Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.

BACKGROUND: In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. METHODS: We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. RESULTS: Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). CONCLUSIONS: More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the National Institutes of Health and others.).

Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative.

RATIONALE: In 2013, the New York State Department of Health (NYSDOH) began a mandatory state-wide initiative to improve early recognition and treatment of severe sepsis and septic shock. OBJECTIVES: This study examines protocol initiation, 3-hour and 6-hour sepsis bundle completion, and risk-adjusted hospital mortality among adult patients with severe sepsis and septic shock. METHODS: Cohort analysis included all patients from all 185 hospitals in New York State reported to the NYSDOH from April 1, 2014, to June 30, 2016. A total of 113,380 cases were submitted to NYSDOH, of which 91,357 hospitalizations from 183 hospitals met study inclusion criteria. NYSDOH required all hospitals to submit and follow evidence-informed protocols (including elements of 3-h and 6-h sepsis bundles: lactate measurement, early blood cultures and antibiotic administration, fluids, and vasopressors) for early identification and treatment of severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Compliance with elements of the sepsis bundles and risk-adjusted mortality were studied. Of 91,357 patients, 74,293 (81.3%) had the sepsis protocol initiated. Among these individuals, 3-hour bundle compliance increased from 53.4% to 64.7% during the study period (P < 0.001), whereas among those eligible for the 6-hour bundle (n = 35,307) compliance increased from 23.9% to 30.8% (P < 0.001). Risk-adjusted mortality decreased from 28.8% to 24.4% (P < 0.001) in patients among whom a sepsis protocol was initiated. Greater hospital compliance with 3-hour and 6-hour bundles was associated with shorter length of stay and lower risk and reliability-adjusted mortality. CONCLUSIONS: New York's statewide initiative increased compliance with sepsis-performance measures. Risk-adjusted sepsis mortality decreased during the initiative and was associated with increased hospital-level compliance.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

The New York Sepsis Severity Score: Development of a Risk-Adjusted Severity Model for Sepsis.

OBJECTIVES: In accordance with Rory's Regulations, hospitals across New York State developed and implemented protocols for sepsis recognition and treatment to reduce variations in evidence informed care and preventable mortality. The New York Department of Health sought to develop a risk assessment model for accurate and standardized hospital mortality comparisons of adult septic patients across institutions using case-mix adjustment. DESIGN: Retrospective evaluation of prospectively collected data. PATIENTS: Data from 43,204 severe sepsis and septic shock patients from 179 hospitals across New York State were evaluated. SETTINGS: Prospective data were submitted to a database from January 1, 2015, to December 31, 2015. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Maximum likelihood logistic regression was used to estimate model coefficients used in the New York State risk model. The mortality probability was estimated using a logistic regression model. Variables to be included in the model were determined as part of the model-building process. Interactions between variables were included if they made clinical sense and if their p values were less than 0.05. Model development used a random sample of 90% of available patients and was validated using the remaining 10%. Hosmer-Lemeshow goodness of fit p values were considerably greater than 0.05, suggesting good calibration. Areas under the receiver operator curve in the developmental and validation subsets were 0.770 (95% CI, 0.765-0.775) and 0.773 (95% CI, 0.758-0.787), respectively, indicating good discrimination. Development and validation datasets had similar distributions of estimated mortality probabilities. Mortality increased with rising age, comorbidities, and lactate. CONCLUSIONS: The New York Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination. This sepsis-specific model provides an accurate, comprehensive method for standardized mortality comparison of adult patients with severe sepsis and septic shock.

Reporting of Sepsis Cases for Performance Measurement Versus for Reimbursement in New York State.

OBJECTIVES: Under "Rory's Regulations," New York State Article 28 acute care hospitals were mandated to implement sepsis protocols and report patient-level data. This study sought to determine how well cases reported under state mandate align with discharge records in a statewide administrative database. DESIGN: Observational cohort study. SETTING: First 27 months of mandated sepsis reporting (April 1, 2014, to June 30, 2016). PATIENTS: Hospitalizations with sepsis at New York State Article 28 acute care hospitals. INTERVENTION: Sepsis regulations with mandated reporting. MEASUREMENTS AND MAIN RESULTS: We compared cases reported to the New York State Department of Health Sepsis Clinical Database with discharge records in the Statewide Planning and Research Cooperative System database. We classified discharges as 1) "coded sepsis discharges"-a diagnosis code for severe sepsis or septic shock and 2) "possible sepsis discharges," using Dombrovskiy and Angus criteria. Of 111,816 sepsis cases reported to the New York State Department of Health Sepsis Clinical Database, 105,722 (94.5%) were matched to discharge records in Statewide Planning and Research Cooperative System. The percentage of coded sepsis discharges reported increased from 67.5% in the first quarter to 81.3% in the final quarter of the study period (mean, 77.7%). Accounting for unmatched cases, as many as 82.7% of coded sepsis discharges were potentially reported, whereas at least 17.3% were unreported. Compared with unreported discharges, reported discharges had higher rates of acute organ dysfunction (e.g., cardiovascular dysfunction 63.0% vs 51.8%; p < 0.001) and higher in-hospital mortality (30.2% vs 26.1%; p < 0.001). Hospital characteristics (e.g., number of beds, teaching status, volume of sepsis cases) were similar between hospitals with a higher versus lower percent of discharges reported, p values greater than 0.05 for all. Hospitals' percent of discharges reported was not correlated with risk-adjusted mortality of their submitted cases (Pearson correlation coefficient 0.11; p = 0.17). CONCLUSIONS: Approximately four of five discharges with a diagnosis code of severe sepsis or septic shock in the Statewide Planning and Research Cooperative System data were reported in the New York State Department of Health Sepsis Clinical Database. Incomplete reporting appears to be driven more by underrecognition than attempts to game the system, with minimal bias to risk-adjusted hospital performance measurement.

Preliminary Performance on the New CMS Sepsis-1 National Quality Measure: Early Insights From the Emergency Quality Network (E-QUAL).

STUDY OBJECTIVE: We describe current hospital-level performance for the Centers for Medicare & Medicaid Services' Severe Sepsis/Septic Shock Early Management Bundle (SEP-1) quality measure and qualitatively assess emergency department (ED) sepsis quality improvement best practice implementation. METHODS: Using a standardized Web-based submission portal, we surveyed quality improvement data from volunteer hospital-based EDs participating in the Emergency Quality Network Sepsis Initiative. Each hospital submitted preliminary SEP-1 local chart review data, using existing Centers for Medicare & Medicaid Services definitions. We report descriptive statistics of SEP-1 data availability and performance. The primary outcome for this study was SEP-1 bundle compliance, defined as the proportion of all severe sepsis and septic shock cases receiving all required bundle elements, and secondary outcomes included conditional compliance on reported SEP-1 numerator components and ED implementation of sepsis quality improvement best practices. RESULTS: A total of 50 EDs participated in the survey; 74% were nonteaching sites and 26% were affiliated with academic centers. Of all participating EDs, 80% were in regions with relatively high population density. The mean hospital SEP-1 bundle compliance was 54% (interquartile range 30% to 75%). Bundle compliance improved during fiscal year 2016 from 39% to 57%. Broad variation existed for each bundle component, with intravenous fluid resuscitation and repeated lactate bundle elements having the widest variation and largest gaps in quality. At least one consensus sepsis quality improvement best practice implementation occurred in 92% of participating sites. CONCLUSION: Preliminary data on SEP-1 performance suggest wide hospital-level variation in performance, with modest improvement during the first year of data collection.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with 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 these critically ill patients with high mortality.

A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria.

Although sepsis was described more than 2,000 years ago, and clinicians still struggle to define it, there is no "gold standard," and multiple competing approaches and terms exist. Challenges include the ever-changing knowledge base that informs our understanding of sepsis, competing views on which aspects of any potential definition are most important, and the tendency of most potential criteria to be distributed in at-risk populations in such a way as to hinder separation into discrete sets of patients. We propose that the development and evaluation of any definition or diagnostic criteria should follow four steps: 1) define the epistemologic underpinning, 2) agree on all relevant terms used to frame the exercise, 3) state the intended purpose for any proposed set of criteria, and 4) adopt a scientific approach to inform on their usefulness with regard to the intended purpose. Usefulness can be measured across six domains: 1) reliability (stability of criteria during retesting, between raters, over time, and across settings), 2) content validity (similar to face validity), 3) construct validity (whether criteria measure what they purport to measure), 4) criterion validity (how new criteria fare compared to standards), 5) measurement burden (cost, safety, and complexity), and 6) timeliness (whether criteria are available concurrent with care decisions). The relative importance of these domains of usefulness depends on the intended purpose, of which there are four broad categories: 1) clinical care, 2) research, 3) surveillance, and 4) quality improvement and audit. This proposed methodologic framework is intended to aid understanding of the strengths and weaknesses of different approaches, provide a mechanism for explaining differences in epidemiologic estimates generated by different approaches, and guide the development of future definitions and diagnostic criteria.

Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria.

The current definition of sepsis is life-threatening, acute organ dysfunction secondary to a dysregulated host response to infection. Criteria to operationalize this definition can be judged by six domains of usefulness (reliability, content, construct and criterion validity, measurement burden, and timeliness). The relative importance of these six domains depends on the intended purpose for the criteria (clinical care, basic and clinical research, surveillance, or quality improvement [QI] and audit). For example, criteria for clinical care should have high content and construct validity, timeliness, and low measurement burden to facilitate prompt care. Criteria for surveillance or QI/audit place greater emphasis on reliability across individuals and sites and lower emphasis on timeliness. Criteria for clinical trials require timeliness to ensure prompt enrollment and reasonable reliability but can tolerate high measurement burden. Basic research also tolerates high measurement burden and may not need stability over time. In an illustrative case study, we compared examples of criteria designed for clinical care, surveillance and QI/audit among 396,241 patients admitted to 12 academic and community hospitals in an integrated health system. Case rates differed four-fold and mortality three-fold. Predictably, clinical care criteria, which emphasized timeliness and low burden and therefore used vital signs and routine laboratory tests, had the greater case identification with lowest mortality. QI/audit criteria, which emphasized reliability and criterion validity, used discharge information and had the lowest case identification with highest mortality. Using this framework to identify the purpose and apply domains of usefulness can help with the evaluation of existing sepsis diagnostic criteria and provide a roadmap for future work.

Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database.

OBJECTIVE: The Surviving Sepsis Campaign guidelines recommend obtaining a serum lactate measurement within 6 hours of presentation for all patients with suspected severe sepsis or septic shock. A lactate greater than 4 mmol/L qualifies for administration of early quantitative resuscitation therapy. We evaluated lactate elevation (with special attention to values > 4 mmol/L) and presence or absence of hypotension as a marker of clinical outcome. DESIGN AND SETTING: The Surviving Sepsis Campaign developed a database to assess the overall effect of the sepsis bundles as a performance improvement tool for clinical practice and patient outcome. This analysis focuses on one element of the Surviving Sepsis Campaign's resuscitation bundle, measuring serum lactate in adult severe sepsis or septic shock patients and its interaction with hypotension. This analysis was conducted on data submitted from January 2005 through March 2010. SUBJECTS: Data from 28,150 subjects at 218 sites were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unadjusted analysis of the 28,150 observations from the Surviving Sepsis Campaign database demonstrated a significant mortality increase with the presence of hypotension in conjunction with serum lactate elevation greater than 2 mmol/L. On multivariable analysis, only lactate values greater than 4 mmol/L, in conjunction with hypotension, significantly increased mortality when compared with the referent group of lactate values less than 2 mmol/L and not hypotensive. Mortality was 44.5% in patients with combined lactate greater than 4 mmol/L and hypotension when compared with 29% mortality in patients not meeting either criteria. CONCLUSIONS: Serum lactate was commonly measured within 6 hours of presentation in the management of severe sepsis or septic shock in this subset analysis of the Surviving Sepsis Campaign database in accordance with the Surviving Sepsis Campaign guidelines. Our results demonstrate that elevated lactate levels are highly associated with in-hospital mortality. However, only patients who presented with lactate values greater than 4 mmol/L, with and without hypotension, are significantly associated with in-hospital mortality and is associated with a significantly higher risk than intermediate levels (2-3 and 3-4 mmol/L). This supports the use of the cutoff of greater than 4 mmol/L as a qualifier for future clinical trials in severe sepsis or septic shock in patient populations who use quantitative resuscitation and the Surviving Sepsis Campaign bundles as standard of care.

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.

PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every three months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 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. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Sepsis severity score: an internationally derived scoring system from the surviving sepsis campaign database*.

OBJECTIVE: As the Surviving Sepsis Campaign was assessing patient-level data over multiple countries, we sought to evaluate the use of a pragmatic and parsimonious severity-of-illness scoring system for patients with sepsis in an attempt to provide appropriate comparisons with practical application. DESIGN: Prospective, observational evaluation. PATIENTS: Data from 23,438 patients with suspected or confirmed sepsis from 218 hospitals in 18 countries were evaluated. SETTING: This analysis was conducted on prospective data submitted to a database from January 2005 through March 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximum likelihood logistic regression was used to estimate model coefficients, and these were then used to develop a Sepsis Severity Score. The probability of hospital mortality was estimated using the Sepsis Severity Score as the sole variable in a logistic regression model. Univariable logistic regression determined which variables were included in the multivariable predictor model. The scale of continuous variables was assessed using fractional polynomials. Two-way interactions between variables were considered for model inclusion if the interaction p value is less than 0.05. The prediction model was developed based on randomly selecting 90% of available patients and was validated on the remaining 10%, as well as by using a bootstrapping technique. The p values for the Hosmer-Lemeshow goodnessof-fit statistic in the developmental and validation datasets were considerably greater than 0.05, suggesting good calibration. Development and validation areas under the receiver operator curve curves were 0.736 and 0.748, respectively. Observed and estimated probabilities of hospital mortality for the total population were both 0.334. The validation and the developmental datasets were gradually compared over deciles of predicted mortality and found to be very similar. CONCLUSION: The Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination, which remained consistent over deciles. It functioned well over international geographic regions. This robust, population-specific evaluation of international severe sepsis patients provides an effective and accurate mortality estimate allowing for appropriate quality comparisons with practical clinical and research application.

Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program.

OBJECTIVES: Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate antibiotic therapy, and organ support are cornerstone for the success in the treatment of patients with sepsis. Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. To perform a retrospective analysis on the Surviving Sepsis Campaign database to evaluate the relationship between timing of antibiotic administration and mortality. DESIGN: Retrospective analysis of a large dataset collected prospectively for the Surviving Sepsis Campaign. SETTING: One hundred sixty-five ICUs in Europe, the United States, and South America. PATIENTS: A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated. INTERVENTIONS: Antibiotic administration and hospital mortality. MEASUREMENTS AND MAIN RESULTS: A total of 17,990 patients received antibiotics after sepsis identification and were included in the analysis. In-hospital mortality was 29.7% for the cohort as a whole. There was a statically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Hospital mortality adjusted for severity (sepsis severity score), ICU admission source (emergency department, ward, vs ICU), and geographic region increased steadily after 1 hour of time to antibiotic administration. Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure. CONCLUSIONS: The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear increase in the risk of mortality for each hour delay in antibiotic administration. These results underscore the importance of early identification and treatment of septic patients in the hospital setting.