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Objectives: International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital., Design: Multicenter, open, parallel-group randomized feasibility trial., Setting: Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals., Patients: Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization., Interventions: IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization., Measurements and Main Results: Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean ( sd ) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1-63). Thirty-day mortality was 17.9% ( n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84-2.83)., Conclusions: Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis., Competing Interests: Dr. Bell is supported by the National Institute of Applied Research Collaboration Northwest London. Dr. Gray’s, Ms. Oatey’s, Dr. Irvine’s, Mr. Kennel’s, Dr. Norrie’s, Dr. Walsh’s, and Dr. Hall’s institutions received funding from the John Moulton Charitable Trust. Dr. Gray, Ms. Grahamslaw, and Dr. Appelboam received support for article research from the John Moulton Charitable Trust. Ms. Oatey disclosed work for hire. Dr. Cafferkey’s institution received funding from the Royal College of Emergency Medicine and the Sepsis FEAT Charity. Dr. Horner’s institution received funding from the National Institute for Health Research (132594). Mr. Skipworth received funding from Helsinn, Faraday Pharmaceuticals, Actimed Therapeutics, and Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals., Design: In vitro/ex vivo investigation., Setting: University laboratory., Subjects: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients., Interventions: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum., Measurements and Results: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs., Conclusion: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes., Competing Interests: Dr. Melis’ institution received funding from the European Union’s Horizon 2020 research and innovation program (number 676129). Dr. Singer’s institution received funding from Biotest, Roche, and Deltex Medical; they received funding from Volition, Calbiochem, AOP Pharma, Aptarion, Matisse, NewB, Paion, Pfizer, Biomerieux, and Hemotune. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications., Design: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup., Setting: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients., Subjects: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2., Interventions: None., Measurements and Main Results: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009)., Conclusions: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts., Competing Interests: Dr. Sinha received funding from the National Heart Lung and Blood Institute as part of the Acute Respiratory Distress Syndrome Network and AstraZeneca ( ClinicalTrials.gov number NCT00979121). Drs. Sinha, Matthay, and Calfee received support for article research from the National Institutes of Health (NIH). Dr. O’Kane’s institution received funding from National Intitute for Health and Care Research (NIHR) Efficacy and Evaluation Mechanism (EME); she received funding from Californian Institute for Regenerative Medicine and Insmed; she disclosed that her spouse has received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lily, Sobi, Vir Biotech, and Faron Pharmaceuticals and disclosed that her spouse holds a patent with Queen’s University (USB962032) and director of the NIHR/Medical Research Council (MRC) EME program and co-director of research for intensive care society of the UK; she received support for article research from the Research Councils UK. Dr. Levitt disclosed the off-label product use of the Experimental use of simvastatin and rosuvastatin for acute respiratory distress syndrome. Dr. Matthay’s institution received funding from Roche-Genentech; received funding from Gilead Therapeutics, Novartis, Quantum Therapeutics, and Johnson and Johnson. Drs. Matthay and Calfee received funding from Gen1Life Science. Dr. Calfee’s institution received funding from the NIH; she received funding from Vasomune, Janssen, Cellenkos, and NGMBio. Dr. McAuley’s institution received funding from the NIHR; he received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis Eli Lilly Vir Biotechnology, Inc SOBI Faron Pharmaceuticals Grants from NIHR, Wellcome Trust, MRC, Innovate UK, NI PHA HSC R&D division, Novavax and Randox; disclosed that his spouse received funding from California Institute for Regenerative Medicine. Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) was supported by the UK EME program, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME program is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care Research and Development Division, Public Health Agency for Northern Ireland. Dr. Moore was supported by T32 HL129970. Dr. Calfee was supported by R35 HL140026. Dr. Baron was supported by R01 HL112747-01 for the original interleukin-18 analyses. Dr. Shankar-Hari was supported by the NIHR Clinician Scientist Award (CS-2016-16-011). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Competing Interests: Dr. Shankar-Hari received funding from the National Institute for Health Research (NIHR) Clinician Scientist Award (NIHR-CS-2016-16-011). Dr. Wunsch received funding from a Canada Research Chair in Critical Care Organization and Outcomes, an Excellence in Research Award from the Department of Anesthesia at the University of Toronto, the Canadian Institutes of Health Research, and the National Institutes of Health (NIH) (R01 DA042299; HL137816). Dr. Singer’s institution received funding from Deltex, Biotest, Fresenius, Roche Diagnostics, and New B; he received funding from a NIHR Emeritus Senior Investigator Award. Dr. Angus received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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.)

Objectives: To identify characteristics that predict 30-day mortality among patients critically ill with coronavirus disease 2019 in England, Wales, and Northern Ireland., Design: Observational cohort study., Setting: A total of 258 adult critical care units., Patients: A total of 10,362 patients with confirmed coronavirus disease 2019 with a start of critical care between March 1, 2020, and June 22, 2020, of whom 9,990 were eligible (excluding patients with a duration of critical care less than 24 hr or missing core variables)., Measurements and Main Results: The main outcome measure was time to death within 30 days of the start of critical care. Of 9,990 eligible patients (median age 60 yr, 70% male), 3,933 died within 30 days of the start of critical care. As of July 22, 2020, 189 patients were still receiving critical care and a further 446 were still in acute hospital. Data were missing for between 0.1% and 7.2% of patients across prognostic factors. We imputed missing data ten-fold, using fully conditional specification and continuous variables were modeled using restricted cubic splines. Associations between the candidate prognostic factors and time to death within 30 days of the start of critical care were determined after adjustment for multiple variables with Cox proportional hazards modeling. Significant associations were identified for age, ethnicity, deprivation, body mass index, prior dependency, immunocompromise, lowest systolic blood pressure, highest heart rate, highest respiratory rate, Pao2/Fio2 ratio (and interaction with mechanical ventilation), highest blood lactate concentration, highest serum urea, and lowest platelet count over the first 24 hours of critical care. Nonsignificant associations were found for sex, sedation, highest temperature, and lowest hemoglobin concentration., Conclusions: We identified patient characteristics that predict an increased likelihood of death within 30 days of the start of critical care for patients with coronavirus disease 2019. These findings may support development of a prediction model for benchmarking critical care providers., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: We aimed to develop and validate an accurate risk prediction model for both mortality and a combined outcome of mortality and morbidity for maternal admissions to critical care., Design: We used data from a high-quality prospectively collected national database, supported with literature review and expert opinion. We tested univariable associations between each risk factor and outcome. We then developed two separate multivariable logistic regression models for the outcomes of acute hospital mortality and death or prolonged ICU length of stay. We validated two parsimonious risk prediction models specific for a maternal population., Setting: The Intensive Care National Audit and Research Centre Case Mix Programme is the national clinical audit for adult critical care in England, Wales, and Northern Ireland., Patients: All female admissions to adult general critical care units, for the period January 1, 2007-December 31, 2016, 16-50 years old, and admitted either while pregnant or within 42 days of delivery-a cohort of 15,480 women., Interventions: None., Measurements and Main Results: We aimed to develop and validate an accurate risk prediction model for both mortality and a combined outcome of mortality and morbidity for maternal admissions to critical care. For the primary outcome of acute hospital mortality, our parsimonious risk model consisting of eight variables had an area under the receiver operating characteristic of 0.96 (95% CI, 0.91-1.00); these variables are commonly available for all maternal admissions. For the secondary composite outcome of death or ICU length of stay greater than 48 hours, the risk model consisting of 17 variables had an area under the receiver operating characteristic of 0.80 (95% CI, 0.78-0.83)., Conclusions: We developed risk prediction models specific to the maternal critical care population. The models compare favorably against general adult ICU risk prediction models in current use within this population.

Objectives: Major increases in the proportion of elderly people in the population are predicted worldwide. These population increases, along with improving therapeutic options and more aggressive treatment of elderly patients, will have major impact on the future need for healthcare resources, including critical care. Our objectives were to explore the trends in admissions, resource use, and risk-adjusted hospital mortality for older patients, admitted over a 20-year period between 1997 and 2016 to adult general ICUs in England, Wales, and Northern Ireland., Design: RETROSPECTIVE ANALYSIS OF NATIONAL CLINICAL AUDIT DATABASE., Setting: The Intensive Care National Audit & Research Centre Case Mix Programme Database, the national clinical audit for adult general ICUs in England, Wales, and Northern Ireland., Patients: All adult patients 16 years old or older admitted to adult general ICUs contributing data to the Case Mix Programme Database between January 1, 1997, and December 31, 2016., Measurements and Main Results: The annual number, trends, and outcomes for patients across four age bands (16-64, 65-74, 75-84, and 85+ yr) admitted to ICUs contributing to the Case Mix Programme Database from 1997 to 2016 were examined. Case mix, activity, and outcome were described in detail for the most recent cohort of patients admitted in 2015-2016. Between 1997 to 2016, the annual number of admissions to ICU of patients in the older age bands increased disproportionately, with increases that could not be explained solely by general U.K. demographic shifts. The risk-adjusted acute hospital mortality decreased significantly within each age band over the 20-year period of the study. Although acute severity at ICU admission was comparable with that of the younger age group, apart from cardiovascular and renal dysfunction, older patients received less organ support. Older patients stayed longer in hospital post-ICU discharge, and hospital mortality increased with age, but the majority of patients surviving to hospital discharge returned home., Conclusions: Over the past two decades, elderly patients have been more commonly admitted to ICU than can be explained solely by the demographic shift. Importantly, as with the wider population, outcomes in elderly patients admitted to ICU are improving over time, with most patients returning home.

Objectives: Quantification of potential for lung recruitment may guide the ventilatory strategy in acute respiratory distress syndrome. However, there are no quantitative data on recruitability in patients with severe acute respiratory distress syndrome who require extracorporeal membrane oxygenation. We sought to quantify potential for lung recruitment and its relationship with outcomes in this cohort of patients., Design: A single-center, retrospective, observational cohort study., Setting: Tertiary referral severe respiratory failure center in a university hospital in the United Kingdom., Patients: Forty-seven adults with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation., Intervention: None., Measurements and Main Results: In patients with severe acute respiratory distress syndrome-mainly of pulmonary origin (86%)-the potential for lung recruitment and the weight of nonaerated, poorly aerated, normally aerated, and hyperaerated lung tissue were assessed at low (5 cmH2O) and high (45 cmH2O) airway pressures. Patients were categorized as high or low potential for lung recruitment based on the median potential for lung recruitment value of the study population. The median potential for lung recruitment was 24.3% (interquartile range = 11.4-37%) ranging from -2% to 76.3% of the total lung weight. Patients with potential for lung recruitment above the median had significantly shorter extracorporeal membrane oxygenation duration (8 vs 13 d; p = 0.013) and shorter ICU stay (15 vs 22 d; p = 0.028), but mortality was not statistically different (24% vs 46%; p = 0.159)., Conclusions: We observed significant variability in potential for lung recruitment in patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. Patients with high potential for lung recruitment had a shorter ICU stay and shorter extracorporeal membrane oxygenation duration.

Objectives: Severe sepsis is a significant cause of healthcare use and morbidity among pediatric patients, but little is known about readmission diagnoses. We sought to determine the most common readmission diagnoses after pediatric severe sepsis, the extent to which post-sepsis readmissions may be potentially preventable, and whether patterns of readmission diagnoses differ compared with readmissions after other common acute medical hospitalizations., Design: Observational cohort study., Setting: National Readmission Database (2013-2014), including all-payer hospitalizations from 22 states., Patients: Four-thousand five-hundred twenty-eight pediatric severe sepsis hospitalizations, matched by age, gender, comorbidities, and length of stay to 4,528 pediatric hospitalizations for other common acute medical conditions., Interventions: None., Measurements and Main Results: We compared rates of 30-day all cause, diagnosis-specific, and potentially preventable hospital readmissions using McNemar's chi-square tests for paired data. Among 5,841 eligible pediatric severe sepsis hospitalizations with live discharge, 4,528 (77.5%) were matched 1:1 to 4,528 pediatric hospitalizations for other acute medical conditions. Of 4,528 matched sepsis hospitalizations, 851 (18.8% [95% CI, 16.0-18.2]) were rehospitalized within 30 days, compared with 775 (17.1% [95% CI, 17.1-20.0]) of matched hospitalizations for other causes (p = 0.02). The most common readmission diagnoses were chemotherapy, device complications, and sepsis, all of which were several-fold higher after sepsis versus after matched nonsepsis hospitalization. Only 11.5% of readmissions were for ambulatory care sensitive conditions compared with 23% of rehospitalizations after common acute medical conditions., Conclusions: More than one in six children surviving severe sepsis were rehospitalized within 30 days, most commonly for maintenance chemotherapy, medical device complications, or recurrent sepsis. Only a small proportion of readmissions were for ambulatory care sensitive conditions.

Objectives: To test whether differences in both general and sepsis-specific patient characteristics explain the observed differences in sepsis mortality between countries, using two national critical care (ICU) databases., Design: Cohort study., Setting: We analyzed 62 and 164 ICUs in Brazil and England, respectively., Patients: Twenty-two-thousand four-hundred twenty-six adult ICU admissions from January 2013 to December 2013., Interventions: None., Measurements and Main Results: After harmonizing relevant variables, we merged the first ICU episode of adult medical admissions from Brazil (ORganizational CHaractEeriSTics in cRitical cAre study) and England (Intensive Care National Audit & Research Centre Case Mix Programme). Sepsis-3 definition was used, and the primary outcome was hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on mortality, after adjustment for general (age, sex, comorbidities, functional status, admission source, time to admission) and sepsis-specific (site of infection, organ dysfunction type and number) patient characteristics. Of medical ICU admissions, 13.2% (4,505/34,150) in Brazil and 30.7% (17,921/58,316) in England met the sepsis definition. The Brazil cohort was older, had greater prevalence of severe comorbidities and dependency compared with England. Respiratory was the most common infection site in both countries. The most common organ dysfunction was cardiovascular in Brazil (41.2%) and respiratory in England (85.8%). Crude hospital mortality was similar (Brazil 41.4% vs England 39.3%; odds ratio, 1.12 [0.98-1.30]). After adjusting for general patient characteristics, there was an important change in the point-estimate of the odds ratio (0.88 [0.75-1.02]). However, after adjusting for sepsis-specific patient characteristics, the direction of effect reversed again with Brazil having higher risk-adjusted mortality (odds ratio, 1.22 [1.05-1.43])., Conclusions: Patients with sepsis admitted to ICUs in Brazil and England have important differences in general and sepsis-specific characteristics, from source of admission to organ dysfunctions. We show that comparing crude mortality from sepsis patients admitted to the ICU between countries, as currently performed, is not reliable and that the adjustment for both general and sepsis-specific patient characteristics is essential for valid international comparisons of mortality amongst sepsis patients admitted to critical care units.

Objectives: Light chains κ and λ are immunoglobulin constituents but also circulate independently in blood as free light chains. We investigated whether a concomitant abnormality in free light chain and immunoglobulin levels could identify a high risk of death sepsis subpopulation to inform future IV immunoglobulin trials. We tested whether light chain allelic inclusion occurs in circulating B cells., Design: Prospective cohort study., Setting: Adult general ICUs., Patients: Adult sepsis patients without any documented immune comorbidity., Interventions: None., Measurements and Main Results: Serum total free light chain, immunoglobulin G, immunoglobulin A, and immunoglobulin M were measured on ICU days 1, 3, and 7. Population normal ranges defined normal and abnormal categories. Logistic regression models tested any independent relationship between high free light chain, immunoglobulins and hospital mortality. CD19 B-cell subsets expressing cell surface κ and λ were quantified by flow cytometry; their frequencies were compared against healthy subjects and correlation assessed against free light chain concentrations. On ICU day 1, high free light chain λ and high free light chain κ were seen in 46.5% and 75.3% of the study cohort (n = 101). Low immunoglobulin levels were commonplace (45.5%) at ICU admission. ICU admission day free light chain and immunoglobulin concentrations were significantly correlated. Septic patients had significantly more CD19 B cells expressing both κ and λ compared with healthy controls (median [interquartile range] 4.1% [2.4-11.0] vs 1.3% [1.2-2.9], respectively; p = 0.0001); these correlated with free light chain concentrations., Conclusions: To our knowledge, abnormalities and associations of free light chain in critically ill adults with sepsis have not been previously reported. The additional prognostic value of free light chain λ and the significance of allelic inclusion in B cells in sepsis require further investigation.

Objective: Sepsis is life-threatening organ dysfunction due to dysregulated host responses to infection. Current knowledge of human B-cell alterations in sepsis is sparse. We tested the hypothesis that B-cell loss in sepsis involves distinct subpopulations of B cells and investigated mechanisms of B-cell depletion., Design: Prospective cohort study., Setting: Critical care units., Patients: Adult sepsis patients without any documented immune comorbidity., Interventions: None., Measurements and Main Results: B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic cells and phosphorylation of intracellular kinases identified activation status of B-cell subsets. B cell-specific survival ligand concentrations were measured. Gene expression in purified B cells was measured by microarray. Differences in messenger RNA abundance between sepsis and healthy controls were compared. Lymphopenia present in 74.2% of patients on admission day was associated with lower absolute B-cell counts (median [interquartile range], 0.133 [0.093-0.277] 10 cells/L) and selective depletion of memory B cells despite normal B cell survival ligand concentrations. Greater apoptotic depletion of class-switched and IgM memory cells was associated with phosphorylation of extracellular signal-regulated kinases, implying externally driven lymphocyte stress and activation-associated cell death. This inference is supported by gene expression profiles highlighting mitochondrial dysfunction and cell death pathways, with enriched intrinsic and extrinsic pathway apoptosis genes., Conclusions: Depletion of the memory B-cell compartment contributes to the immunosuppression induced by sepsis. Therapies targeted at reversing this immune memory depletion warrant further investigation.

Objectives: Sepsis generates significant global acute illness burden. The international variations in sepsis epidemiology (illness burden) have implications for region specific health policy. We hypothesised that there have been changes over time in the sepsis definitional elements (infection and organ dysfunction), and these may have impacted on hospital mortality., Design: Cohort study., Setting: We evaluated a high quality, nationally representative, clinical ICU database including data from 181 adult ICUs in England., Patients: Nine hundred sixty-seven thousand five hundred thirty-two consecutive adult ICU admissions from January 2000 to December 2012., Interventions: None., Measurements and Main Results: To address the proposed hypothesis, we evaluated a high quality, nationally representative, clinical, ICU database of 967,532 consecutive admissions to 181 adult ICUs in England, from January 2000 to December 2012, to identify sepsis cases in a robust and reproducible way. Multinomial logistic regression was used to report unadjusted trends in sepsis definitional elements and in mortality risk categories based on organ dysfunction combinations. We generated logistic regression models and assessed statistical interactions with acute hospital mortality as outcome and cohort characteristics, sepsis definitional elements, and mortality risk categories as covariates. Finally, we calculated postestimation statistics to illustrate the magnitude of clinically meaningful improvements in sepsis outcomes over the study period. Over the study period, there were 248,864 sepsis admissions (25.7%). Sepsis mortality varied by infection sources (19.1% for genitourinary to 43.0% for respiratory; p < 0.001), by number of organ dysfunctions (18.5% for 1 to 69.9% for 5; p < 0.001), and organ dysfunction combinations (18.5% for risk category 1 to 58.0% for risk category 4). The rate of improvement in adjusted hospital mortality was significant (odds ratio, 0.939 [0.934-0.945] per year; p < 0.001), but showed different secular trends in improvement between infection sources., Conclusions: Within a sepsis cohort, we illustrate case-mix heterogeneity using definitional elements (infection source and organ dysfunction). In the context of improving outcomes, we illustrate differential secular trends in impact of these variables on adjusted mortality and propose this as a valid reason for international variations in sepsis epidemiology. Our article highlights the need to determine standardized reporting elements for optimal comparisons of international sepsis epidemiology.