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Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Faced with the COVID-19 pandemic, the US system for developing and testing technologies was challenged in unparalleled ways. This article describes the multi-institutional, transdisciplinary team of the “RADxSM Tech Test Verification Core” and its role in expediting evaluations of COVID-19 testing devices. Expertise related to aspects of diagnostic testing was coordinated to evaluate testing devices with the goal of significantly expanding the ability to mass screen Americans to preserve lives and facilitate the safe return to work and school. Focal points included: laboratory and clinical device evaluation of the limit of viral detection, sensitivity, and specificity of devices in controlled and community settings; regulatory expertise to provide focused attention to barriers to device approval and distribution; usability testing from the perspective of patients and those using the tests to identify and overcome device limitations, and engineering assessment to evaluate robustness of design including human factors, manufacturability, and scalability.

OBJECTIVE The use of remote real-time continuous glucose monitoring (CGM) in the hospital has rapidly emerged to preserve personal protective equipment and reduce potential exposures during coronavirus disease 2019 (COVID-19). RESEARCH DESIGN AND METHODS We linked a hybrid CGM and point-of-care (POC) glucose testing protocol to a computerized decision support system for continuous insulin infusion and integrated a validation system for sensor glucose values into the electronic health record. We report our proof-of-concept experience in a COVID-19 intensive care unit. RESULTS All nine patients required mechanical ventilation and corticosteroids. During the protocol, 75.7% of sensor values were within 20% of the reference POC glucose with an associated average reduction in POC of 63%. Mean time in range (70–180 mg/dL) was 71.4 ± 13.9%. Sensor accuracy was impacted by mechanical interferences in four patients. CONCLUSIONS A hybrid protocol integrating real-time CGM and POC is helpful for managing critically ill patients with COVID-19 requiring insulin infusion.

The current coronavirus pandemic has impacted heavily on ICUs worldwide. Although many hospitals and healthcare systems had plans in place to manage multiple casualties as a result of major natural disasters or accidents, there was insufficient preparation for the sudden, massive influx of severely ill patients with COVID-19. As a result, systems and staff were placed under immense pressure as everyone tried to optimize patient management. As the pandemic continues, we must apply what we have learned about our response, both good and bad, to improve organization and thus patient care in the future., SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives To review published clinical evidence on management of Clostridioides difficile infection in critically ill patients. Data sources We obtained relevant studies from a PubMed literature review and bibliographies of reviewed articles. Study selection We selected English-language studies addressing aspects of C. difficile infection relevant to critical care clinicians including epidemiology, risk factors, diagnosis, treatment, and prevention, with a focus on high-quality clinical evidence. Data extraction We reviewed potentially relevant studies and abstracted information on study design, methods, patient selection, and results of relevant studies. This is a synthetic (i.e., not systematic) review. Data synthesis C. difficile infection is the most common healthcare-associated infection in the United States. Antibiotics are the most significant C. difficile infection risk factor, and among antibiotics, cephalosporins, clindamycin, carbapenems, fluoroquinolones, and piperacillin-tazobactam confer the highest risk. Age, diabetes mellitus, inflammatory bowel disease, and end-stage renal disease are risk factors for C. difficile infection development and mortality. C. difficile infection diagnosis is based on testing appropriately selected patients with diarrhea or on clinical suspicion for patients with ileus. Patients with fulminant disease (C. difficile infection with hypotension, shock, ileus, or megacolon) should be treated with oral vancomycin and IV metronidazole, as well as rectal vancomycin in case of ileus. Patients who do not respond to initial therapy should be considered for fecal microbiota transplant or surgery. Proper infection prevention practices decrease C. difficile infection risk. Conclusions Strong clinical evidence supports limiting antibiotics when possible to decrease C. difficile infection risk. For patients with fulminant C. difficile infection, oral vancomycin reduces mortality, and adjunctive therapies (including IV metronidazole) and interventions (including fecal microbiota transplant) may benefit select patients. Several important questions remain regarding fulminant C. difficile infection management, including which patients benefit from fecal microbiota transplant or surgery.

Modalities of fluid management in patients sustaining the acute respiratory distress syndrome (ARDS) are challenging and controversial. Optimal fluid management should provide adequate oxygen delivery to the body, while avoiding inadvertent increase in lung edema which further impairs gas exchange. In ARDS patients, positive fluid balance has been associated with prolonged mechanical ventilation, longer ICU and hospital stay, and higher mortality. Accordingly, a restrictive strategy has been compared to a more liberal approach in randomized controlled trials conducted in various clinical settings. Restrictive strategies included fluid restriction guided by the monitoring of extravascular lung water, pulmonary capillary wedge or central venous pressure, and furosemide targeted to diuresis and/or albumin replacement in hypoproteinemic patients. Overall, restrictive strategies improved oxygenation significantly and reduced duration of mechanical ventilation, but had no significant effect on mortality. Fluid management may require different approaches depending on the time course of ARDS (i.e., early vs. late period). The effects of fluid strategy management according to ARDS phenotypes remain to be evaluated. Since ARDS is frequently associated with sepsis-induced acute circulatory failure, the prediction of fluid responsiveness is crucial in these patients to avoid hemodynamically inefficient-hence respiratory detrimental-fluid administration. Specific hemodynamic indices of fluid responsiveness or mini-fluid challenges should be preferably used. Since the positive airway pressure contributes to positive fluid balance in ventilated ARDS patients, it should be kept as low as possible. As soon as the hemodynamic status is stabilized, correction of cumulated fluid retention may rely on diuretics administration or renal replacement therapy.

Background The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. Methods A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). Results Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. Conclusions MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. Trial registration ClinicalTrials.gov, NCT03145428. First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

OBJECTIVE This study explored underlying metabolism-related dysfunction by examining metabolomic profiles in adults categorized as lean, as having normal weight obesity (NWO), or as having overweight/obesity. METHODS Participants (N = 179) had fasting plasma analyzed by liquid chromatography and high-resolution mass spectrometry for high-resolution metabolomics. Body composition was assessed by dual-energy x-ray absorptiometry. NWO was defined as BMI 30% for women and > 23% for men. Differentiating metabolomic features were determined by using linear regression models and likelihood ratio tests with false discovery rate correction. Mummichog was used for pathway and network analyses. RESULTS A total of 222 metabolites significantly differed between the groups at a false discovery rate of q = 0.2. Linoleic acid, β-alanine, histidine, and aspartate/asparagine metabolism pathways were significantly enriched (all P

There are two categories of pulmonary edema: edema caused by increased capillary pressure (hydrostatic or cardiogenic edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome). This review focuses on cardiogenic pulmonary edema and describes the general approach to patients with suspected cardiogenic pulmonary edema. The pathogenesis, diagnosis, treatment, and outcome of cardiogenic pulmonary edema are reviewed. Figures include chest scans showing pulmonary edema and noncardiogenic pulmonary edema, an illustration of the differences between cardiogenic and noncardiogenic edema, and a chart comparing lung mechanics and other variables in experimental models of cardiogenic pulmonary edema and noncardiogenic edema. Tables show clinical characteristics of patients with cardiogenic pulmonary edema and treatment options. This review contains 3 figures, 4 tables, and 29 references Keywords: cardiogenic pulmonary edema, congestive heart failure, pulmonary edema, Starling’s law

Introduction Current medications for idiopathic pulmonary fibrosis (IPF) have not been shown to impact patient-reported outcome measures (PROMs), highlighting the need for accurate minimal clinically important difference (MCID) values. Recently published consensus standards for MCID studies support using anchor-based over distribution-based methods. The aim of this study was to estimate MCID values for worsening in IPF using only an anchor-based approach. Methods We conducted secondary analyses of three randomised controlled trials with different inclusion criteria and follow-up intervals. The health transition question in the 36-Item Short-Form Health Survey (SF-36) questionnaire was used as the anchor. We used receiver operating curves to assess responsiveness between the anchor and 10 variables (four physiological measures and six PROMs). We used an anchor-based method to determine the MCID values of variables that met the responsiveness criteria (area under the curve ≥0.70). Results 6-min walk distance (6MWD), the St George's Respiratory Questionnaire (SGRQ), physical component score (PCS) of SF-36 and University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) met the responsiveness criteria. The MCID value for 6MWD was −75 m; the MCID value for SF-36 PCS was −7 points; the MCID value for SGRQ was 11 points; and the MCID value for the UCSD SOBQ was 11 points. Conclusions The MCID estimates of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based methods were considerably higher compared to previously proposed values. A single MCID value may not be applicable across all classes of disease severity or durations of follow-up time., Current consensus approaches recommend anchor-based estimation of MCID over distribution-based methods. MCID values of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based method were higher than previously reported values. https://bit.ly/37hm0zv

The electronic health records (EHR) infrastructure offers a tremendous resource for identifying controls who match the characteristics of study participants in a single-arm trial. The objectives are to (1) demonstrate the feasibility of curating a synthetic control group for an existing study cohort through EHR data extraction and (2) evaluate the effect of a lifestyle intervention on selected cardiovascular health metrics. A total of 711 university employees were recruited between 2008 and 2012 to participate in a health partner intervention to improve cardiovascular health and were followed for five years. Data of nearly 8000 eligible subjects were extracted from the EHR to create a synthetic control cohort during the same study period. To minimize confounding, crude comparison, exact matching, propensity score matching, and doubly robust estimation were used to compare the selected cardiovascular health metrics at 1 and 5 years of follow-up. Blood pressure and body mass index improved in the intervention group compared to the EHR synthetic controls. The findings of changes in lipid measurements were somewhat unexpected. When analyzing the subgroup without lipid-lowering medications, the intervention group exhibited better control of cholesterol levels over time than did our synthetic controls. Some measurements in the EHR system may be more robust for synthetic selection than others. EHR synthetic controls can provide an alternative to estimate intervention effects appropriately in single-arm studies for these measurements.

Supplemental Digital Content is available in the text., Objectives: Describe the longitudinal national epidemiology of tracheostomies performed in acute care hospitals and describe the annual rate of tracheostomy performed for patients with respiratory failure with invasive mechanical ventilation. DESIGN: Serial cross-sectional study. Setting: The 2002–2014 and 2016–2017 Healthcare Utilization Project’s National Inpatient Sample datasets. Patients: Discharges greater than or equal to 18 years old, excluding those with head and neck cancer or transferred from another hospital. We used diagnostic and procedure codes from the International Classification of Diseases, 9th and 10th revisions to define cases of respiratory failure, invasive mechanical ventilation, and tracheostomy. Interventions: None. Measurements and Main Results: There were an estimated 80,612 tracheostomies performed in 2002, a peak of 89,545 tracheostomies in 2008, and a nadir of 58,840 tracheostomies in 2017. The annual occurrence rate was 37.5 (95% CI, 34.7–40.4) tracheostomies per 100,000 U.S. adults in 2002, with a peak of 39.7 (95% CI, 36.5–42.9) in 2003, and with a nadir of 28.4 (95% CI, 27.2–29.6) in 2017. Specifically, among the subgroup of hospital discharges with respiratory failure with invasive mechanical ventilation, an annual average of 9.6% received tracheostomy in the hospital. This changed over the study period from 10.4% in 2002, with a peak of 10.9% in 2004, and with a nadir of 7.4% in 2017. Among respiratory failure with invasive mechanical ventilation discharges with tracheostomy, the annual proportion of patients 50–59 and 60–69 years old increased, whereas patients from 70 to 79 and greater than or equal to 80 years old decreased. The mean hospital length of stay decreased, and in-hospital mortality decreased, whereas discharge to intermediate care facilities increased. Conclusions: Over the study period, there were decreases in the annual total case volume and adult occurrence rate of tracheostomy as well as decreases in the rate of tracheostomy among the subgroup with respiratory failure with invasive mechanical ventilation. There is some evidence of changing patterns of patient selection for in-hospital tracheostomy among those with respiratory failure with invasive mechanical ventilation with decreasing proportions of patients with advanced age.

The impact of repeated sample collection on COVID-19 test performance is unknown. The FDA and CDC currently recommend the primary collection of diagnostic samples to minimize the perceived risk of false-negative findings. We therefore evaluated the association between repeated sample collection and test performance among 325 symptomatic patients undergoing COVID-19 testing in Atlanta, GA. High concordance was found between consecutively collected mid-turbinate samples with both molecular (n = 74, 100% concordance) and antigen-based (n = 147, 97% concordance, kappa = 0.95, CI = 0.88–1.00) diagnostic assays. Repeated sample collection does not decrease COVID-19 test performance, demonstrating that multiple samples can be collected for assay validation and clinical diagnosis.

While there has been significant progress in the development of rapid COVID-19 diagnostics, as the pandemic unfolds, new challenges have emerged, including whether these technologies can reliably detect the more infectious variants of concern and be viably deployed in non-clinical settings as “self-tests”. Multidisciplinary evaluation of the Abbott BinaxNOW COVID-19 Ag Card (BinaxNOW, a widely used rapid antigen test, included limit of detection, variant detection, test performance across different age-groups, and usability with self/caregiver-administration. While BinaxNOW detected the highly infectious variants, B.1.1.7 (Alpha) first identified in the UK, B.1.351 (Beta) first identified in South Africa, P.1 (Gamma) first identified in Brazil, B.1.617.2 (Delta) first identified in India and B.1.2, a non-VOC, test sensitivity decreased with decreasing viral loads. Moreover, BinaxNOW sensitivity trended lower when devices were performed by patients/caregivers themselves compared to trained clinical staff, despite universally high usability assessments following self/caregiver-administration among different age groups. Overall, these data indicate that while BinaxNOW accurately detects the new viral variants, as rapid COVID-19 tests enter the home, their already lower sensitivities compared to RT-PCR may decrease even more due to user error.

ObjectiveTo identify priorities for administrative, epidemiologic and diagnostic research in sepsis.DesignAs a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis.MethodsSix questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process.ResultsThe document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis?ConclusionsThere is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.

BACKGROUND Rapid loss of lean mass during catabolic states is associated with impaired convalescence and increased mortality rates. An understanding of metabolic pathways related to lean mass is needed to enable future interventions designed to combat malnutrition. This study assessed the plasma metabolome in relation to lean mass in clinically stable working adults in a US cohort. METHODS This cross-sectional study included 180 adults (mean ± SD, aged 49.7 ± 10.0 years; body mass index, 27.3 ± 5.5 kg/m2 ; 64% female [n=116]). Fasting plasma was analyzed using high-resolution metabolomics (HRM) via liquid chromatography/mass spectrometry. Lean mass was assessed by dual-energy x-ray absorptiometry and expressed as lean mass index (LMI, lean mass kg/height m2 ). Multiple linear regression, metabolic pathway enrichment, and module analyses were used to characterize systemic metabolism associated with LMI. RESULTS Of 5360 metabolites used in analyses, 593 were related to LMI, either upregulated or downregulated (P < .05). These were enriched within 11 metabolic pathways, including branched-chain amino acid degradation, metabolism of alanine and aspartate and other amino acids, butyrate, purines, and niacin metabolism. Module analysis revealed central associations between LMI and L-glutamate, L-leucine/L-isoleucine, L-valine, L-phenylalanine, L-methionine, and L-aspartate, among other validated metabolites. CONCLUSION These novel plasma HRM data demonstrate the wide-reaching associations of lean mass with systemic metabolism in a single snapshot. Such data may inform targeted nutrition support interventions designed to mitigate loss of lean mass and promote regaining skeletal muscle mass and function after illness or injury.

Access to rapid diagnostic information is a core value of point-of-care (POC) technology. This is particularly relevant in acute, emergency, and critical care settings where diagnostic speed and precision directly guide the management of patients with potentially life-threatening conditions. Many POC diagnostics described in the literature, however, remain largely unproven and have yet to enter the market entirely. Only a few have traversed the translation and commercialization pathways to reach widespread clinical adoption. Moreover, even technologies that have successfully translated to the patient bedside still frequently lack an evidence base showing improvement of clinical outcomes. In this review, we present aspects of diagnosis of acute life-threatening diseases and describe the potential role of POC technologies, emphasizing the available evidence of clinical outcomes. Finally, we discuss what is needed to identify clinically meaningful new technologies and translate them toward the long-promised goal of better health through rapid POC diagnosis.

In March 2020, the National Institutes of Health COVID-19 Treatment Guidelines Panel began developing evidence-based guidelines for the treatment of COVID-19. In this article, Panel members summarize some of the lessons learned from their first year of work., The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually—as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Summary 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.

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. 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 × 103 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. 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. 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. NCT02960854.

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:Randomize

Guidelines recommend crystalloids for fluid resuscitation in sepsis/shock and switching to albumin in cases where crystalloids are insufficient. We evaluated hemodynamic response to crystalloids/colloids in critically ill adults.The primary research question was: "Are crystalloids sufficient for volume replacement in severe indications (intensive care unit [ICU]/critical illness)?" Randomized, controlled trials (RCTs) were identified using PubMed and EMBASE, and screened against predefined inclusion/exclusion criteria. Meta-analyses were performed on extracted data.Fifty-five RCTs (N = 27,036 patients) were eligible. Central venous pressure was significantly lower with crystalloids than with albumin, hydroxyethyl starch (HES), or gelatin (all p .001). Mean arterial pressure was significantly lower with crystalloids vs. albumin (mean difference [MD]: -3.5 mm Hg; p = .03) or gelatin (MD: -9.2 mm Hg; p = .02). Significantly higher volumes of crystalloids were administered vs. HES (MD: +1775 mL); volume administered was numerically higher vs. albumin (MD: +1985 mL). Compared with the albumin group, cardiac index was significantly lower in the crystalloid group (MD: -0.6 L/min/mCrystalloids were less efficient than colloids at stabilizing resuscitation endpoints; guidance on when to switch is urgently required.

To address the need for critically ill patients around the world to receive high quality critical care from trained professionals, SCCM created the Fundamentals of Critical Care Support, or FCCS, course THRIVE was instrumental in characterizing the post-intensive care syndrome, and SCCM has made PICS a common expression in the critical care lexicon and helped to develop strategies that may one day eliminate PICS as a consequence of critical illness These, and other remarkable women leaders at SCCM, laid the groundwork for our Women in Critical Care KEG-one of the first and most active groups of its kind in critical care medicine I am a better intensivist and a better person for having met all of the incredibly talented critical care colleagues who volunteer their time to serve on the SCCM Council, and so many of our leaders on SCCM committees and within our regional SCCM chapters as well as our international collaborators and colleagues [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

The National Institutes of Health (NIH) launched the Rapid Acceleration of Diagnostics (RADxSM) Tech initiative to support the development and commercialization of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) point-of-care test devices. The primary objective of the Clinical Studies Core (CSC) was to perform SARS-CoV-2 device studies involving diverse populations and settings. Within a few months, the infrastructure for clinical studies was developed, including a master protocol, digital study platform, data management system, single IRB, and multi-site partnerships. Data from some studies are being used to support Emergency Use Authorization of novel SARS-CoV-2 test devices. The CSC reduced the typical time and cost of developing medical devices and highlighted the impactful role of academic and NIH partnership in addressing public health needs at a rapid pace during a global pandemic. The structure, deployment, and lessons learned from this experience are widely applicable to future in vitro diagnostic device clinical studies.

Coronavirus disease 19 (COVID-19) has posed unprecedented healthcare system challenges, some of which will lead to transformative change. It is obvious to healthcare workers and policymakers alike that an effective critical care surge response must be nested within the overall care delivery model. The COVID-19 pandemic has highlighted key elements of emergency preparedness. These include having national or regional strategic reserves of personal protective equipment, intensive care unit (ICU) devices, consumables and pharmaceuticals, as well as effective supply chains and efficient utilization protocols. ICUs must also be prepared to accommodate surges of patients and ICU staffing models should allow for fluctuations in demand. Pre-existing ICU triage and end-of-life care principles should be established, implemented and updated. Daily workflow processes should be restructured to include remote connection with multidisciplinary healthcare workers and frequent communication with relatives. The pandemic has also demonstrated the benefits of digital transformation and the value of remote monitoring technologies, such as wireless monitoring. Finally, the pandemic has highlighted the value of pre-existing epidemiological registries and agile randomized controlled platform trials in generating fast, reliable data. The COVID-19 pandemic is a reminder that besides our duty to care, we are committed to improve. By meeting these challenges today, we will be able to provide better care to future patients. ispartof: INTENSIVE CARE MEDICINE vol:47 issue:3 pages:282-291 ispartof: location:United States status: published

Importance Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, setting, and participants Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main outcomes and measures The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and relevance Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial registration ClinicalTrials.gov Identifier: NCT03509350.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Supplemental Digital Content is available in the text., Objectives: Coronavirus disease 2019 is associated with high mortality rates and multiple organ damage. There is increasing evidence that these patients are at risk for various cardiovascular insults; however, there are currently no guidelines for the diagnosis and management of such cardiovascular complications in patients with coronavirus disease 2019. We share data and recommendations from a multidisciplinary team to highlight our institution’s clinical experiences and guidelines for managing cardiovascular complications of coronavirus disease 2019. Design, Setting, and Patients: This was a retrospective cohort study of patients admitted to one of six ICUs dedicated to the care of patients with coronavirus disease 2019 located in three hospitals within one academic medical center in Atlanta, Georgia. Measurements/Interventions: Chart review was conducted for sociodemographic, laboratory, and clinical data. Rates of specific cardiovascular complications were assessed, and data were analyzed using a chi-square or Wilcoxon rank-sum test for categorical and continuous variables. Additionally, certain cases are presented to demonstrate the sub committee’s recommendations. Main Results: Two-hundred eighty-eight patients were admitted to the ICU with coronavirus disease 2019. Of these, 86 died (29.9%), 242 (84.03%) had troponin elevation, 70 (24.31%) had dysrhythmias, four (1.39%) had ST-elevation myocardial infarction, eight (2.78%) developed cor pulmonale, and 190 (65.97%) with shock. There was increased mortality risk in patients with greater degrees of troponin elevation (p < 0.001) and with the development of arrhythmias (p < 0.001), cor pulmonale (p < 0.001), and shock (p < 0.001). Conclusions: While there are guidelines for the diagnosis and management of pulmonary complications of coronavirus disease 2019, there needs to be more information regarding the management of cardiovascular complications as well. These recommendations garnered from the coronavirus disease 2019 cardiology subcommittee from our institution will add to the existing knowledge of these potential cardiovascular insults as well as highlight suggestions for the diagnosis and management of the range of cardiovascular complications of coronavirus disease 2019. Additionally, with the spread of coronavirus disease 2019, our case-based recommendations provide a bedside resource for providers newly caring for patients with coronavirus disease 2019.

Acute respiratory failure (ARF) is a common problem in medicine that utilizes significant healthcare resources and is associated with high morbidity and mortality. Classification of acute respiratory failure is complicated, and it is often determined by the level of mechanical support that is required, or the discrepancy between oxygen supply and uptake. These phenotypes make acute respiratory failure a continuum of syndromes, rather than one homogenous disease process. Early recognition of the risk factors for new or worsening acute respiratory failure may prevent that process from occurring. Predictive analytical methods using machine learning leverage clinical data to provide an early warning for impending acute respiratory failure or its sequelae. The aims of this review are to summarize the current literature on ARF prediction, to describe accepted procedures and common machine learning tools for predictive tasks through the lens of ARF prediction, and to demonstrate the challenges and potential solutions for ARF prediction that can improve patient outcomes.

Objectives Describe the epidemiology of sepsis across the transition from the International Classification of Diseases, 9th Edition, and International Classification of Diseases, 10th Edition, coding systems, evaluating estimates of two previously published International Classification of Diseases, 10th Edition, coding strategies. Design Serial cross-sectional analysis. Setting Healthcare Utilization Project's annual Nationwide Inpatient Sample of U.S. hospital discharges, 2012-2017. Patients Discharges greater than or equal to 18 years old, which met one of the three case definitions for sepsis. For the records using International Classification of Diseases, 9th Edition, we used previously published modified Angus criteria, and for records using International Classification of Diseases, 10th Edition, we deployed a case definition used by the Centers for Medicare & Medicaid Services and a case definition developed by the Institute for Health Metrics and Evaluation. Interventions None. Measurements and main results During the study period, there were discontinuities in the sepsis incidence estimates using the modified Angus International Classification of Diseases, 9th Edition, criteria in 2014 and either Centers for Medicare & Medicaid Services or Institute for Health Metrics and Evaluation International Classification of Diseases, 10th Edition, criteria in 2016. In 2014, there were an estimated 1,009 cases (95% CI, 989-1,030) of modified Angus sepsis per 100,000 persons, whereas in 2016, there were 709 cases (95% CI, 694-724) of Centers for Medicare & Medicaid Services sepsis and 1,498 cases (95% CI, 1,471-1,092) of Institute for Health Metrics and Evaluation sepsis per 100,000 persons. Furthermore, the Institute for Health Metrics and Evaluation definition identified a sepsis cohort with similar hospital characteristics but a younger age distribution, higher proportion of women, lower severity of illness, and lower hospital mortality. Conclusions The Institute for Health Metrics and Evaluation International Classification of Diseases, 10th Edition, coding strategy for identifying sepsis may capture a larger patient population within administrative datasets that are different from those identified with previously deployed International Classification of Diseases-based methods. Further work is required to determine the optimal International Classification of Diseases, 10th Edition, coding strategy for use in hospital discharge data.

Purpose To survey haemodynamic monitoring and management practices in ICU patients with the coronavirus disease 2019 (COVID-19). Methods A questionnaire was shared on social networks or via email by the authors and by Anaesthesia and/or Critical Care societies from France, Switzerland, Belgium, Brazil, and Portugal. Intensivists and anaesthetists involved in COVID-19 ICU care were invited to answer 14 questions about haemodynamic monitoring and management. Results Globally, 1000 questionnaires were available for analysis. Responses came mainly from Europe (n = 460) and America (n = 434). According to respondents, a majority of COVID-19 ICU patients frequently or very frequently received continuous vasopressor support (56%) and had an echocardiography performed (54%). Echocardiography revealed a normal cardiac function, a hyperdynamic state (43%), hypovolaemia (22%), a left ventricular dysfunction (21%) and a right ventricular dilation (20%). Fluid responsiveness was frequently assessed (84%), mainly using echo (62%), and cardiac output was measured in 69%, mostly with echo as well (53%). Venous oxygen saturation was frequently measured (79%), mostly from a CVC blood sample (94%). Tissue perfusion was assessed biologically (93%) and clinically (63%). Pulmonary oedema was detected and quantified mainly using echo (67%) and chest X-ray (61%). Conclusion Our survey confirms that vasopressor support is not uncommon in COVID-19 ICU patients and suggests that different cardiac function phenotypes may be observed. Ultrasounds were used by many respondents, to assess cardiac function but also to predict fluid responsiveness and quantify pulmonary oedema. Although we observed regional differences, current international guidelines were apparently followed by most respondents.

Supplemental Digital Content is available in the text., Objectives: Increasing time to mechanical ventilation and high-flow nasal cannula use may be associated with mortality in coronavirus disease 2019. We examined the impact of time to intubation and use of high-flow nasal cannula on clinical outcomes in patients with coronavirus disease 2019. Design: Retrospective cohort study. Setting: Six coronavirus disease 2019-specific ICUs across four university-affiliated hospitals in Atlanta, Georgia. Patients: Adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection who received high-flow nasal cannula or mechanical ventilation. Interventions: None. Measurements and Main Results: Among 231 patients admitted to the ICU, 109 (47.2%) were treated with high-flow nasal cannula and 97 (42.0%) were intubated without preceding high-flow nasal cannula use. Of those managed with high-flow nasal cannula, 78 (71.6%) ultimately received mechanical ventilation. In total, 175 patients received mechanical ventilation; 44.6% were female, 66.3% were Black, and the median age was 66 years (interquartile range, 56–75 yr). Seventy-six patients (43.4%) were intubated within 8 hours of ICU admission, 57 (32.6%) between 8 and 24 hours of admission, and 42 (24.0%) greater than or equal to 24 hours after admission. Patients intubated within 8 hours were more likely to have diabetes, chronic comorbidities, and higher admission Sequential Organ Failure Assessment scores. Mortality did not differ by time to intubation (≤ 8 hr: 38.2%; 8–24 hr: 31.6%; ≥ 24 hr: 38.1%; p = 0.7), and there was no association between time to intubation and mortality in adjusted analysis. Similarly, there was no difference in initial static compliance, duration of mechanical ventilation, or ICU length of stay by timing of intubation. High-flow nasal cannula use prior to intubation was not associated with mortality. Conclusions: In this cohort of critically ill patients with coronavirus disease 2019, neither time from ICU admission to intubation nor high-flow nasal cannula use were associated with increased mortality. This study provides evidence that coronavirus disease 2019 respiratory failure can be managed similarly to hypoxic respiratory failure of other etiologies.

Background: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. Methods: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. Results: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p

Objectives: Respiratory failure with mechanical ventilation is a limited labor-intensive resource that is associated with high mortality. Understanding the longitudinal national epidemiology is essential for the organization of healthcare resources. Design: Serial cross-sectional study. Setting: The 2002–2017 Healthcare Utilization Project’s National Inpatient Sample datasets. Interventions: None. Measurements: We use six diagnosis codes and five procedural codes from International Classification of Diseases, 9th Revision, Clinical Modification, and 19 diagnosis codes and 15 procedures codes from International Classification of Diseases, 10th Revision, Clinical Modification to examine national epidemiology of different case definitions for respiratory failure. Results: In the United States in 2017, there were an estimated 1,146,195 discharges with a diagnosis of respiratory failure and procedural code for mechanical ventilation, with an average length of stay of 10.5 days and hospital charge of $158,443. Over the study period, there was an 83% increase in incidence from 249 to 455 cases per 100,000 adults with a 48% decrease in hospital mortality from 34% to 23%. Exploring a case definition that captures only diagnosis codes for respiratory failure, there was a 197% increase in annual incidence, from 429 to 1,275 cases per 100,000 adults with a 57% decrease in hospital mortality from 28% to 12%. For invasive mechanical ventilation without a requisite diagnosis code, there was no change in incidence over the study period, with the 2017 incidence at 359 cases per 100,000 adults, but a 19% decrease in hospital mortality from 37% to 30%. For the noninvasive mechanical ventilation procedural codes, there was a 437% increase in incidence from 41 to 220 cases per 100,000 adults, with a 38% decrease in hospital mortality from 16% to 10%. Conclusions: Examining different case definitions for respiratory failure, there was a large increase in the population incidence and decrease in the hospital mortality for respiratory failure diagnosis codes with more modest changes procedural codes for invasive mechanical ventilation. There was a large increase in incidence of noninvasive mechanical ventilation.

Objectives To determine mortality rates among adults with critical illness from coronavirus disease 2019. Design Observational cohort study of patients admitted from March 6, 2020, to April 17, 2020. Setting Six coronavirus disease 2019 designated ICUs at three hospitals within an academic health center network in Atlanta, Georgia, United States. Patients Adults greater than or equal to 18 years old with confirmed severe acute respiratory syndrome-CoV-2 disease who were admitted to an ICU during the study period. Interventions None. Measurements and main results Among 217 critically ill patients, mortality for those who required mechanical ventilation was 35.7% (59/165), with 4.8% of patients (8/165) still on the ventilator at the time of this report. Overall mortality to date in this critically ill cohort is 30.9% (67/217) and 60.4% (131/217) patients have survived to hospital discharge. Mortality was significantly associated with older age, lower body mass index, chronic renal disease, higher Sequential Organ Failure Assessment score, lower PaO2/FIO2 ratio, higher D-dimer, higher C-reactive protein, and receipt of mechanical ventilation, vasopressors, renal replacement therapy, or vasodilator therapy. Conclusions Despite multiple reports of mortality rates exceeding 50% among critically ill adults with coronavirus disease 2019, particularly among those requiring mechanical ventilation, our early experience indicates that many patients survive their critical illness.

Sepsis clinically manifests as life-threatening organ dysfunction due to a dysregulated host response to infection.1 Optimal fluid resuscitation is relevant for all sepsis patients, and perhaps it is most important for those with septic shock. Septic shock is defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greatest risk of mortality, and septic shock is clinically identified as sepsis patients with serum lactate level >2 mmol/L and who require vasopressor infusion to maintain a mean arterial pressure ≥ 65 mm Hg in the absence of hypovolemia. Sepsis is among the most common conditions in the intensive care unit (ICU), accounting for up to half of all hospital deaths and being the third leading cause of death overall in the United States.2 Sepsis and septic shock are medical emergencies for which treatment and resuscitation should begin immediately. The goals of fluid resuscitation for these patients are: a) to rapidly replace intravascular volume and restore tissue perfusion, and b) to minimize organ dysfunction through timely interventions that either halt or reverse the physiologic derangements. If hypoperfusion is present, at least 30 mL/kg of IV crystalloid fluid should be given rapidly, and additional fluids should be guided by frequent reassessment of hemodynamic status, preferably using dynamic indices to indicate the likelihood of a beneficial response to fluid administration. Fluid administration should be targeted to achieve a MAP of at least 65 mm Hg, and to normalize lactate in patients with elevated lactate due to hypoperfusion.3 Balanced crystalloids are the fluid of first choice for sepsis resuscitation based on ready availability and taking medication costs into account. Use of 0.9% saline compared to a balanced crystalloid, such as lactated Ringer's or PlasmaLyte, produces more kidney dysfunction and with a greater risk of dying.4 The individual side effect profiles may best differentiate the natural and synthetic colloids. Albumin may be considered for administration to sepsis patients with refractory shock or who have received substantial amounts of crystalloid fluids, but should not be administered to patients with severe traumatic brain injury.5 Hydroxyethyl starch (HES) products should not be administered to patients with sepsis because of increased risk of acute kidney injury and death. Gelatin solutions are not recommended in sepsis. Norepinephrine is the vasopressor of first choice for patients with septic shock, and should be administered to achieve a mean arterial pressure of at least 65 mm Hg after excluding hypovolemia as a cause for hypotension. The selection of a second line vasopressor, such as vasopressin, dopamine, phenylephrine, epinephrine or angiotensin-2, depends on patient factors such as underlying cardiac dysfunction, presence of arrhythmias, and current response to vasoconstrictor or inotropic agents. Dopamine should not be used for renal perfusion or protection and it should be avoided in patients with tachyarrhythmias.

The last two decades of epidemiologic studies in acute respiratory distress syndrome (ARDS) have revealed several insights. First, understanding the burden of ARDS involves understanding the metrics of its population incidence, intensive care unit (ICU) incidence, and, importantly, its ICU prevalence that incorporates ICU length of stay in understanding the prolonged burden within ICUs. There have been varied published estimates of these measures but the majority reveal that ARDS is rare in the general population but a common and persistent problem inside ICUs. The heterogeneity of published estimates probably stems from the challenges in precisely studying a syndrome without a gold standard diagnostic test and whose incidence reflects the underlying population’s ICU resource availability and allocation practices. Furthermore, the broad clinical definition used to capture ARDS appears to encompass different phenotypes, with current literature supporting subclassification of ARDS by the level of underlying inflammation with potential therapeutic and prognostic implications. Finally, while unfortunately ARDS appears to be underrecognized and proven treatment strategies underutilized, there is provocative early evidence that ARDS can be prevented using systems-level strategies.

Background Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. Methods and design The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. Trial registration ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.

Background Higher inspiratory airway pressures are associated with worse outcomes in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). This relationship, however, has not been well investigated in patients without ARDS. We hypothesized that higher driving pressures (ΔP) and plateau pressures (Pplat) are associated with worse patient-centered outcomes in mechanically ventilated patients without ARDS as well as those with ARDS. Methods Using data collected during a prospective, observational cohort study of 6179 critically ill participants enrolled in 59 ICUs across the USA, we used multivariable logistic regression to determine whether ΔP and Pplat at enrollment were associated with hospital mortality among 1132 mechanically ventilated participants. We stratified analyses by ARDS status. Results Participants without ARDS (n = 822) had lower average severity of illness scores and lower hospital mortality (27.3% vs. 38.7%; p n = 310). Average Pplat (20.6 vs. 23.9 cm H2O; p 2O; p 2O; p p 2O, 95% CI 1.14–1.62) and Pplat (adjusted OR = 1.42 per 8 cm H2O, 95% CI 1.17–1.73) were associated with higher mortality. We found similar relationships with mortality among those participants with ARDS. Conclusions Higher ΔP and Pplat are associated with increased mortality for participants without ARDS. ΔP may be a viable target for lung-protective ventilation in all mechanically ventilated patients.

Objective To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. Design A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Methods Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. Results The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? Conclusions While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock. Electronic supplementary material The online version of this article (10.1007/s00134-018-5175-z) contains supplementary material, which is available to authorized users.

Background Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. Methods The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees (n = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. Results Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02–2.85), p = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain (p = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. Conclusion Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.