19% and 36% for 3- and 6-hr elements, respectively), patients whose care included compliance with all of the metrics had a 40% reduction in the odds of dying in-hospital with the 3-hour bundle and 36% for the 6-hour bundle (⁴⁵). Subsequent bundle approaches included removal of EGDT elements from the 6-hour bundle (⁴⁶) and creation of the “Hour-1 Bundle,” intended to encourage initiation (but not necessarily completion) of essential therapies in the first hour after recognition of sepsis (⁴⁷).

In the United States, the adoption of sepsis bundle approaches spread beyond the Campaign itself. In 2008, Henry Ford Hospital (Detroit, MI) first developed a sepsis bundle strategy based on the SSC’s bundles endorsed by the National Quality Forum (NQF) as a sepsis quality measure. By 2012, this measure would evolve to include EGDT and was again endorsed by NQF. However, with publication of studies demonstrating noninferiority of usual care compared with EGDT (recognizing that usual care had likely changed significantly over the 15 yr between the Rivers EGDT trial and the more recent trials) (⁴⁶), the EGDT approach was removed from the measure after a review requested by the American College of Emergency Physicians. The measure was then re-endorsed by NQF with the addition of a requirement for a clinician’s documentation of reassessment of perfusion. In 2013, the New York State Department of Health and Human Services required all hospitals to report adherence to and outcomes associated with evidence-informed sepsis protocols (⁴⁸), utilizing the 3- and 6-hour bundles. In 2015, the Centers for Medicare and Medicaid Services (CMS) adopted the measure as “SEP-1” (Centers for Medicare and Medicaid Services first hospital sepsis performance metric) in the United States.

The New York State initiative, sometimes called Rory’s Regulations (influenced by the Rory Staunton Foundation’s patient advocacy after the tragic septic death of Rory Staunton at age 12), was associated with substantial improvements in mortality in patients among whom a sepsis protocol was initiated. As compliance with protocols increased from April 1, 2014, to June 30, 2016, risk-adjusted mortality decreased from 28.8% to 24.4% (p < 0.001) (⁴⁹). The initiative also crystalized the association between time to treatment and mortality (⁵⁰). The New York State results were robust when compared with other states that did not implement sepsis protocols (⁵¹). Similarly, a report on SEP-1 outcomes analyzing patient-level data reported to Medicare by 3,241 hospitals from October 1, 2015, to March 31, 2017, found compliance was associated with a reduction in 30-day mortality (21.81% vs 27.48%), yielding an absolute risk reduction of 5.67% (95% CI, 5.33–6.00; p < 0.001) (⁵²).

SSC—CONTROVERSIES

The SSC has been both controversial and politically charged from the outset, tackling a problem of such magnitude, with the goal of a hard mortality reduction target. The original bundles contained elements that were not then part of routine practice and, therefore, often required considerable local change to be achieved. The specific time windows and the all-or-nothing bundle scoring methodology, made this more challenging, but, consistent with the IHI approach to bundles, were thought essential to drive improvement and resourcing for the frontline clinicians with whom the SSC resonated. Some disagreed with specific elements and disliked the prescriptive methodology, perceiving it as a challenge to physician expertise and autonomy, and the SSC became a focus for their opprobrium (⁵³).

Although unrestricted, the industry funding that supported the initial years of the SSC (with the majority coming from Eli Lilly and Co and lesser amounts from Baxter and Edwards) became a focus for criticism, reaching an apotheosis when Eichacker et al (⁵⁴) in the New England Journal of Medicine opined the whole enterprise gave the appearance of a Lilly-funded marketing exercise. Despite the safeguards that had been put in place to isolate industry funding from decisions on recommendations and carefully scrutinize for COI, these criticisms emphasized the need to put the SSC’s funding, governance, and COI management beyond reproach. Based on these criticisms, a decision was made by the administering organizations to no longer accept industry funding. Funding was transitioned to the administering professional societies and a series of grants from the Gordon and Betty Moore Foundation. In the spirit of this decision, the ISF (which receives industry funding) stepped away from serving as an administering organization. The 2008 guidelines and forward were accomplished without any industry funding.

When the first positive results of bundle use appeared, not as RCTs but as medium to large prospective cohort studies, some still sought to explain them away on the basis that outcomes were improving anyway. Analysis of the effects and timing of individual bundle components led to their distillation into the fundamentals of prompt recognition, testing and treatment (antibiotics, fluids and vasopressors, source control), but with earlier initiation through the 3-hour and 6-hour bundles leading to better outcomes. As the true burden of avoidable deaths and injury became better known and more widely published, powerful patient advocacy groups emerged, such as the Global Sepsis Alliance (led by a collaboration of the Sepsis Alliance, the ISF, the World Federation of Pediatric Intensive and Critical Care Societies, and the World Federation of Societies of Intensive and Critical Care Medicine) and the Rory Staunton Foundation, increasing pressure on health systems to ensure that the basic bundle measures were being delivered reliably. The subsequent imposition in the United States of mandatory sepsis standards, with associated performance metrics, was the consequence, although the perceived loss of physician autonomy and necessary focus on compliance has continued to generate some opposition. More recently introduction of the Hour-1 Bundle promotes the concept that sepsis is an emergency, just like trauma, stroke, and heart attack. Some critics have raised concerns that the push for prompt antibiotic administration is problematic as it relates to antibiotic stewardship. Others have challenged early fluid resuscitation by choosing obvious exceptions where it might be harmful, such as full volume fluid resuscitation in severe congestive heart failure. From the first rendition of the guidelines, it was clearly stated “These recommendations are intended to provide guidance for the clinician caring for a patient with severe sepsis or septic shock, but they are not applicable for all patients. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when he or she is provided with a patient’s unique set of clinical variables.” This was the intuitive implication of the bundles as well. Of note, in recent years, this has been more explicitly outlined and defined by U.S. regulatory for assessment of sepsis metric performance as it relates to achieving metric target with less than 30 mL/kg crystalloid administration when healthcare provider documents that decision based on presence of heart failure and morbid obesity (⁵⁵). In addition, the 2021 guidelines downgraded the strength of the 30 mL/kg initial fluid resuscitation recommendation.

Criticism has been the minority response among stakeholders and the SSC has proven highly successful. Today, the sepsis landscape has changed beyond recognition compared with 20 years ago. Education programs are widespread, “code sepsis” programs are common to many institutions across the globe, and (increasingly automated) systems for recognition, treatment and reporting are embedded in most advanced hospital information systems and are welcomed by patients and staff. Constructive debate designed to generate further improvements is necessary and to be welcomed. However, as a healthcare culture, we recognize the importance of the patient and public voice and the ultimate right of democratic societies to set standards within their healthcare systems following consideration of physician input.

FUTURE OF SSC AND SSC GUIDELINES

Over the past 20 years, the SSC guidelines have evolved. Recommendations changed in response to changing evidence, a separate guideline for sepsis in children was published (¹¹), and panel diversity increased, including more representation from LMICs. To maintain their relevance and impact on patient care, the guidelines must continue to evolve. Shorter, more frequent updates in response to major new evidence, and increasing use of visual presentations of data and recommendations can help accomplish these goals without diminishing the rigor of the process. Using technology from point-of-care access and electronic health record integration can help facilitate the most difficult challenge in guidelines—implementation into bedside practice. In the United States, the SSC performance improvement program and bundles developed through collaboration with the IHI was the base for first the NQF and then the CMS sepsis quality metrics.

To determine priorities for research within the field of sepsis, the SSC established the SSC Research Committee that is explicitly charged with developing a list of research priorities related to sepsis (⁵⁶). This important committee has published articles that delineate research priorities in the areas of: 1) infection and blood purification therapies; 2) administration, epidemiology, scoring, and identification of sepsis; 3) fluid resuscitation and vasopressor therapy in adult patients; 4) coronavirus disease in critical illness; and 5) basic/translational research (^57–61).

Sepsis as a syndrome spans the continuum of care and the range of medical professions and disciplines. Improvement in sepsis care and short- and long-term patient outcomes requires engagement and cooperation across care settings, professions and medical specialties. Accordingly, since the inception of the SSC in 2002, a commitment to cooperation across professional societies has been constant, with more than 25 professional societies participating in and endorsing the adult SSC guidelines. Consensus has not always been easy to achieve, but working toward consensus is essential to improving patient care. As the SSC continues to move forward, we see an inclusive process with the focus always on the patient, with up-to-date recommendations, effective implementation tools, and attention to the gaps in our knowledge as the best route forward to continued improvement in sepsis care. The SSC guidelines have been science based, objective and have followed the data, even if the trajectory has not always been a straight line. There was enormous learning along the way. The SSC will likely be viewed as one of the most successful scientific campaigns of the last 50 years. The overall SSC program was a major factor in bringing sepsis to the forefront of international discussion as an entity that mandates our ongoing attention, resource allocation and continued efforts to optimize disease management.

ACKNOWLEDGMENTS

The authors thank the staff support offered the Surviving Sepsis Campaign (SSC) from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, with special mention of Lori Harmon. As well, they are thankful for the support of Deborah McBride, Deborah Branch, and Elaine Rinicker. Graham Ramsay, MD (now deceased), who through his leadership role as a cofounder, was key in the early success of the SSC.