Sepsis Trials Research Articles

In-Hospital Mortality of Sepsis Differs Depending on the Origin of Infection: An Investigation of Predisposing Factors.

Sepsis is a heterogeneous syndrome characterized by a variety of clinical features. Analysis of large clinical datasets may serve to define groups of sepsis with different risks of adverse outcomes. Clinical experience supports the concept that prognosis, treatment, severity, and time course of sepsis vary depending on the source of infection. We analyzed a large publicly available database to test this hypothesis. In addition, we developed prognostic models for the three main types of sepsis: pulmonary, urinary, and abdominal sepsis. We used logistic regression using routinely available clinical data for mortality prediction in each of these groups. The data was extracted from the eICU collaborative research database, a multi-center intensive care unit with over 200,000 admissions. Sepsis cohorts were defined using admission diagnosis codes. We used univariate and multivariate analyses to establish factors relevant for outcome prediction in all three cohorts of sepsis (pulmonary, urinary and abdominal). For logistic regression, input variables were automatically selected using a sequential forward search algorithm over 10 dataset instances. Receiver operator characteristics were generated for each model and compared with established prognostication tools (APACHE IV and SOFA). A total of 3,958 sepsis admissions were included in the analysis. Sepsis in-hospital mortality differed depending on the cause of infection: abdominal 18.93%, pulmonary 19.27%, and renal 12.81%. Higher average heart rate was associated with increased mortality risk. Increased average Mean Arterial Pressure (MAP) showed a reduced mortality risk across all sepsis groups. Results from the LR models found significant factors that were relevant for specific sepsis groups. Our models outperformed APACHE IV and SOFA scores with AUC between 0.63 and 0.74. Predictive power decreased over time, with the best results achieved for data extracted for the first 24 h of admission. Mortality varied significantly between the three sepsis groups. We also demonstrate that factors of importance show considerable heterogeneity depending on the source of infection. The factors influencing in-hospital mortality vary depending on the source of sepsis which may explain why most sepsis trials have failed to identify an effective treatment. The source of infection should be considered when considering mortality risk. Planning of sepsis treatment trials may benefit from risk stratification based on the source of infection.

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study

BackgroundMultiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.MethodsWe measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter.ResultsAmong 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91–0.95) with a summary AUROC of 0.80 (0.76–0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables—ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1—contributed to the models’ predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively.ConclusionsThe newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.Graphical abstract

Update on vitamin C administration in critical illness.

Several studies have recently explored the effects of intravenous vitamin C in sepsis. We aimed to summarize their findings to provide perspectives for future research. Sepsis trials examined 6 g/day of intravenous vitamin C with or without the thiamine and/or hydrocortisone compared with placebo or hydrocortisone. Network meta-analysis reported that intravenous vitamin C, thiamine, hydrocortisone, or combinations of these drugs was not proven to reduce long-term mortality. However, the component network meta-analysis suggested an association of high-dose (>6 g/day) and very-high dose vitamin C (>12 g/day) and decreased mortality but with low certainty. The preclinical investigations have, however, advanced to much higher doses of intravenous vitamin C therapy since a scoping review on harm reported that mega-doses of intravenous vitamin C (50-100 g/day) had been administered without any conclusive adverse effects. In a Gram-negative sheep model, renal tissue hypoperfusion was reversed, followed by improvements in kidney function when a mega-dose of vitamin C (150 g/day equivalent) was administered. The effect of intravenous vitamin C in critically ill patients has yet to be determined and might be dose-dependent. Clinical studies of very high or mega doses of vitamin C are justified by preclinical data.

The Association of Long-Term Use of Proton Pump Inhibitors and Histamine H2 Receptor Antagonists with Clinical Complications in Patients with Severe Sepsis.

Objective Proton pump inhibitors (PPIs) are commonly used to treat gastric acidity, and their frequent use may trigger various malfunctioning, such as cardiac, renal, and liver function failure. In the current study, we evaluated the association between the excessive use of the PPIs and the clinical complications of intensive care unit (ICU) septic patients. Methods A total of 208188 patients were analyzed from 2016 to 2017 through the China Critical Care Sepsis Trial (CCCST) database. The characteristics of the study group and outcome of events from the PPI- and H2 blocker-using groups were reported. To get unbiased results, the data from the target trials were randomly assigned for PPI and H2 blocker groups. Result The data revealed 43.34 excess deaths (95% confidence intensive (CI) 25.12 to 62.02) per 1000 patients in patients extensively consuming PPI drugs. The sepsis with chronic kidney disease attributed to deaths 21.36; 95% CI (9.34 to 23.23). However, comorbidities, including circulatory diseases (16.34; 95% CI 5.78 to 23.45), nervous system (2.08; 95% CI 1.56 to 6.34), mental disorders (1.87; 95% CI 1.65 to 2.95), genitourinary system (5.23; 95% CI 3.69 to 8.89), and infectious and parasitic disease (4.17; 95% CI 1.44 to 7.49), were also reported. Extensive use of the PPIs and H2 blockers was associated with esophageal adenocarcinoma, Barrett's esophagus, neoplasms, and GI cancers. Conclusion We conclude that the excessive use of PPI in sepsis patients triggers chronic kidney disease which has a higher clinical complication rate among others.

IV ASCORBATE REDUCTION OF ARDS MORTALITY IS CONTINGENT AND DOSE-DEPENDENT WITH THE DEGREE OF HYPEROXIC SUPPORT

TYPE: Late Breaking Abstract TOPIC: Critical Care PURPOSE: Several randomized trials have failed to demonstrate a mortality benefit of high-dose intravenous ascorbate (vitamin C) in patients with sepsis. Recent ex-vivo human lung experiments have revealed that ascorbate acts directly on lung endothelium in hyperoxic conditions. We hypothesized that similar effects may have occurred in CITRIS-ALI trial patients, a double-blind randomized controlled trial of high-dose intravenous vitamin C in patients with ARDS. METHODS: CITRIS-ALI patients were classified, post-hoc, into three groups: Low, moderate, and severe hyperoxia based upon FiO2 < 50%, 50-80%, and ≥ 80% respectively. Logistic regression analysis was applied to evaluate the statistical interactions between hyperoxic groups and 28-day mortality and marginal analysis was performed. RESULTS: Severe hyperoxia support significantly interacted with vitamin C administration instead of placebo (p<0.001). Patients with mild hyperoxia had mortality 30% (95% CI 13.6–46.4%) and 42.4% (95% CI 25.6–59.3) for placebo and vitamin C arms respectively, p=0.3. Moderate hyperoxia groups exhibited mortality of 41.4% (95% CI 23.5 – 59.3%) and 26.7% (95% CI10.8–42.5) for placebo and vitamin C arms, p=0.2. The highest degree of hyperoxia group had mortality 74% (95% CI 56–92%) and 14.3% (95% CI 0–29.3%) for placebo and vitamin C arms, p<0.001. CONCLUSIONS: These findings suggest that high-dose intravenous vitamin C reduction of ARDS mortality is significantly linked to the degree of hyperoxia required for support, being most significant in patients who require the highest levels of hyperoxia. CLINICAL IMPLICATIONS: These findings explain the heterogeneity of outcomes in vitamin C sepsis trials in contrast to CITRIS-ALI and could guide the design of future clinical trials. DISCLOSURE: Nothing to declare. KEYWORD: Hyperoxia

Machine learning and murine models explain failures of clinical sepsis trials.

Multiple clinical trials failed to demonstrate the efficacy of hydrocortisone, ascorbic acid, and thiamine (HAT) in sepsis. These trials were dominated by patients with pulmonary sepsis and have not accounted for differences in the inflammatory responses across varying etiologies of injury/illness. Hydrocortisone, ascorbic acid, and thiamine have previously revealed tremendous benefits in animal peritonitis sepsis models (cecal ligation and puncture [CLP]) in contradiction to the various clinical trials. The impact of HAT remains unclear in pulmonary sepsis. Our objective was to investigate the impact of HAT in pneumonia, consistent with the predominate etiology in the discordant clinical trials. We hypothesized that, in a pulmonary sepsis model, HAT would act synergistically to reduce end-organ dysfunction by the altering the inflammatory response, in a unique manner compared with CLP. Using Pseudomonas aeruginosa pneumonia, a pulmonary sepsis model (pneumonia [PNA]) was compared directly to previously investigated intra-abdominal sepsis models. Machine learning applied to early vital signs stratified animals into those predicted to die (pDie) versus predicted to live (pLive). Animals were then randomized to receive antibiotics and fluids (vehicle [VEH]) vs. HAT). Vitals, cytokines, vitamin C, and markers of liver and kidney function were assessed in the blood, bronchoalveolar lavage, and organ homogenates. PNA was induced in 119 outbred wild-type Institute of Cancer Research mice (predicted mortality approximately 50%) similar to CLP. In PNA, interleukin 1 receptor antagonist in 72-hour bronchoalveolar lavage was lower with HAT (2.36 ng/mL) compared with VEH (4.88 ng/mL; p = 0.04). The remaining inflammatory cytokines and markers of liver/renal function showed no significant difference with HAT in PNA. PNA vitamin C levels were 0.62 mg/dL (pDie HAT), lower than vitamin C levels after CLP (1.195 mg/dL). Unlike CLP, PNA mice did not develop acute kidney injury (blood urea nitrogen: pDie, 33.5 mg/dL vs. pLive, 27.6 mg/dL; p = 0.17). Furthermore, following PNA, HAT did not significantly reduce microscopic renal oxidative stress (mean gray area: pDie, 16.64 vs. pLive, 6.88; p = 0.93). Unlike CLP where HAT demonstrated a survival benefit, HAT had no impact on survival in PNA. Hydrocortisone, ascorbic acid, and thiamine therapy has minimal benefits in pneumonia. The inflammatory response induced by pulmonary sepsis is unique compared with the response during intra-abdominal sepsis. Consequently, different etiologies of sepsis respond differently to HAT therapy.

Personalised immunotherapy in sepsis: a scoping review protocol

IntroductionSepsis, a life-threatening organ dysfunction syndrome occurring in the context of severe infections, remains a major burden on global health with high morbidity and high mortality rates. Despite recent advances...

Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients (REFACED Sepsis)\u2014protocol for a multicenter, randomized, clinical, proof-of-concept trial

BackgroundIntravenous fluids are often used in the treatment of sepsis. The better strategy regarding fluid volume is debated, but preliminary data in patients with septic shock or sepsis-related hypotension favor restrictive fluid administration. We describe the protocol and statistical analysis plan for the Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients (REFACED Sepsis)—a multicenter, randomized clinical proof-of-concept trial. The aim of the REFACED Sepsis trial is to test if a restrictive intravenous fluid protocol in emergency department patients with sepsis without shock is feasible and decreases the intravenous fluid volume administered in comparison to standard care.MethodsThis is an investigator-initiated, multicenter, randomized, parallel-group, open-labeled, feasibility trial investigating volumes of crystalloid fluid within 24 h in 124 patients with sepsis without shock enrolled at three emergency departments in the Central Denmark Region. Patients are allocated to two different intravenous fluid regimens: a restrictive approach using four trigger criteria for fluid administration vs. standard care.The primary, feasibility outcome is total intravenous, crystalloid fluid volume within 24 h, and key secondary outcomes include protocol violations, total fluids (intravenous and oral) within 24 h, and serious adverse reactions and suspected unexpected serious adverse reactions.Status: The trial started in November 2021, and the last patient is anticipated to be included in January 2022.DiscussionSepsis is very common in emergency department patients and fluid administration is very frequently administered in these patients. However, the evidence to guide fluid administration is very sparse. This feasibility trial will be the foundation for a potential future large-scale trial investigating restrictive vs. standard fluid administration in patients with sepsis.Trial registrationEudraCT number: 2021-000224-35 (date: 2021 May 03), ClinicalTrials.gov number: NCT05076435 (date: 2021 October 13), Committee on Health Research Ethics – Central Denmark Region: 1-10-72-163-21 (date: 2021 June 28).

Retrospective identification of infection in the emergency department: A significant challenge in sepsis clinical trials

BackgroundThis study examined three methods for retrospectively identifying infection in emergency department (ED) patients: modified objective definitions of infection (MODI) from the CDC/NHSN, physician adjudication determination of infection, and ED treating physician behavior. MethodsThis study used a subset of data from a prospective sepsis trial. We used Fleiss's Kappa to compare agreement between two physicians retrospectively adjudicating infection based on the patient's medical record, modified infection definition from the CDC/NHSN, and ED treating physician behavior. ResultsOverall, there was similar agreement between physician adjudication of infection and MODI criteria (Kappa=0.59) compared to having two physicians independently identify infection through retrospective chart review (Kappa=0.58). ED treating physician behavior was a poorer proxy for infection when compared to the MODI criteria (0.41) and physician adjudication (Kappa = 0.50). ConclusionsRetrospective identification of infection poses a significant challenge in sepsis clinical trials. Using modified definitions of infection provides a standardized, less time consuming, and equally effective means of identifying infection compared to having multiple physicians adjudicate a patient's chart.

Temperature Trajectory Sub-phenotypes and the Immuno-Inflammatory Response in Pediatric Sepsis.

Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 h have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 h, and compare cytokine, immune function, and immunometabolic markers across subgroups. This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 h of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3-11%; P = 0.26). Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.

Efficacy and safety of Shengmai injection as an adjunctive therapy on sepsis: A protocol for systematic review and meta-analysis.

Introduction:Sepsis is a common life-threatening, acute and severe disease with high morbidity and mortality, which seriously endangers patient health. Shengmai injection (SMI) is typically used as an alternative treatment for sepsis patients. This investigation aimed at designing a comprehensive recollection and meta-analytical exercise for evaluating efficacy and safety-profile for employing SMI against sepsis.Methods:Multiple research literature repositories, both localized and global, were examined for randomized controlled trials of sepsis treated by SMI - from repository inception to December 2021 as a timeframe. Primary outcome measures contained 28-day all-cause mortality, while secondary outcome measures consisted of Sequential Organ Failure Assessment scorings, acute Physiology and Chronic Health Evaluation II scorings, ICU-based hospitalization length, mechanical ventilation timespan, ICU mortality rate, and adverse effects/events. RevMan V.5.3 was employed for data analyses. Two reviewers evaluated bias risks/investigation quality through Cochrane Collaboration risk of bias tool / Grades of Recommendations Assessment Development and Evaluation, separately.Results:Such a comprehensive reviewing protocol review protocol systematically and objectively analyzes the effectiveness and safety-profile of SMI for therapy against sepsis, together with providing scientific grounds for clinic-based employment for SMI.PROSPERO registration number:CRD42021245247.

Contribution to development of remedies for COVID-19: focusing on Eritoran

Eritoran (E5564) is Eisai's in-house discovered and developed investigational Toll-Like Receptor 4 (TLR4) antagonist created with natural product organic synthesis technology. It is a structural analogue of Lipid A, which is an activator of endotoxins of bacteria. It has been previously observed to be safe in 14 clinical studies including a large Phase 3 randomized trial in severe sepsis. In order to evaluate therapeutic efficacy by eritoran, we are participating in the international network REMAP-CAP-COVID (Randomized, Embedded, Multi-factorial, Adaptive Platform-Community Acquired Pneumonia COVID) which aims for novel coronavirus medicine development through drug repurposing, and began an international collaborative clinical trial in October 2020 which is designated for confirmed novel coronavirus patients who are hospitalized and are in a progressing disease state. It is hoped that through suppressing the most upstream TLR4 activity which controls production of multiple cytokines by eritoran, the cytokine storm in patients can be suppressed and pneumonia can thus be prevented from becoming severe. On the other hand, E6011 is the only humanized anti-fractalkine (FKN) monoclonal antibody in the world created by KAN Research Institute. E6011 inhibits the tight binding of CD16-positive monocytes (a cell population that highly expresses the FKN receptor CX3CR1) to vascular endothelial cells, which are important for the local inflammatory response. This is expected to suppress the formation and exacerbation of vasculopathy in COVID-19.

2023 updates on the closed or open after-source control for severe complicated intraabdominal sepsis (COOL) trial

2023 updates on the closed or open after-source control for severe complicated intraabdominal sepsis (COOL) trial

An international survey on the use of intrapleural tissue plasminogen activator/DNase therapy for pleural infection.

IntroductionIntrapleural tissue plasminogen activator (tPA) combined with human recombinant DNase (DNase) could be an effective alternative to surgery in managing pleural infection, as demonstrated in the Multi-centre Intrapleural Sepsis Trial (MIST)-2. However, the optimal delivery regimen is still unknown. The aim of this survey was to identify the current practice of tPA/DNase use by physicians with published interests in pleural infection, and their opinions on dose de-escalation of tPA/DNase therapy.MethodsPotential participants were identified using four search strategies. Only practising physicians who were managing patients with pleural infections and either actively involved in pleural research and publications, or were members of relevant pleural disease guideline panels at the time of survey were included.ResultsAn invitation email with the questionnaire was sent to 102 participants, of whom 49 (48%) responded. Most respondents (90%, n=44) have used tPA/DNase to manage pleural infection, but the dosing and delivery regimens employed varied. Many (86%, 38 out of 44) respondents have used 10 mg tPA, while 73% (n=32), 16% (n=7) and 9% (n=4) have used 5 mg, 2.5 mg and 1 mg doses, respectively. Most respondents instilled tPA/DNase concurrently (61%, n=27) and routinely administered six doses of tPA/DNase (52%, n=23) twice daily (82%, n=36). Respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if a median 80% (interquartile range 50–80%) of patients could be successfully treated at that dose.ConclusionThis survey observed a large variation in the current treatment protocol of intrapleural tPA/DNase therapy worldwide and the need for more data on this subject.

Higher levels of IgA and IgG at sepsis onset are associated with higher mortality: results from the Albumin Italian Outcome Sepsis (ALBIOS) trial

BackgroundThe role of intravenous immunoglobulins (IVIG) during sepsis is controversial, as different trials on IVIG have observed inconsistent survival benefits. We aimed to elucidate the possible association and clinical significance between circulating levels of immunoglobulins.MethodsIn a subset of 956 patients with severe sepsis and septic shock of the multicentre, open-label RCT ALBIOS, venous blood samples were serially collected 1, 2, and 7 days after enrolment (or at ICU discharge, whichever came first). IgA, IgG and IgM concentrations were assayed in all patients on day 1 and in a subgroup of 150 patients on days 2 and 7. Ig concentrations were measured employing a turbidimetric assay, OSR61171 system.ResultsIgA on day 1 had a significant predictive value for both 28-day and 90-day mortality (28-day mortality, HR: 1.50 (95% CI 1.18–1.92); 90-day mortality, HR: 1.54 (95% CI 1.25–1.91)). IgG, but not IgM, on day 1 showed similar results for 28-day (HR 1.83 (95% CI 1.33–2.51) and 90-day mortality HR: 1.66 (95% CI 1.23–2.25)). In addition, lower levels of IgG but not of IgA and IgM, at day 1 were associated with significantly higher risk of secondary infections (533 [406–772] vs 600 [452–842] mg/dL, median [Q1–Q3], p = 0.007).ConclusionsIn the largest cohort study of patients with severe sepsis or septic shock, we found that high levels of IgA and IgG on the first day of diagnosis were associated with a decreased 90-day survival. No association was found between IgM levels and survival. As such, the assessment of endogenous immunoglobulins could be a useful tool to identify septic patients at high risk of mortality.Trial registration #NCT00707122, Clinicaltrial.gov, registered 30 June 2008

A systematic review and meta-analysis of enrollment into ARDS and sepsis trials published between 2009 and 2019 in major journals

BackgroundEnrollment problems are common among randomized controlled trials conducted in the ICU. However, little is known about actual trial enrollment rates and influential factors. We set out to determine the overall enrollment rate in recent randomized controlled trials (RCTs) of patients with acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or sepsis, and which factors influenced enrollment rate.MethodsWe conducted a systematic review by searching Pubmed using predefined terms for ARDS/ALI and sepsis to identify individually RCTs published among the seven highest impact general medicine and seven highest impact critical care journals between 2009 and 2019. Cluster randomized trials were excluded. Data were extracted by two independent reviewers using an electronic database management system. We conducted a random-effects meta-analysis of the eligible trials for the primary outcome of enrollment rate by time and site.ResultsOut of 457 articles identified, 94 trials met inclusion criteria. Trials most commonly evaluated pharmaceutical interventions (53%), were non-industry funded (78%), and required prospective informed consent (81%). The overall mean enrollment rate was 0.83 (95% confidence interval: 0.57–1.21) participants per month per site. Enrollment in ARDS/ALI and sepsis trials were 0.48 (95% CI 0.32–0.70) and 0.98 (95% CI 0.62–1.56) respectively. The enrollment rate was significantly higher for single-center trials (4.86; 95% CI 2.49–9.51) than multicenter trials (0.52; 95% CI 0.41–0.66). Of the 36 trials that enrolled < 95% of the target sample size, 8 (22%) reported slow enrollment as the reason.ConclusionsIn this systematic review and meta-analysis, recent ARDS/ALI and sepsis clinical trials had an overall enrollment rate of less than 1 participant per site per month. Novel approaches to improve critical care trial enrollment efficiency are needed to facilitate the translation of best evidence into practice.

The Association Between Etiologies and Mortality in Acute Respiratory Distress Syndrome: A Multicenter Observational Cohort Study.

Background: Lung-protective ventilation (LPV) strategies have been beneficial in patients with acute respiratory distress syndrome (ARDS). As a vital part of LPV, positive end-expiratory pressure (PEEP) can enhance oxygenation. However, randomized clinical trials of different PEEP strategies seem to show no advantages in clinical outcomes in patients with ARDS. A potential reason is that diverse etiologies and phenotypes in patients with ARDS may account for different PEEP responses, resulting in variations in mortality. We consider hospital mortality to be associated with a more specific classification of ARDS, such as sepsis induced or not, and pulmonary or extrapulmonary one. Our study aimed to compare clinical outcomes in various patients with ARDS by etiologies using the China Critical Care Sepsis Trial (CCCST) database. This was a retrospective analysis of a prospective cohort of 2,138 patients with ARDS in the CCCST database. According to ARDS induced by sepsis or not and medical history, patients were stratified into different four groups. Differences among groups were assessed in hospital mortality, ventilation-free days, and other clinical features.Results: A total of 2,138 patients with ARDS were identified in the database, including 647 patients with sepsis-induced pulmonary ARDS (30.3%), 396 patients with sepsis-induced extrapulmonary ARDS (18.5%), 536 patients with non-sepsis pulmonary ARDS (25.1%), and 559 patients with non-sepsis extrapulmonary ARDS (26.1%). The pulmonary ARDS group had higher mortality compared with the extrapulmonary group (45.9 vs. 23.0%, p < 0.01), longer intensive care unit (ICU) and hospital stays (9 vs. 6 days, p < 0.01, 20 vs. 18 days, p = 0.01, respectively), and fewer ventilation-free days (5 vs. 9 days) in the presence of sepsis. However, the mortality in ARDS without sepsis was inverted compared with extrapulmonary ARDS (pulmonary 23.5% vs. extrapulmonary 29.2%, p = 0.04). After adjusting for the Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores and other clinical features, the sepsis-induced pulmonary condition was still a risk factor for death in patients with ARDS (hazard ratio 0.66, 95% CI, 0.54–0.82, p < 0.01) compared with sepsis-induced extrapulmonary ARDS and other subphenotypes.Conclusions: In the presence of sepsis, hospital mortality in pulmonary ARDS is higher compared with extrapulmonary ARDS; however, mortality is inverted in ARDS without sepsis. Sepsis-induced pulmonary ARDS should attract more attention from ICU physicians and be cautiously treated.Trial registration: ChiCTR-ECH-13003934. Registered August 3, 2013, http://www.chictr.org.cn.

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS.

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.

376 Dynamic Changes in High Sensitivity Troponin T Are Associated With Increased Sepsis Mortality

Elevated serum cardiac troponin is a marker of myocardial injury associated with increased mortality in sepsis. Increasing use of high sensitivity troponin T (hsTrop) in the emergency department (ED) has allowed earlier and more sensitive detection of myocardial injury in acute coronary syndromes but has yet to be studied in relation to sepsis. The objective of this study was to determine the association between hsTrop changes and mortality in sepsis. This was a retrospective cohort study performed at a single, tertiary academic center. A concurrent multicenter sepsis trial was being conducted during the study period (June 1st, 2018 and March 20th, 2020) and the cohort for this study was derived from the screening log of this unrelated study. Adult patients with a suspected infection and hypotension after 1 liter of crystalloid fluids were included. All data were collected via direct database query to the electronic health record. hsTrop was measured in the ED and again approximately 2 hours later. The difference (delta) between the second and first measurements was the primary exposure and treated as a 4- level categorical variable (delta >6 ng/L, - 6 > delta > 6, delta <- 6 and no delta obtained). The primary outcome was 28- day mortality and secondary outcomes included mechanical ventilation, use of vasopressors, and crystalloid fluid received. Inverse probability weighting (IPW) was used to weight covariates for the probability of obtaining a hsTrop delta measurement in the ED. Using IPW derived weights, a multivariable logistic regression model was used to determine the association between hsTrop delta and 28- day mortality. Descriptive statistics and univariate analyses were also performed. After exclusion of clinician suspected baseline hypotension or hypotension not due to sepsis cause, as well as non- sepsis causes of hsTrop delta, 763 patients met the inclusion and exclusion criteria. 48 had a delta > 6 ng/L, 54 had a delta < - 6 ng/L, 175 had a delta between - 6 and 6, and 486 had no hsTrop delta obtained in the ED. Patients who had a hsTrop testing skewed male, older and with history of renal, heart disease or with chief complaints of chest pain or shortness of breath. In the weighted multivariable analysis and after adjustment for sex, age, and Charlson comorbidity index, both an hsTrop delta > 6 (OR 3.4 [95% CI 1.7 - 7.2]) and delta < - 6 (OR 2.2 [95% CI 1.1 - 4.4]) were associated with increased mortality at 28 days. The hsTrop delta >6 group was also associated with an increased risk for early mechanical ventilation (HR 3.0 [95% CI 1.8 - 4.9]), use of vasopressors (OR 3.7 [95% CI 2.0 - 7.0]), and increased crystalloid fluids administered during the first 24 hours (mean 4060 mL vs. ∼ 3000 mL for all other groups, p = 0.01). Dynamic changes in hsTrop obtained at ED presentation are associated with increased mortality in sepsis. Both an increasing and decreasing hsTrop delta are associated with a higher risk for 28- day mortality. This study was limited by its retrospective and single site design. Future studies are required to determine how hsTrop can be used to modify treatment.

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles