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.

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.

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.

Does gender affect experiences in the operating room for surgeons and anesthesiologists at a large academic center?

BACKGROUND: Although the number of women medical trainees has increased in recent years, they remain a minority of the academic workforce. Gender-based implicit biases may lead to deleterious effects on surgical workforce retention and productivity. METHODS: All 440 attending surgeons and anesthesiologists employed at our institution were invited to complete a survey regarding perceptions of the perioperative work environment and resources. Odds ratios for dichotomous variables were calculated using logistic regressions, and for trichotomous variables, polytomous regressions. RESULTS: 243 participants (55.2%) provided complete survey responses. Relative to men, women faculty reported a greater need to prove themselves to staff; less respect and fewer resources and opportunities; more frequent assumptions about their capabilities; and a greater need to adjust their demeanor to connect with their team (p â€‹< â€‹0.05). CONCLUSION: Perceived gender bias remains present in the perioperative environment. We need greater efforts to address barriers and create an equitable work environment.

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

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.

The diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin in the prediction of acute kidney injury in emergency department patients with suspected sepsis.

STUDY OBJECTIVE: We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. METHODS: We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. RESULTS: There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). CONCLUSION: In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.

A Multi-mRNA Host-Response Molecular Blood Test for the Diagnosis and Prognosis of Acute Infections and Sepsis: Proceedings from a Clinical Advisory Panel.

Current diagnostics are insufficient for diagnosis and prognosis of acute infections and sepsis. Clinical decisions including prescription and timing of antibiotics, ordering of additional diagnostics and level-of-care decisions rely on understanding etiology and implications of a clinical presentation. Host mRNA signatures can differentiate infectious from noninfectious etiologies, bacterial from viral infections, and predict 30-day mortality. The 29-host-mRNA blood-based InSepTM test (Inflammatix, Burlingame, CA, formerly known as HostDxTM Sepsis) combines machine learning algorithms with a rapid point-of-care platform with less than 30 min turnaround time to enable rapid diagnosis of acute infections and sepsis, as well as prediction of disease severity. A scientific advisory panel including emergency medicine, infectious disease, intensive care and clinical pathology physicians discussed technical and clinical requirements in preparation of successful introduction of InSep into the market. Topics included intended use; patient populations of greatest need; patient journey and sample flow in the emergency department (ED) and beyond; clinical and biomarker-based decision algorithms; performance characteristics for clinical utility; assay and instrument requirements; and result readouts. The panel identified clear demand for a solution like InSep, requirements regarding test performance and interpretability, and a need for focused medical education due to the innovative but complex nature of the result readout. Innovative diagnostic solutions such as the InSep test could improve management of patients with suspected acute infections and sepsis in the ED, thereby lessening the overall burden of these conditions on patients and the healthcare system.

A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis.

OBJECTIVE: To define a biomarker panel to predict organ dysfunction, shock, and in-hospital mortality in emergency department (ED) patients with suspected sepsis. DESIGN: Prospective observational study. SETTING: EDs of ten academic medical centers. PATIENTS: There were 971 patients enrolled. INCLUSION CRITERIA: 1) ED patients age > 18; 2) suspected infection or a serum lactate level > 2.5 mmol/L; and 3) two or more systemic inflammatory response syndrome criteria. EXCLUSION CRITERIA: pregnancy, do-not-resuscitate status, or cardiac arrest. MEASUREMENTS AND MAIN RESULTS: Nine biomarkers were assayed from blood draws obtained on ED presentation. Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. The derived formula for weighting biomarker values was used to calculate a "sepsis score," which was the predicted probability of the primary outcome of severe sepsis (sepsis plus organ dysfunction) within 72 hrs. We also assessed the ability of the sepsis score to predict secondary outcome measures of septic shock within 72 hrs and in-hospital mortality. The overall rates of each outcome were severe sepsis, 52%; septic shock, 39%; and in-hospital mortality 7%. Among the nine biomarkers tested, the optimal 3-marker panel was neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist. The area under the curve for the accuracy of the sepsis score derived from these three biomarkers was 0.80 for severe sepsis, 0.77 for septic shock, and 0.79 for death. When included in multivariate models with clinical variables, the sepsis score remained highly significant (p < 0.001) for all the three outcomes. CONCLUSIONS: A biomarker panel of neutrophil gelatinase-associated lipocalin, interleukin-1ra, and Protein C was predictive of severe sepsis, septic shock, and death in ED patients with suspected sepsis. Further study is warranted to prospectively validate the clinical utility of these biomarkers and the sepsis score in risk-stratifying patients with suspected sepsis.

Comparison of Automated Sepsis Identification Methods and Electronic Health Record-based Sepsis Phenotyping: Improving Case Identification Accuracy by Accounting for Confounding Comorbid Conditions.

To develop and evaluate a novel strategy that automates the retrospective identification of sepsis using electronic health record data. DESIGN: Retrospective cohort study of emergency department and in-hospital patient encounters from 2014 to 2018. SETTING: One community and two academic hospitals in Maryland. PATIENTS: All patients 18 years old or older presenting to the emergency department or admitted to any acute inpatient medical or surgical unit including patients discharged from the emergency department. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From the electronic health record, 233,252 emergency department and inpatient encounters were identified. Patient data were used to develop and validate electronic health record-based sepsis phenotyping, an adaptation of "the Centers for Disease Control Adult Sepsis Event toolkit" that accounts for comorbid conditions when identifying sepsis patients. The performance of this novel system was then compared with 1) physician case review and 2) three other commonly used strategies using metrics of sensitivity and precision relative to sepsis billing codes, termed "billing code sensitivity" and "billing code predictive value." Physician review of electronic health record-based sepsis phenotyping identified cases confirmed 79% as having sepsis; 88% were confirmed or had a billing code for sepsis; and 99% were confirmed, had a billing code, or received at least 4 days of antibiotics. At comparable billing code sensitivity (0.91; 95% CI, 0.88-0.93), electronic health record-based sepsis phenotyping had a higher billing code predictive value (0.32; 95% CI, 0.30-0.34) than either the Centers for Medicare and Medicaid Services Sepsis Core Measure (SEP-1) definition or the Sepsis-3 consensus definition (0.12; 95% CI, 0.11-0.13; and 0.07; 95% CI, 0.07-0.08, respectively). When compared with electronic health record-based sepsis phenotyping, Adult Sepsis Event had a lower billing code sensitivity (0.75; 95% CI, 0.72-0.78) and similar billing code predictive value (0.29; 95% CI, 0.26-0.31). Electronic health record-based sepsis phenotyping identified patients with higher in-hospital mortality and nearly one-half as many false-positive cases when compared with SEP-1 and Sepsis-3. CONCLUSIONS: By accounting for comorbid conditions, electronic health record-based sepsis phenotyping exhibited better performance when compared with other automated definitions of sepsis.