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Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype., (© 2024. The Author(s).)

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety., Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition., Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group., Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified., (© 2024. The Author(s).)

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain., Objective: To determine whether vitamin C improves outcomes for patients with COVID-19., Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents., Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses)., Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility., Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy., Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival., Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Purpose: The heterogeneity in sepsis is held responsible, in part, for the lack of precision treatment. Many attempts to identify subtypes of sepsis patients identify those with shared underlying biology or outcomes. To date, though, there has been limited effort to determine overlap across these previously identified subtypes. We aimed to determine the concordance of critically ill patients with sepsis classified by four previously described subtype strategies., Methods: This secondary analysis of a multicenter prospective observational study included 522 critically ill patients with sepsis assigned to four previously established subtype strategies, primarily based on: (i) clinical data in the electronic health record (α, β, γ, and δ), (ii) biomarker data (hyper- and hypoinflammatory), and (iii-iv) transcriptomic data (Mars1-Mars4 and SRS1-SRS2). Concordance was studied between different subtype labels, clinical characteristics, biological host response aberrations, as well as combinations of subtypes by sepsis ensembles., Results: All four subtype labels could be adjudicated in this cohort, with the distribution of the clinical subtype varying most from the original cohort. The most common subtypes in each of the four strategies were γ (61%), which is higher compared to the original classification, hypoinflammatory (60%), Mars2 (35%), and SRS2 (54%). There was no clear relationship between any of the subtyping approaches (Cramer's V = 0.086-0.456). Mars2 and SRS1 were most alike in terms of host response biomarkers (p = 0.079-0.424), while other subtype strategies showed no clear relationship. Patients enriched for multiple subtypes revealed that characteristics and outcomes differ dependent on the combination of subtypes made., Conclusion: Among critically ill patients with sepsis, subtype strategies using clinical, biomarker, and transcriptomic data do not identify comparable patient populations and are likely to reflect disparate clinical characteristics and underlying biology., (© 2023. The Author(s).)

Abstract: Urinary tract infections (UTIs) are a common cause of sepsis worldwide. Annually, more than 60,000 US deaths can be attributed to sepsis secondary to UTIs, and African American/Black adults have higher incidence and case-fatality rates than non-Hispanic White adults. Molecular-level factors that may help partially explain differences in sepsis survival outcomes between African American/Black and Non-Hispanic White adults are not clear. In this study, patient samples (N = 166) from the Protocolized Care for Early Septic Shock cohort were analyzed using discovery-based plasma proteomics. Patients had sepsis secondary to UTIs and were stratified according to self-identified racial background and sepsis survival outcomes. Proteomics results suggest patient heterogeneity across mechanisms driving survival from sepsis secondary to UTIs. Differentially expressed proteins (n = 122, false discovery rate-adjusted P < 0.05) in Non-Hispanic White sepsis survivors were primarily in immune system pathways, while differentially expressed proteins (n = 47, false discovery rate-adjusted P < 0.05) in African American/Black patients were mostly in metabolic pathways. However, in all patients, regardless of racial background, there were 16 differentially expressed proteins in sepsis survivors involved in translation initiation and shutdown pathways. These pathways are potential targets for prognostic intervention. Overall, this study provides information about molecular factors that may help explain disparities in sepsis survival outcomes among African American/Black and Non-Hispanic White patients with primary UTIs., (Copyright © 2023 by the Shock Society.)

Background: Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations., Methods: Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, β, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality., Results: 55,169 hospitalizations from 155 hospitals were included (34% α, 30% β, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02-1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02-1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05-1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99-1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97-1.01]) and did not differ among subtypes (p-interaction = 0.41)., Conclusion: Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype., (© 2023. The Author(s).)

Introduction: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings., Methods and Analysis: This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial., Ethics and Dissemination: The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal., Trial Registration Number: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results., Clinicaltrials: gov number: NCT04411472., Competing Interests: Competing interests: PP received advisory board consultancy and travel reimbursements from AM-Pharma. DCA and CJD serve as advisory board consultants for AM-Pharma. JA, EvdB and JB are employees of AM-Pharma. RB, MB, KD, BF, JAK, P-FL, VP and PY received advisory board consultancy reimbursements from AM Pharma. KB worked as an employee of Berry Consultants KB and acted as a consultant to numerous pharmaceutical and device companies. KB is currently an employee of and holds stock in AstraZeneca. JC, ALK and SR are consultants to AM-Pharma. RF received advisory board consultancy reimbursements from AM Pharma and additional consulting reimbursements from BioMerieux, Baxter, Pfizer, MSD, Gilead, Shionogi, Grifols and Beckton Dickinson unrelated to the current study. MJ received advisory board consultancy reimbursements from AM Pharma, additional consulting reimbursement from Baxter and Gilead and grant support from Fresenius and Baxter, unrelated to the current study. KL received advisory board consultancy reimbursements from AM-Pharma, owns stock in Amgen and consultant for Biomerieux, Neumora, Seastar and BOA Medical. RLM received advisory board consultancy reimbursements from AM Pharma and additional consulting reimbursement from BioMerieux, Baxter, Nova Biomed, Abiomed, GE Healthcare, Medtronic, Sanofi and Mallinckrodt, unrelated to the current study. PTM received Trial Steering Committee consultancy payments from AM-Pharma. Other consultancy payments: FAST Biomedical, Novartis, Renibus Therapeutics. MO received speaker honoraria from Fresenius Medical Care, Biomerieux, Baxter and Gilead, and research funding from Fresenius Medical Care, Biomerieux, Baxter and LaJolla Pharma and advisory board consultancy reimbursements from AM-Pharma. AZ received advisory board consultancy reimbursements from AM-Pharma. AZ has received consulting and/or lecture fees from Astute Medical/BioMerieux, Fresenius, Paion, Guard Therapeutics, and Baxter, unrelated to the current study. AZ has received grant support from Astute Medical/BioMerieux, Fresenius and Baxter, unrelated to the current study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to assess the prevalence, patient allocation adequacy, and mortality of adults with sepsis in Brazilian emergency departments (ED) in a point-prevalence 3-day investigation of patients with sepsis who presented to the ED and those who remained there due to inadequate allocation. Allocation was considered adequate if the patient was transferred to the intensive care unit (ICU), ward, or remained in the ED without ICU admission requests. Prevalence was estimated using the total ED visit number. Prognostic factors were assessed with logistic regression. Of 33,902 ED visits in 74 institutions, 183 were acute admissions (prevalence: 5.4 sepsis per 1000 visits [95% confidence interval (CI): 4.6-6.2)], and 148 were already in the ED; totaling 331 patients. Hospital mortality was 32% (103/322, 95% CI 23.0-51.0). Age (odds ratio (OR) 1.22 [95% CI 1.10-1.37]), Sequential Organ Failure Assessment (SOFA) score (OR 1.41 [95% CI 1.28-1.57]), healthcare-associated infections (OR 2.59 [95% CI 1.24-5.50]) and low-resource institution admission (OR 2.65 [95% CI 1.07-6.90]) were associated with higher mortality. Accredited institutions (OR 0.42 [95% CI 0.21-0.86]) had lower mortality rates. Allocation within 24 h was adequate in only 52.8% of patients (public hospitals: 42.4% (81/190) vs. private institutions: 67.4% (89/132, p < 0.001) with 39.2% (74/189) of public hospital patients remaining in the ED until discharge, of whom 55.4% (41/74) died. Sepsis exerts high burden and mortality in Brazilian EDs with frequent inadequate allocation. Modifiable factors, such as resources and quality of care, are associated with reduced mortality., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Intra-abdominal infection is a common cause of sepsis, and intra-abdominal sepsis leads to ∼156 000 U.S. deaths annually. African American/Black adults have higher incidence and mortality rates from sepsis compared to Non-Hispanic White adults. A limited number of studies have traced survival outcomes to molecular changes; however, these studies primarily only included Non-Hispanic White adults. Our goal is to better understand molecular changes that may contribute to differences in sepsis survival in African American/Black and Non-Hispanic White adults with primary intra-abdominal infection. We employed discovery-based plasma proteomics of patient samples from the Protocolized Care for Early Septic Shock (ProCESS) cohort ( N = 107). We identified 49 proteins involved in the acute phase response and complement system whose expression levels are associated with both survival outcome and racial background. Additionally, 82 proteins differentially-expressed in survivors were specific to African American/Black or Non-Hispanic White patients, suggesting molecular-level heterogeneity in sepsis patients in key inflammatory pathways. A smaller, robust set of 19 proteins were in common in African American/Black and Non-Hispanic White survivors and may represent potential universal molecular changes in sepsis. Overall, this study identifies molecular factors that may contribute to differences in survival outcomes in African American/Black patients that are not fully explained by socioeconomic or other non-biological factors.

Importance: Rapid source control is recommended to improve patient outcomes in sepsis. Yet there are few data to guide how rapidly source control is required., Objective: To determine the association between time to source control and patient outcomes in community-acquired sepsis., Design, Setting, and Particpants: Multihospital integrated health care system cohort study of hospitalized adults (January 1, 2013, to December 31, 2017) with community-acquired sepsis as defined by Sepsis-3 who underwent source control procedures. Follow-up continued through January 1, 2019, and data analyses were completed March 17, 2022., Exposures: Early (<6 hours) compared with late (6-36 hours) source control as well as each hour of source control delay (1-36 hours) from sepsis onset., Main Outcomes and Measures: Multivariable models were clustered at the level of hospital with adjustment for patient factors, sepsis severity, resource availability, and the physiologic stress of procedures generating adjusted odds ratios (aOR) and 95% CI., Results: Of 4962 patients with sepsis (mean [SD] age, 62 [16] years; 52% male; 85% White; mean [SD] Sequential Organ Failure Assessment score, 3.8 [2.5]), source control occurred at a median (IQR) of 15.4 hours (5.5-21.7) after sepsis onset, with 1315 patients (27%) undergoing source control within 6 hours. The crude 90-day mortality was similar for early and late source control (n = 177 [14%] vs n = 529 [15%]; P = .35). In multivariable models, early source control was associated with decreased risk-adjusted odds of 90-day mortality (aOR, 0.71; 95% CI, 0.63-0.80). This association was greater among gastrointestinal and abdominal (aOR, 0.56; 95% CI, 0.43-0.80) and soft tissue interventions (aOR, 0.72; 95% CI, 0.55-0.95) compared with orthopedic and cranial interventions (aOR, 1.33; 95% CI, 0.96-1.83; P < .001 for interaction)., Conclusions and Relevance: Source control within 6 hours of community-acquired sepsis onset was associated with a reduced risk-adjusted odds of 90-day mortality. Prioritizing the rapid identification of septic foci and initiation of source control interventions can reduce the number of avoidable deaths among patients with sepsis.

Objectives: Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis., Design: Retrospective cohort study., Setting: Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014., Patients: Adult critical ill patients with type 2 diabetes mellitus and sepsis., Interventions: None., Measurements and Main Results: We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1)., Conclusions: Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis., Competing Interests: Dr. Gomez reports support as principal investigator of the Limiting Acute Kidney Injury Progression in Sepsis (LAPIS) trial from Biomerieux. Drs. Gomez and Murugan report personal fees from AM-Pharma for enrolling patients in clinical trial of recombinant alkaline phosphatase in sepsis-associated acute kidney injury. Drs. Gomez’s, Zuckerbraun’s, and Angus’s institutions received funding from the National Institute of General Medical Sciences. Drs. Gomez, Zuckerbraun, Murugan, and Angus received support for article research from the National Institutes of Health (NIH). Dr. Priyanka disclosed work for hire. Dr. Zuckerbraun’s institution received funding from the Veteran’s Affairs; he disclosed government work. Dr. Murugan’s institution received funding from AM Pharma and Baxter; he received funding from the National Institute of Diabetes and Digestive and Kidney Diseases; and he disclosed the off-label product use of metformin of sepsis-associated acute kidney injury. Dr. Angus’ institution received funding from the NIH (R01 NR018434) and (R01 HS025146). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: The 23rd Acute Disease Quality Initiative (ADQI-23) consensus conference proposed a framework to integrate biomarkers into the staging of acute kidney injury (AKI). It is unknown whether tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP7) could be used for staging., Objective: To test whether higher levels of urinary [TIMP-2] × [IGFBP7] are associated with lower survival among patients with the same functional stage of AKI., Design, Setting, and Participants: This cohort study was performed using data from the Protocolized Care for Early Septic Shock (ProCESS) trial, which enrolled critically ill patients with septic shock who presented at academic and community emergency departments and intensive care units in the US from March 2008 to May 2013. Patients with end-stage kidney disease, a reference serum creatinine level of 4 mg/dL or greater (to convert to μmol/L, multiply by 76.25), or missing data on serum creatinine levels or urinary levels of [TIMP-2] × [IGFBP7] were excluded. Data were analyzed from October 2020 to October 2021., Exposures: The presence of AKI, assessed using Kidney Disease: Improving Global Outcomes criteria within 24 hours after enrollment and the highest AKI stage as well as urinary [TIMP-2] × [IGFBP7] level at 6 hours after enrollment. A previously reported high-specificity cutoff level for [TIMP-2] × [IGFBP7] of 2.0 (ng/mL)2/1000 was used to categorize patients (including those without functional criteria of AKI) according to the new staging system proposed by the ADQI-23 as biomarker negative (urinary [TIMP-2] × [IGFBP7] level ≤2.0 [ng/mL]2/1000) or biomarker positive ([TIMP-2] × [IGFBP7] >2.0 [ng/mL]2/1000)., Main Outcomes and Measures: Survival (assessed using Kaplan-Meier plots and the log-rank test) and mortality (assessed using relative risk [RR] 30 days after enrollment)., Results: The analysis included 999 patients with a median age of 61 years (IQR, 50-73 years); 554 (55.5%) were male. Biomarker-positive patients had lower survival and higher mortality at 30 days in the groups with AKI stage 1 (RR, 2.20; 95% CI, 1.02-4.72), stage 2 (RR, 1.53; 95% CI, 1.04-2.27), and stage 3 (RR, 1.61; 95% CI, 1.00-2.60). The associations were specific to patients with AKI. No difference in 30-day survival was found between biomarker-positive and biomarker-negative patients in the absence of functional criteria for AKI (RR, 1.16; 95% CI, 0.45-3.01)., Conclusions and Relevance: The findings suggest that assessment of the cell-cycle arrest biomarkers TIMP-2 and IGFBP7 may augment AKI staging for patients with functional criteria for AKI.

Rationale: Extremity threat and amputation after sepsis is a well-publicized and devastating event. However, there is a paucity of data about the epidemiology of extremity threat after sepsis onset. Objectives: To estimate the incidence of extremity threat with or without surgical amputation in community sepsis. Methods: Retrospective cohort study of adults with Sepsis-3 hospitalized at 14 academic and community sites from 2013 to 2017. Vasopressor-dependent sepsis was identified by administration of epinephrine, norepinephrine, phenylephrine, vasopressin, or dopamine for more than 1 hour during the 48 hours before to 24 hours after sepsis onset. Outcomes included the incidence of extremity threat, defined as acute onset ischemia, with or without amputation, in the 90 days after sepsis onset. The association between extremity threat, demographics, comorbid conditions, and time-varying sepsis treatments was evaluated using a Cox proportional hazards model. Results: Among 24,365 adults with sepsis, 12,060 (54%) were vasopressor dependent (mean ± standard deviation age, 64 ± 16 years; male, 6,548 [54%]; sequential organ failure assessment [SOFA], 10 ± 4). Of these, 231 (2%) patients had a threatened extremity with 26 undergoing 37 amputations, a risk of 2.2 (95% confidence interval [CI], 1.4-3.2) per 1,000, and 205 not undergoing amputation, a risk of 17.0 (95% CI, 14.8-19.5) per 1,000. Most amputations occurred in lower extremities (95%), a median (interquartile range) of 16 (6-40) days after sepsis onset. Compared with patients with no extremity threat, patients with threat had a higher SOFA score (11 ± 4 vs. 10 ± 4; P  < 0.001), serum lactate (4.6 mmol/L [2.4-8.7] vs. 3.1 [1.7-6.0]; P  < 0.001), and more bacteremia ( n  = 37 [37%] vs. n  = 2,087 [26%]; P  < 0.001) at sepsis onset. Peripheral vascular disease, congestive heart failure, SOFA score, and norepinephrine equivalents were significantly associated with extremity threat. Conclusions: The evaluation of a threatened extremity resulting in surgical amputation occurred in 2 per 1,000 patients with vasopressor-dependent sepsis.

Competing Interests: Dr. Alhazzani is the Chair of the Guidelines Chapter for the Saudi Critical Care Society and is the chair of the guidelines in intensive care, development and evaluation (GUIDE) Group, McMaster University Canada. Dr. Antonelli received funding from GE, Toray-Estor, Baxter, Pfizer, Orion, Maquet, and Fisher and Paykel; he was on the board of Baxter and Pfizer, and is a member of the executive committee and past president of Società Italiana di Anestesia Rianimazione e Terapia Intensiva (SIAARTI). Dr. French contributed to the ANZICS Guidelines and the National COVID-19 Guidelines. Dr. Machado is a member of the Executive Committee for the Basics Study (for which Baxter provided the drugs and logistics) and AMIB. Dr. McIntyre is a member of the Canadian Critical Care Society and serves on the Surviving Sepsis Campaign Steering Committee. Dr. Ostermann is a council member of the Intensive Care Society UK and member of the Renal Association UK and World Sepsis Alliance. Dr. Prescott is a member of the ATS Critical Care Program Committee. Dr. Simpson is the president-elect and Chair of CHEST, is a member of the board of directors and medical director of Sepsis Alliance, and Chair of the Sepsis Institute Advisory Board. Dr. Wiersinga is a member of ISF, ESCIMID, and SWAB. Dr. Angus received funding from Ferring Pharmaceuticals, Inc and ALung Technologies, Inc. Dr. Beale provides consultancy services for Philips Healthcare with his time billed by his institution. Dr. Beilman is the president of the Surgical Infection Society. Dr. Belley-Cote received grants from Roche and Bayer and is a panel member on the Saudi Critical Care Society COVID-19 Thrombosis Guidelines. Dr. Cecconi is a consultant for Edwards Lifesciences, Cheetah Medical, and Directed Systems and is President of the European Society of Intensive Care Medicine. Dr. Coz is a board member of the American College of Chest Physicians. Dr. De Waele consulted for Accelerate, Bayer, Grifols, Pfizer, and MSD with all honoraria paid to Ghent University; he is a Senior Clinical Investigator with the Research Foundation Flanders. Dr. Dellinger serves as an expert witness on occasional medical legal case reviews. Dr. Doi is a member of the Japanese Society of Intensive Care Medicine. Dr. Du is a member of the Chinese Society of Critical Care Medicine and the Chinese College of Intensive Care Medicine. Dr. Ferrer received funding from Grifols, MSD, Pfizer, Shionogi, Toray, Jafron, and Cytosorbents; he is a member of SEMICYUC. Dr. Gomersall is a member of an educational subgroup of the International Forum of Acute Care Trialists. Dr. Hodgson is a member of the Australian National Health and Medical Research Council guidelines (COVID-19) and leading funded trials in early rehabilitation and ECMO. Dr. Møller contributed to guideline work for DASAIM, SSAI, GUIDE, and ESA. Dr. Iwashyna is a member of the ATS, the NIH, and an informal (unincorporated) organization called the Critical and Acute Illness Recovery Organization. Dr. Jacob co-directs the African Research Collaboration on Sepsis (ARCS, funded by UK National Institute for Health Research, sponsored by Liverpool School of Tropical Medicine), he is Secretary General for the African Sepsis Alliance, and is a technical expert for the World Health Organization panels. Dr. Kleinpell is a board member of the World Federation of Intensive and Critical Care, American Nurses Credentialing Center, and the Tennessee Nurses Association Political Action Committee. Dr. Klompas received funding from Up-to-Date; he is a member of the guidelines committees of the Infectious Disease Society of America (IDSA) and Society of Healthcare Epidemiologists of America (SHEA). Dr. Koh is a member of The Korean Society of Critical Care Medicine, The Korean Academy of Tuberculosis and Respiratory Diseases, The Korean Society of Medical Ethics, and the Asia Ventilation Forum. Dr. Kumar served as an expert witness regarding a lethal dose of narcotics. Dr. Kwizera is president of the Intensive Care Society of Uganda and PRO for the Association of Anesthesiologists of Uganda. Dr. Lobo received funding from Pfizer, MSD, Edwards, and Nestle; she is the principal investigator in new antibiotics research led by CROs/industry; she is a member of the AMIB Executive Board and was elected president for 2020-2021. Dr. McGloughlin is a member of ANZICS (Australian New Zealand Intensive Care Society). Dr. Mehta participated in two non-interventional studies by ISCCM-Hermes and Indicaps. Dr. Mer has been an invited speaker for educational talks in industry-sponsored symposia for which honoraria was received; he is the current Vice President of the Southern African Society of Thrombosis and Haemostasis (SASTH), and is involved in annual congress organization; he is an invited author of the Global guidelines for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Dr. Nunnally is the treasurer of SOCCA, committee member of ASA, NYSSA, IARS, AUA, and SAAAPM and serves on the American College of Critical Care Medicine Board of Regents. Dr. Oczkowski is a member of the European Respiratory Society, and contributed to the High Flow Nasal Cannula Guidelines, the Non-Invasive Ventilation in COPD Guidelines. Dr. Osborn received funding from Viven Inc, Inflammatrix, Beckman, and the Foundation for Barnes Jewish Hospital; she is on the advisory board for Beckman, Inflammatix, and Viven; she is a member of the American College of Emergency Physicians, American College of Chest Physicians, American Medical Association, Society of Academic Emergency Medicine, and American Academy of Emergency Physicians; she served as an expert witness in a case related to viral as compared to bacterial sepsis. Dr. Papathanassoglou is a member of the World Federation of Critical Care Nurses (Editor of Journal) and the Canadian Association of Critical Care Nurses. Dr. Perner received a research grant from Pfizer Denmark. Dr. Puskarich is the co-inventor of a patent to assess L0carnitine drug responsiveness in sepsis (USPO 10330685); he is a member of the Society for Academic Emergency Medicine, American College of Emergency Physicians (ACEP); he was invited to a recently gathered ACEP early sepsis treatment policy task force asked to develop specialty recommendations for early sepsis treatment. Dr. Roberts received funding from MSD, The Medicines Company, Cardeas Pharma, Biomerieux, QPEX, Cipla, and Pfizer; he consulted for MSD, QPEX, Discuva Ltd, Accelerate Diagnostics, Bayer, Biomerieux, UptoDate, and Australian Therapeutic Guidelines; he is a member of the Society of Hospital Pharmacists of Australia Leadership Committees for Critical Care and Infectious Diseases and the Lead of Sepsis Working group for the International Society of Anti-infective Chemotherapy. Dr. Schweickert is a paid consultant to the American College of Physicians (last performed in Spring, 2019). Dr. Seckel volunteers for AACN and is a paid consultant to revise online Critical Care Orientation. Dr. Sevransky received funding from the Marcus Foundation- PI VICTAS Trial and serves on the American College of Critical Care Medicine Board of Regents. Dr. Welte received funding from Astellas, AstraZeneca, Boehringer, Basilea, Bayer, Berlin-Chemie, Grifols, Infectopharm, Mundipharma, MSD, Novartis, Pfizer, DFG, EU, BMBF, and Insmed; he is on the advisory board for AstraZeneca, Boehringer, Bayer, Gilead, GSK, Insmed, Novartis, Pfizer, Roche; he is a member of the European Respiratory Society, German Society of Pneumology, and Paul Ehrlich Gesellschaft. Dr. Zimmerman is a member of the ACP, AACP, and WFPICCS. Dr. Levy is a legal consultant for a few cases involving sepsis and serves as co-chair of the Surviving Sepsis Campaign Steering Committee. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. Methods: This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. Results: The following six priority recommendations were developed by the working group: 1 ) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; 2 ) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; 3 ) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; 4 ) further development of the tools necessary for the real-time application of precision medicine approaches; 5 ) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and 6 ) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.

Background: Medicare requires that hospitals report on their adherence to the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1)., Objective: To evaluate the effect of SEP-1 on treatment patterns and patient outcomes., Design: Longitudinal study of hospitals using repeated cross-sectional cohorts of patients., Setting: 11 hospitals within an integrated health system., Patients: 54 225 encounters between January 2013 and December 2017 for adults with sepsis who were hospitalized through the emergency department., Intervention: Onset of the SEP-1 reporting requirement in October 2015., Measurements: Changes in SEP-1-targeted processes, including antibiotic administration, lactate measurement, and fluid administration at 3 hours from sepsis onset; repeated lactate and vasopressor administration for hypotension within 6 hours of sepsis onset; and sepsis outcomes, including risk-adjusted intensive care unit (ICU) admission, in-hospital mortality, and home discharge among survivors., Results: Two years after its implementation, SEP-1 was associated with variable changes in process measures, with the greatest effect being an increase in lactate measurement within 3 hours of sepsis onset (absolute increase, 23.7 percentage points [95% CI, 20.7 to 26.7 percentage points]; P < 0.001). There were small increases in antibiotic administration (absolute increase, 4.7 percentage points [CI, 1.9 to 7.6 percentage points]; P = 0.001) and fluid administration of 30 mL/kg of body weight within 3 hours of sepsis onset (absolute increase, 3.4 percentage points [CI, 1.5 to 5.2 percentage points]; P < 0.001). There was no change in vasopressor administration. There was a small increase in ICU admissions (absolute increase, 2.0 percentage points [CI, 0 to 4.0 percentage points]; P = 0.055) and no changes in mortality (absolute change, 0.1 percentage points [CI, -0.9 to 1.1 percentage points]; P = 0.87) or discharge to home., Limitation: Data are from a single health system., Conclusion: Implementation of the SEP-1 mandatory reporting program was associated with variable changes in process measures, without improvements in clinical outcomes. Revising the measure may optimize its future effect., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Sepsis survivors experience high morbidity and mortality, and healthcare systems lack effective strategies to address patient needs after hospital discharge. The Sepsis Transition and Recovery (STAR) program is a navigator-led, telehealth-based multicomponent strategy to provide proactive care coordination and monitoring of high-risk patients using evidence-driven, post-sepsis care tasks. The purpose of this study is to evaluate the effectiveness of STAR to improve outcomes for sepsis patients and to examine contextual factors that influence STAR implementation., Methods: This study uses a hybrid type I effectiveness-implementation design to concurrently test clinical effectiveness and gather implementation data. The effectiveness evaluation is a two-arm, pragmatic, stepped-wedge cluster randomized controlled trial at eight hospitals in North Carolina comparing clinical outcomes between sepsis survivors who receive Usual Care versus care delivered through STAR. Each hospital begins in a Usual Care control phase and transitions to STAR in a randomly assigned sequence (one every 4 months). During months that a hospital is allocated to Usual Care, all eligible patients will receive usual care. Once a hospital transitions to STAR, all eligible patients will receive STAR during their hospitalization and extending through 90 days from discharge. STAR includes centrally located nurse navigators using telephonic counseling and electronic health record-based support to facilitate best-practice post-sepsis care strategies including post-discharge review of medications, evaluation for new impairments or symptoms, monitoring existing comorbidities, and palliative care referral when appropriate. Adults admitted with suspected sepsis, defined by clinical criteria for infection and organ failure, are included. Planned enrollment is 4032 patients during a 36-month period. The primary effectiveness outcome is the composite of all-cause hospital readmission or mortality within 90 days of discharge. A mixed-methods implementation evaluation will be conducted before, during, and after STAR implementation., Discussion: This pragmatic evaluation will test the effectiveness of STAR to reduce combined hospital readmissions and mortality, while identifying key implementation factors. Results will provide practical information to advance understanding of how to integrate post-sepsis management across care settings and facilitate implementation, dissemination, and sustained utilization of best-practice post-sepsis management strategies in other heterogeneous healthcare delivery systems., Trial Registration: NCT04495946 . Submitted July 7, 2020; Posted August 3, 2020.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care., Competing Interests: Dr. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: A cornerstone of precision medicine is the identification and use of biomarkers that help subtype patients for targeted treatment. Such an approach requires the development and subsequent interrogation of large-scale biobanks linked to well-annotated clinical data. Traditional means of creating these data-linked biobanks are costly and lengthy, especially in acute conditions that require time-sensitive clinical data and biospecimens., Objectives: To develop a virtually enabled biorepository and electronic health record (EHR)-embedded, scalable cohort for precision medicine (VESPRE) and compare the feasibility, enrollment, and costs of VESPRE with those of a traditional study design in acute care., Design, Setting, and Participants: In a prospective cohort study, the EHR-embedded screening alert was generated for 3428 patients, and 2199 patients (64%) were eligible and screened. Of these, 1027 patients (30%) were enrolled. VESPRE was developed for regulatory compliance, feasibility, internal validity, and cost in a prospective cohort of 1027 patients (aged ≥18 years) with sepsis-3 within 6 hours of presentation to the emergency department. The VESPRE infrastructure included (1) automated EHR screening, (2) remnant blood collection for creation of a virtually enabled biorepository, and (3) automated clinical data abstraction. The study was conducted at an academic institution in southwestern Pennsylvania from October 17, 2017, to June 6, 2019., Main Outcomes and Measures: Regulatory compliance, enrollment, internal validity of automated screening, biorepository acquisition, and costs., Results: Of the 1027 patients enrolled in the study, 549 were included in the proof-of-concept analysis (305 [56%] men); median (SD) age was 59 (17) years. VESPRE collected 12 963 remnant blood and urine samples and demonstrated adequate feasibility for clinical, biomarker, and microbiome analyses. Over the 20-month test, the total cost beyond the existing operations infrastructure was $39 417.50 ($14 880.00 project management, $22 717.50 laboratory supplies/staff, and $1820.00 data management)-approximately $39 per enrolled patient vs $239 per patient for a traditional cohort study., Conclusions and Relevance: Results of this study suggest that, in a large US health system that collects data using a common EHR platform and centralized laboratory system, VESPRE, a large-scale, inexpensive EHR-embedded infrastructure for precision medicine can be used. Tested in the sepsis setting, VESPRE appeared to capture a high proportion of eligible patients at low incremental cost.

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin., Competing Interests: No author claims competing interest.

Background: In 2013, New York introduced regulations mandating that hospitals develop pediatric-specific protocols for sepsis recognition and treatment., Methods: We used hospital discharge data from 2011 to 2015 to compare changes in pediatric sepsis outcomes in New York and 4 control states: Florida, Massachusetts, Maryland, and New Jersey. We examined the effect of the New York regulations on 30-day in-hospital mortality using a comparative interrupted time-series approach, controlling for patient and hospital characteristics and preregulation temporal trends., Results: We studied 9436 children admitted to 237 hospitals. Unadjusted pediatric sepsis mortality decreased in both New York (14.0% to 11.5%) and control states (14.4% to 11.2%). In the primary analysis, there was no significant effect of the regulations on mortality trends (differential quarterly change in mortality in New York compared with control states: -0.96%; 95% confidence interval [CI]: -1.95% to 0.02%; P = .06). However, in a prespecified sensitivity analysis excluding metropolitan New York hospitals that participated in earlier sepsis quality improvement, the regulations were associated with improved mortality trends (differential change: -2.08%; 95% CI: -3.79% to -0.37%; P = .02). The regulations were also associated with improved mortality trends in several prespecified subgroups, including previously healthy children (differential change: -1.36%; 95% CI: -2.62% to -0.09%; P = .04) and children not admitted through the emergency department (differential change: -2.42%; 95% CI: -4.24% to -0.61%; P = .01)., Conclusions: Implementation of statewide sepsis regulations was generally associated with improved mortality trends in New York State, particularly in prespecified subpopulations of patients, suggesting that the regulations were successful in affecting sepsis outcomes., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Angus received personal fees from Ferring Pharmaceutical Inc, Bristol-Myers Squibb, Bayer AG, GenMark Diagnostics, Sobi Inc, Beckman Coulter Inc, and ALung Technologies Inc and has patents pending from Selepressin and Proteomic; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017., Methods: We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates., Findings: In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia., Interpretation: Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa., Funding: The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access Article under the CC BY 4.0 licence. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids., Methods: We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration., Results: Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02)., Conclusions: We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

An estimated 14.1 million patients survive sepsis each year. Many survivors experience poor long-term outcomes, including new or worsened neuropsychological impairment; physical disability; and vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, clinical trials and guidelines have focused on shorter-term survival, so there are few data on promoting longer-term recovery. To address this unmet need, the International Sepsis Forum convened a colloquium in February 2018 titled "Understanding and Enhancing Sepsis Survivorship." The goals were to identify gaps and limitations of current research and shorter- and longer-term priorities for understanding and enhancing sepsis survivorship. Twenty-six experts from eight countries participated. The top short-term priorities identified by nominal group technique culminating in formal voting were to better leverage existing databases for research, develop and disseminate educational resources on postsepsis morbidity, and partner with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to study mechanisms of long-term morbidity through large cohort studies with deep phenotyping, build a harmonized global sepsis registry to facilitate enrollment in cohorts and trials, and complete detailed longitudinal follow-up to characterize the diversity of recovery experiences. This perspective reviews colloquium discussions, the identified priorities, and current initiatives to address them.

Purpose: Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis., Methods: Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 10 3 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters., Results: Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase., Conclusions: In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854.

Importance: Long-term immune sequelae after sepsis are poorly understood., Objective: To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge., Design, Settings, and Participants: This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals., Exposures: Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified., Main Outcomes and Measures: Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality., Results: A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses., Conclusions and Relevance: In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.

Objectives: Most septic patients are initially encountered in the emergency department where sepsis recognition is often delayed, in part due to the lack of effective biomarkers. This study evaluated the diagnostic accuracy of peripheral blood monocyte distribution width alone and in combination with WBC count for early sepsis detection in the emergency department., Design: An Institutional Review Board approved, blinded, observational, prospective cohort study conducted between April 2017 and January 2018., Setting: Subjects were enrolled from emergency departments at three U.S. academic centers., Patients: Adult patients, 18-89 years, with complete blood count performed upon presentation to the emergency department, and who remained hospitalized for at least 12 hours. A total of 2,212 patients were screened, of whom 2,158 subjects were enrolled and categorized per Sepsis-2 criteria, such as controls (n = 1,088), systemic inflammatory response syndrome (n = 441), infection (n = 244), and sepsis (n = 385), and Sepsis-3 criteria, such as control (n = 1,529), infection (n = 386), and sepsis (n = 243)., Interventions: The primary outcome determined whether an monocyte distribution width of greater than 20.0 U, alone or in combination with WBC, improves early sepsis detection by Sepsis-2 criteria. Secondary endpoints determined monocyte distribution width performance for Sepsis-3 detection., Measurements and Main Results: Monocyte distribution width greater than 20.0 U distinguished sepsis from all other conditions based on either Sepsis-2 criteria (area under the curve, 0.79; 95% CI, 0.76-0.82) or Sepsis-3 criteria (area under the curve, 0.73; 95% CI, 0.69-0.76). The negative predictive values for monocyte distribution width less than or equal to 20 U for Sepsis-2 and Sepsis-3 were 93% and 94%, respectively. Monocyte distribution width greater than 20.0 U combined with an abnormal WBC further improved Sepsis-2 detection (area under the curve, 0.85; 95% CI, 0.83-0.88) and as reflected by likelihood ratio and added value analyses. Normal WBC and monocyte distribution width inferred a six-fold lower sepsis probability., Conclusions: An monocyte distribution width value of greater than 20.0 U is effective for sepsis detection, based on either Sepsis-2 criteria or Sepsis-3 criteria, during the initial emergency department encounter. In tandem with WBC, monocyte distribution width is further predicted to enhance medical decision making during early sepsis management in the emergency department.

Background: Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation., Methods: We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate., Results: Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113-341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45-79] ng/ml), as well as in a second cohort of sepsis patients (283 [155-584] ng/ml) at emergency department presentation) compared to controls (177 [144-262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment., Conclusions: Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.

Importance: Beginning in 2013, New York State implemented regulations mandating that hospitals implement evidence-based protocols for sepsis management, as well as report data on protocol adherence and clinical outcomes to the state government. The association between these mandates and sepsis outcomes is unknown., Objective: To evaluate the association between New York State sepsis regulations and the outcomes of patients hospitalized with sepsis., Design, Setting, and Participants: Retrospective cohort study of adult patients hospitalized with sepsis in New York State and in 4 control states (Florida, Maryland, Massachusetts, and New Jersey) using all-payer hospital discharge data (January 1, 2011-September 30, 2015) and a comparative interrupted time series analytic approach., Exposures: Hospitalization for sepsis before (January 1, 2011-March 31, 2013) vs after (April 1, 2013-September 30, 2015) implementation of the 2013 New York State sepsis regulations., Main Outcomes and Measures: The primary outcome was 30-day in-hospital mortality. Secondary outcomes were intensive care unit admission rates, central venous catheter use, Clostridium difficile infection rates, and hospital length of stay., Results: The final analysis included 1 012 410 sepsis admissions to 509 hospitals. The mean age was 69.5 years (SD, 16.4 years) and 47.9% were female. In New York State and in the control states, 139 019 and 289 225 patients, respectively, were admitted before implementation of the sepsis regulations and 186 767 and 397 399 patients, respectively, were admitted after implementation of the sepsis regulations. Unadjusted 30-day in-hospital mortality was 26.3% in New York State and 22.0% in the control states before the regulations, and was 22.0% in New York State and 19.1% in the control states after the regulations. Adjusting for patient and hospital characteristics as well as preregulation temporal trends and season, mortality after implementation of the regulations decreased significantly in New York State relative to the control states (P = .02 for the joint test of the comparative interrupted time series estimates). For example, by the 10th quarter after implementation of the regulations, adjusted absolute mortality was 3.2% (95% CI, 1.0% to 5.4%) lower than expected in New York State relative to the control states (P = .004). The regulations were associated with no significant differences in intensive care unit admission rates (P = .09) (10th quarter adjusted difference, 2.8% [95% CI, -1.7% to 7.2%], P = .22), a significant relative decrease in hospital length of stay (P = .04) (10th quarter adjusted difference, 0.50 days [95% CI, -0.47 to 1.47 days], P = .31), a significant relative decrease in the C difficile infection rate (P < .001) (10th quarter adjusted difference, -1.8% [95% CI, -2.6% to -1.0%], P < .001), and a significant relative increase in central venous catheter use (P = .02) (10th quarter adjusted difference, 4.8% [95% CI, 2.3% to 7.4%], P < .001)., Conclusions and Relevance: In New York State, mandated protocolized sepsis care was associated with a greater decrease in sepsis mortality compared with sepsis mortality in control states that did not implement sepsis regulations. Because baseline mortality rates differed between New York and comparison states, it is uncertain whether these findings are generalizable to other states.

Importance: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care., Objective: To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs)., Design, Settings, and Participants: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737)., Exposures: All clinical and laboratory variables in the electronic health record., Main Outcomes and Measures: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs., Results: The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm)., Conclusions and Relevance: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.

Objectives: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression., Design: Randomized, placebo-controlled, dose-escalation., Setting: Seven U.S. hospital ICUs., Study Population: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL., Interventions: Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels., Measurements and Main Results: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days., Conclusions: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.

Background and Objectives: The decline in hospital mortality in children hospitalized with sepsis has increased the number of survivors. These survivors are at risk for adverse long-term outcomes, including readmission and recurrent or unresolved infections. We described the epidemiology of 90-day readmissions after sepsis hospitalization in children. We tested the hypothesis that a sepsis hospitalization increases odds of 90-day readmissions., Methods: Retrospective cohort analysis of the Nationwide Readmissions Database. We included index unplanned admissions of non-neonatal pediatric patients and described the proportion of readmissions, including those involving infection or sepsis. We performed multivariable analysis to determine the odds of readmission after a sepsis and nonsepsis admission and compared costs of readmission after sepsis and nonsepsis admissions., Results: Of 562 817 pediatric admissions, 7634 (1.4%) and 555 183 (98.6%) were discharged alive after admissions with and without sepsis. The rate of 90-day readmission after sepsis was 21.4%: 7.2% and 25.5% in previously healthy and chronically ill patients. The adjusted mean cost during readmission was $7385. Half of readmissions (52.9%) involved recurrent infection or sepsis. Sepsis admissions were associated with higher odds of readmission at 90 days compared with nonsepsis admissions (adjusted odds ratio 1.15, 95% confidence interval 1.08-1.23). The results remained unchanged for 30-day and 6-month readmissions., Conclusions: Readmissions occur after 1 in 5 pediatric sepsis hospitalizations and increase health care costs. Sepsis hospitalization increased odds of readmission and commonly involved recurrent infection or sepsis. Clinicians caring for these patients should consider surveillance for recurrent or unresolved infection, and researchers should explore underlying mechanisms and potential interventions to reduce readmissions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objectives: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons., Design, Setting, and Patients: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013-2014., Interventions: None., Measurements and Main Results: Sepsis was defined using electronic health record-derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals' claims data was low and variable: median 30% (range, 5-54%) for sepsis, 66% (range, 26-84%) for acute kidney injury, 39% (range, 16-60%) for thrombocytopenia, 36% (range, 29-44%) for hepatic injury, and 66% (range, 29-84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data., Conclusions: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals' sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.

Objectives: Sepsis-3 defines organ dysfunction as an increase in the Sequential Organ Failure Assessment score by greater than or equal to 2 points. However, some Sequential Organ Failure Assessment score components are not routinely recorded in all hospitals' electronic health record systems, limiting its utility for wide-scale sepsis surveillance. The Centers for Disease Control and Prevention recently released the Adult Sepsis Event surveillance definition that includes simplified organ dysfunction criteria optimized for electronic health records (eSOFA). We compared eSOFA versus Sequential Organ Failure Assessment with regard to sepsis prevalence, overlap, and outcomes., Design: Retrospective cohort study., Setting: One hundred eleven U.S. hospitals in the Cerner HealthFacts dataset., Patients: Adults hospitalized in 2013-2015., Interventions: None., Measurements and Main Results: We identified clinical indicators of presumed infection (blood cultures and antibiotics) concurrent with either: 1) an increase in Sequential Organ Failure Assessment score by 2 or more points (Sepsis-3) or 2) 1 or more eSOFA criteria: vasopressor initiation, mechanical ventilation initiation, lactate greater than or equal to 2.0 mmol/L, doubling in creatinine, doubling in bilirubin to greater than or equal to 2.0 mg/dL, or greater than or equal to 50% decrease in platelet count to less than 100 cells/μL (Centers for Disease Control and Prevention Adult Sepsis Event). We compared area under the receiver operating characteristic curves for discriminating in-hospital mortality, adjusting for baseline characteristics. Of 942,360 patients in the cohort, 57,242 (6.1%) had sepsis by Sequential Organ Failure Assessment versus 41,618 (4.4%) by eSOFA. Agreement between sepsis by Sequential Organ Failure Assessment and eSOFA was good (Cronbach's alpha 0.81). Baseline characteristics and infectious diagnoses were similar, but mortality was higher with eSOFA (17.1%) versus Sequential Organ Failure Assessment (14.4%; p < 0.001) as was discrimination for mortality (area under the receiver operating characteristic curve, 0.774 vs 0.759; p < 0.001). Comparisons were consistent across subgroups of age, infectious diagnoses, and comorbidities., Conclusions: The Adult Sepsis Event's eSOFA organ dysfunction criteria identify a smaller, more severely ill sepsis cohort compared with the Sequential Organ Failure Assessment score, but with good overlap and similar clinical characteristics. Adult Sepsis Events may facilitate wide-scale automated sepsis surveillance that tracks closely with the more complex Sepsis-3 criteria.

Objectives: Among patients with suspected infection, a single measurement of the quick Sepsis-related Organ Failure Assessment has good predictive validity for sepsis, yet the increase in validity from repeated measurements is unknown. We sought to determine the incremental predictive validity for sepsis of repeated quick Sepsis-related Organ Failure Assessment measurements over 48 hours compared with the initial measurement., Design: Retrospective cohort study., Setting: Twelve hospitals in southwestern Pennsylvania in 2012., Patients: All adult medical and surgical encounters in the emergency department, hospital ward, postanesthesia care unit, and ICU., Interventions: None., Measurements and Main Results: Among 1.3 million adult encounters, we identified those with a first episode of suspected infection. Using the maximum quick Sepsis-related Organ Failure Assessment score in each 6-hour epoch from onset of suspected infection until 48 hours later, we characterized repeated quick Sepsis-related Organ Failure Assessment with: 1) summary measures (e.g., mean over 48 hr), 2) crude trajectory groups, and 3) group-based trajectory modeling. We measured the predictive validity of repeated quick Sepsis-related Organ Failure Assessment using incremental changes in the area under the receiver operating characteristic curve for in-hospital mortality beyond that of baseline risk (age, sex, race/ethnicity, and comorbidity). Of 37,591 encounters with suspected infection, 1,769 (4.7%) died before discharge. Both the mean quick Sepsis-related Organ Failure Assessment at 48 hours (area under the receiver operating characteristic, 0.86 [95% CI, 0.85-0.86]) and crude trajectory groups (area under the receiver operating characteristic, 0.83 [95% CI, 0.83-0.83]) improved predictive validity compared with initial quick Sepsis-related Organ Failure Assessment (area under the receiver operating characteristic, 0.79 [95% CI, 0.78-0.80]) (p < 0.001 for both). Group-based trajectory modeling found five trajectories (quick Sepsis-related Organ Failure Assessment always low, increasing, decreasing, moderate, and always high) with greater predictive validity than the initial measurement (area under the receiver operating characteristic, 0.85 [95% CI, 0.84-0.85]; p < 0.001)., Conclusions: Repeated measurements of quick Sepsis-related Organ Failure Assessment improve predictive validity for sepsis using in-hospital mortality compared with a single measurement of quick Sepsis-related Organ Failure Assessment at the time a clinician suspects infection.

Background: The use of in vivo videomicroscopy at the bedside has demonstrated microcirculatory flow disturbances in sepsis. The ability of in vivo videomicroscopy to detect changes in the prevalence of rolling and adhered leukocytes that occur in sepsis is not well-described in humans. We sought to (1) develop methodology for accessing and quantifying sublingual leukocyte rolling and adherence with sidestream dark field (SDF) imaging; (2) compare the number of rolling and adhered leukocytes between patients with septic shock and non-infected controls; and (3) compare the number of rolling and adhered leukocytes between survivors and non-survivors of septic shock., Methods: We included adult (age > 18 years) patients in the emergency department presenting with septic shock prospectively enrolled in the ProCESS trial. We recruited comparison non-infected patients as emergency department controls. Using a SDF videomicroscope, we obtained image sequences from the sublingual mucosa, quantifying rolling and adhered leukocytes per 1 mm × 1 mm visual field in a standardized 3-s clip. We report data as median and interquartile range and depicted as box plots. We compared groups using the Mann-Whitney U test, considering a p value < 0.05 significant., Results: We included a total of 64 patients with septic shock and 32 non-infected controls. The median number of adhered leukocytes per field in the sepsis group was 1.0 (IQR 0-3.5) compared to 0 (0-0) in the non-infected group (p < 0.001). The median number of rolling leukocytes was 26 (10.3-42) in the sepsis group and 9.8 (4.8-17.3) in the non-infected group (p < 0.001) per field. Among the patients with sepsis (n = 64), there was an increased number of adhered leukocytes in non-survivors compared to survivors (3.0 (1-5.5) vs. 1.0 (0-3.0)) (p < 0.05); however, there was no difference in rolling leukocytes (35 (20-48) vs. 26 (10-41)) (p = 0.31)., Conclusions: Our results demonstrated a higher number of rolling and adhered leukocytes in patients with septic shock when compared to non-infected controls, and an increased number of adhered leukocytes in non-survivors., Trial Registration: ClinicalTrials.gov , NCT00793442 ; Registered on 19 November 2008 PG0GM076659 (US NIH Grant/Contract). First submitted 18 July 2007. First posted 2 August 2007.

Sepsis is a major contributor to the global burden of disease. The majority of sepsis cases and deaths are estimated to occur in low and middle-income countries. Barriers to reducing the global burden of sepsis include difficulty quantifying attributable morbidity and mortality, low awareness, poverty and health inequity, and under-resourced and low-resilience public health and acute health care delivery systems. Important differences in the populations at risk, infecting pathogens, and clinical capacity to manage sepsis in high and low-resource settings necessitate context-specific approaches to this significant problem. We review these challenges and propose strategies to overcome them. These strategies include strengthening health systems, accurately identifying and quantifying sepsis cases, conducting inclusive research, establishing data-driven and context-specific management guidelines, promoting creative clinical interventions, and advocacy.

Point-of-care sensors that enable the fast collection of information relevant to a patient's health state can facilitate improved health access, reduce healthcare costs and improve the quality of healthcare delivery. In the diagnosis of sepsis - defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and the leading cause of in-patient death and of hospital readmission in the United States - predicting which infections will lead to life-threatening organ dysfunction and developing specific anti-sepsis treatments remain challenging because of the significant heterogeneity of the host response. Yet the use of point-of-care devices could reduce the time from the onset of a patient's infection to the administration of appropriate therapeutics. In this Perspective, we describe the current state of point-of-care sensors for the diagnosis and monitoring of sepsis, and outline opportunities in the use of these devices to dramatically improve patient care.

Objectives: The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis., Design: Laboratory animal research, pilot human feasibility trial., Setting: University basic science laboratory and tertiary care hospital., Subjects: Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis., Interventions: Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light., Measurements and Main Results: Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations., Conclusions: Modifying the spectrum of light may offer therapeutic utility in sepsis.