Nyt fra tidsskrifterne

by Dhruv Puri, Yasir Bin Nisar, Antoinette Tshefu, Adrien Lokangaka Longombe, Fabian Esamai, Irene Marete, Adejumoke Idowu Ayede, Ebunoluwa A. Adejuyigbe, Robinson D. Wammanda, Shamim Ahmad Qazi, Rajiv Bahl Background Community-based data on the prevalence of clinical signs of possible serious bacterial infection (PSBI) and the mortality associated with them are scarce. The aim was to examine the prevalence for each sign of infection and mortality associated with infants in the first two months of life, using community surveillance through community health workers (CHW). Methods We used population-based surveillance data of infants up to two months of age from the African Neonatal Sepsis Trial (AFRINEST). In this study, CHWs visited infants up to 10 times during the first two months of life at five sites in three sub-Saharan African countries. CHW assessed the infant for signs of infection (local or systemic) and referred infants who presented with any sign of infection to a health facility. We used a longitudinal analysis to calculate the risk of death associated with the presence of a sign of infection at the time of the visit until the subsequent visit. Results During the first two months of their life, CHWs visited 84,759 live-born infants at least twice. In 11,089 infants (13.1%), one or more signs of infection were identified, of which 237 (2.1%) died. A sign of infection was detected at 2.1% of total visits. In 52% of visits, infants had one or more sign of systemic infection, while 25% had fast breathing in 7–59 days period and 23% had a local infection. All signs of infection, including multiple signs, were more frequently seen in the first week of life. The risk of mortality was very low (0.2%) for local infections and fast breathing in 7–59 days old, it was low for fast breathing 0–6 days old (0.6%), high body temperature (0.7%) and severe chest indrawing (1.0%), moderate for low body temperature (4.9%) and stopped feeding well/not able to feed at all (5.0%) and high for movement only when stimulated or no movement at all (10%) and multiple signs of systemic infection (15.5%). The risk of death associated with most clinical signs was higher (1.5 to 9 times) in the first week of life than at later age, except for low body temperature (4 times lower) as well as high body temperature (2 times lower). Conclusion Signs of infections are common in the first two months of life. The mortality risk differs with clinical signs and can be grouped as very low (local infections, fast breathing 7–59 days), low (fever, severe chest indrawing and fast breathing 0–6 days), moderate (low body temperature and stopped feeding well/not able to feed at all) and high (for movements only on stimulation or no movements at all and multiple signs of infection). New treatment strategies that consider differential mortality risk could be developed and evaluated based on these findings. Clinical trial registration The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Antimicrobial resistance in intensive care units (ICUs) is one of the most challenging problems for managing critically ill patients (Johnson et al., 2020; Weiner-Lastinger et al., 2020). It is known that more than one-third of patients admitted to the ICU have sepsis; thus, antimicrobial agents could be over- and mis-prescribed to increase the chance of administering appropriate antibiotics or simply to relieve the anxiety of clinicians (Luyt et al., 2014; Vincent et al., 2006). Therefore, the antimicrobial stewardship program (ASP) is highly recommended in critical care to improve antibiotic utilization and patient outcome (Barlam et al., 2016; Luyt et al., 2014; Pickens and Wunderink, 2019; Zhang and Singh, 2015).

Objective Assessment of the expertise of medical students in evaluating vital signs and their implications for the current risk of a patient, an appropriate monitoring frequency, and a proper clinical response. Methods 251 second-year and 267 fifth-year medical students in a curriculum consisting of 6 years of medical school at Ulm University, Germany, were interviewed in a paper-based questionnaire. The students were asked to rate their proficiency in interpreting vital signs and to give pathological thresholds of vital signs. Based on the National Early Warning Score 2 (NEWS2), nine vital signs of fictional patients were created and students were asked to comment on their clinical risk, to set an appropriate monitoring frequency as well as a clinical response. Results Interviewing medical students regarding each vital sign individually, the students indicated a pathological threshold in accordance with the NEWS2 for respiratory rate, temperature, and heart rate. By contrast, inappropriate pathological limits were given regarding oxygen saturation and systolic blood pressure. Translating the vital signs into nine fictional patients, fifth-year medical students overall chose an appropriate response in 78% (67%–78%, median±IQR). In detail, fifth-year students successfully identified patients at very high or low risk and allocated them accordingly. However, cases on the edge were often stratified inappropriately. For example, a fictional case with vital signs indicating a surging sepsis was frequently underappreciated (48.5%) and allocated to an insufficient clinical response by fifth-year students. Conclusions Recognising the healthy as well as the deteriorating patient is a key ability for future physicians. NEWS2-based education might be a valuable tool to assess and give feedback on student’s knowledge in this vital professional activity.

This randomized trial compares the effect of vitamin C, thiamine, and hydrocortisone vs matching placebo on 30-day ventilator- and vasopressor-free days among patients with sepsis-induced respiratory and/or cardiovascular dysfunction.

The randomized trial, alone or as part of a meta-analysis, is the pinnacle of the evidence pyramid. Rigorously performed randomized trials offer key insights into the benefit of a treatment vs a control or of a new treatment compared with a standard treatment, although clinicians do not always adopt trial findings into practice. The resulting practice variability is inherent to the art of medicine but not always to the benefit of patients.

Abstract Background Melioidosis is an infectious disease caused by Burkholderia pseudomallei. In Mexico, the disease is rarely diagnosed in humans and there is no evidence of simultaneous environmental isolation of the pathogen. Here, we describe clinical profiles of fatal cases of melioidosis in two children, in a region without history of that disease. Case presentation About 48 h before onset of symptoms, patients swam in a natural body of water, and thereafter they rapidly developed fatal septicemic illness. Upon necropsy, samples from liver, spleen, lung, cerebrospinal fluid, and bronchial aspirate tissues contained Burkholderia pseudomallei. Environmental samples collected from the locations where the children swam also contained B. pseudomallei. All the clinical and environmental strains showed the same BOX-PCR pattern, suggesting that infection originated from the area where the patients were swimming. Conclusions The identification of B. pseudomallei confirmed that melioidosis disease exists in Sonora, Mexico. The presence of B. pseudomallei in the environment may suggest endemicity of the pathogen in the region. This study highlights the importance of strengthening laboratory capacity to prevent and control future melioidosis cases.

Introduction Acute kidney injury (AKI) is one of the most common organ dysfunction in sepsis, and increases the risk of unfavourable outcomes. Renal replacement therapy (RRT) is the predominant treatment for sepsis-associated AKI (SAKI). However, to date, no prospective randomised study has adequately addressed whether initiating RRT earlier will attenuate renal injury and improve the outcome of sepsis. The objective of the trial is to compare the early strategy with delayed strategy on the outcomes in patients with SAKI in the intensive care unit (ICU). Methods and analysis This is a large-scale, multicentre, randomised controlled trial about SAKI. In total, 460 patients with sepsis and evidence of AKI stage 2 of Kidney Disease Improving Global Outcomes (KDIGO) will be recruited and equally randomised into the early group and the delay group in a ratio of 1:1. In the early group, continuous RRT (CRRT) will be started immediately after randomisation. In the delay group, CRRT will initiated if at least one of the following criteria was met: stage 3 of KDIGO, severe hyperkalaemia, pulmonary oedema, blood urea nitrogen level higher than 112 mg/dL after randomisation. The primary outcome is overall survival in a 90-day follow-up period (90-day all-cause mortality). Other end points include 28-day, 60-day and 1-year mortality, recovery rate of renal function by day 28 and day 90, ICU and hospital length of stay, the numbers of CRRT-free days, mechanical ventilation-free days and vasopressor-free days, the rate of complications potentially related to CRRT, CRRT-related cost, and concentrations of inflammatory mediators in serum. Ethics and dissemination The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2017–31-ks-01). Participants will be screened and enrolled from patients in the ICU with SAKI by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. Trial registration NCT03175328.

Objective To evaluate the effectiveness of a Sepsis Fast Track (SFT) programme initiated at a regional referral hospital in Thailand in January 2015. Design A retrospective analysis using the data of a prospective observational study (Ubon-sepsis) from March 2013 to January 2017. Setting General medical wards and medical intensive care units (ICUs) of a study hospital. Participants Patients with community-acquired sepsis observed under the Ubon-sepsis cohort. Sepsis was defined as modified Sequential Organ Failure Assessment (SOFA) Score ≥2. Main exposure The SFT programme was a protocol to identify and initiate sepsis care on hospital admission, implemented at the study hospital in 2015. Patients in the SFT programme were admitted directly to the ICUs when available. The non-exposed group comprised of patients who received standard of care. Main outcome The primary outcome was 28-day mortality. The secondary outcomes were measured sepsis management interventions. Results Of 3806 sepsis patients, 903 (24%) were detected and enrolled in the SFT programme of the study hospital (SFT group) and 2903 received standard of care (non-exposed group). Patients in the SFT group had more organ dysfunction, were more likely to receive measured sepsis management and to be admitted directly to the ICU (19% vs 4%). Patients in the SFT group were more likely to survive (adjusted HR 0.72, 95% CI 0.58 to 0.88, p=0.001) adjusted for admission year, gender, age, comorbidities, modified SOFA Score and direct admission to the ICUs. Conclusions The SFT programme is associated with improved sepsis care and lower risk of death in sepsis patients in rural Thailand, where some critical care resources are limited. The survival benefit is observed even when all patients enrolled in the programme could not be admitted directly into the ICUs. Trial registration number NCT02217592.

Objectives This study aims to examine the outcome of haematological and patients with solid cancer presenting with sepsis to the emergency department (ED). Design Single-centred, retrospective cohort study. Setting conducted at an academic emergency department of a tertiary hospital. Participants All patients >18 years of age admitted with sepsis were included. Interventions Patients were stratified into two groups: haematological and solid malignancy. Primary and secondary outcome The primary outcome of the study was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) mortality, ICU and hospital lengths of stay and mechanical ventilation duration. Results 442 sepsis cancer patients were included in the study, of which 305 patients (69%) had solid tumours and 137 patients (31%) had a haematological malignancy. The mean age at presentation was 67.92 (±13.32) and 55.37 (±20.85) (p<0.001) for solid and liquid tumours, respectively. Among patients with solid malignancies, lung cancer was the most common source (15.6%). As for the laboratory workup, septic solid cancer patients were found to have a higher white blood count (12 576.90 vs 9137.23; p=0.026). During their hospital stay, a total of 158 (51.8%) patients with a solid malignancy died compared with 57 (41.6%) patients with a haematological malignancy (p=0.047). There was no statistically significant association between cancer type and hospital mortality (OR 1.15 for liquid cancer p 0.58). There was also no statistically significant difference regarding intravenous fluid administration, vasopressor use, steroid use or intubation. Conclusion Solid tumour patients with sepsis or septic shock are at the same risk of mortality as patients with haematological tumours. However, haematological malignancy patients admitted with sepsis or septic shock have higher rates of bacteraemia.

Introduction In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation. Methods and analysis STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines. Ethics and dissemination This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368). The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration. Registration The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14.

Introduction In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. Methods and analysis The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. Ethics and dissemination The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell’Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. Trial registration details The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

Rationale Mortality prediction scores are increasingly being evaluated in low and middle income countries (LMICs) for research comparisons, quality improvement and clinical decision-making. The modified early warning score (MEWS), quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA), and Universal Vital Assessment (UVA) score use variables that are feasible to obtain, and have demonstrated potential to predict mortality in LMIC cohorts. Objective To determine the predictive capacity of adapted MEWS, qSOFA and UVA in a Rwandan hospital. Design, setting, participants and outcome measures We prospectively collected data on all adult patients admitted to a tertiary hospital in Rwanda with suspected infection over 7 months. We calculated an adapted MEWS, qSOFA and UVA score for each participant. The predictive capacity of each score was assessed including sensitivity, specificity, positive and negative predictive value, OR, area under the receiver operating curve (AUROC) and performance by underlying risk quartile. Results We screened 19 178 patient days, and enrolled 647 unique patients. Median age was 35 years, and in-hospital mortality was 18.1%. The proportion of data missing for each variable ranged from 0% to 11.7%. The sensitivities and specificities of the scores were: adapted MEWS >4, 50.4% and 74.9%, respectively; qSOFA >2, 24.8% and 90.4%, respectively; and UVA >4, 28.2% and 91.1%, respectively. The scores as continuous variables demonstrated the following AUROCs: adapted MEWS 0.69 (95% CI 0.64 to 0.74), qSOFA 0.65 (95% CI 0.60 to 0.70), and UVA 0.71 (95% CI 0.66 to 0.76); there was no statistically significant difference between the discriminative capacities of the scores. Conclusion Three scores demonstrated a modest ability to predict mortality in a prospective study of inpatients with suspected infection at a Rwandan tertiary hospital. Careful consideration must be given to their adequacy before using them in research comparisons, quality improvement or clinical decision-making.

Background Patients surviving critical illnesses, such as sepsis, often suffer from long-term complications. After discharge from hospital, most patients are treated in primary care. Little is known how general practitioners (GPs) perform critical illness aftercare and how it can be improved. Within a randomised controlled trial, an outreach training programme has been developed and applied. Objectives The aim of this study is to describe GPs’ views and experiences of caring for postsepsis patients and of participating a specific outreach training. Design Semistructured qualitative interviews. Setting 14 primary care practices in the metropolitan area of Berlin, Germany. Participants 14 GPs who had participated in a structured sepsis aftercare programme in primary care. Results Themes identified in sepsis aftercare were: continuity of care and good relationship with patients, GP’s experiences during their patient’s critical illness and impact of persisting symptoms. An outreach education as part of the intervention was considered by the GPs to be acceptable, helpful to improve knowledge of the management of postintensive care complications and useful for sepsis aftercare in daily practice. Conclusions GPs provide continuity of care to patients surviving sepsis. Better communication at the intensive care unit–GP interface and training in management of long-term complications of sepsis may be helpful to improve sepsis aftercare. Trial registration number ISRCTN61744782.

Objectives: Cognitive impairment is an important consequence of sepsis. We sought to determine long-term trajectories of cognitive function after sepsis. Design: Prospective study of the Reasons for Geographic and Racial Differences in Stroke cohort. Setting: United States. Patients: Twenty-one thousand eight-hundred twenty-three participants greater than or equal to 45 years, mean (SD) age 64.3 (9.2) years at first cognitive assessment, 30.9% men, and 27.1% Black. Measurements and Main Results: The main exposure was time-dependent sepsis hospitalization. The primary outcome was global cognitive function (Six-Item Screener range, 0–6). Secondary outcomes were incident cognitive impairment (Six-Item Screener score ≤ 4 [impaired] vs ≥5 [unimpaired]), new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning range, 0–30), verbal memory (word list delayed recall range, 0–10), and executive function/semantic fluency (animal fluency test range, ≥ 30). Over a median follow-up of 10 years (interquartile range, 6–12 yr), 840 (3.8%) experienced sepsis (incidence 282 per 1,000 person-years). Sepsis was associated with faster long-term declines in Six-Item Screener (–0.02 points per year faster [95% CI, –0.01 to –0.03]; p < 0.001) and faster long-term rates of incident cognitive impairment (odds ratio 1.08 per year [95% CI, 1.02–1.15]; p = 0.008) compared with presepsis slopes. Although cognitive function acutely changed after sepsis (0.05 points [95% CI, 0.01–0.09]; p = 0.01), the odds of acute cognitive impairment (Six-Item Screener ≤ 4) immediately after sepsis was not significant (odds ratio, 0.81 [95% CI, 0.63–1.06]; p = 0.12). Sepsis hospitalization was not associated with acute changes or faster declines in word list learning, word list delayed recall, or animal fluency test. Conclusions: Sepsis is associated with accelerated long-term decline in global cognitive function. Current affiliation for Dr. Wang: Department of Emergency Medicine, The Ohio State University, Columbus, OH. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal. A full list of participating Reasons for Geographic And Racial Differences in Stroke investigators and institutions and institutions can be found at http://www.regardsstudy.org. Drs. Wang and Levine conceived the study. Drs. Wang and Safford obtained funding. Drs. Wang and Safford oversaw data collection. Mr. Kabeto conducted the analysis. Dr. Wang drafted the article and all authors contributed to its critical review. Mr. Kabeto had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Wang assumes overall responsibility for the article. Supported, in part, by award R01-NR012726 from the National Institute for Nursing Research, UL1-RR025777 from the National Center for Research Resources, as well as by grants from the Center for Clinical and Translational Science and the Lister Hill Center for Health Policy of the University of Alabama at Birmingham. The parent Reasons for Geographic And Racial Differences in Stroke research project is supported by a cooperative agreement U01-NS041588 from the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. Dr. Wang’s institution received funding from the National Institutes of Health (NIH) National Institute of Nursing Research. Drs. Wang, Wadley, Muntner, Judd, Safford, and Levine received support for article research from the NIH. Dr. Safford reports the following potential conflicts of interest: Amgen—salary support to study patterns of statin use in Medicare and other large databases; diaDexus—salary support for a research grant on lipids and cardiovascular disease outcomes; diaDexus—consulting to help with U.S. Food and Drug Administration application; NIH, Agency for Healthcare Research and Quality (AHRQ)—salary support for research grants. Drs. Wadley’s and Judd’s institutions received funding from the NIH. Dr. Safford’s institution received funding from Amgen. Dr. Kempker’s institution received funding from AHRQ, and he received funding from Grifols; and he received support (K08HS025240) for article research from AHRQ. Dr. Levine’s institution received funding from National Institute on Aging and National Institute of Neurological Disorders and Stroke, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurologic Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the article but not directly involved in the collection, management, analysis, or interpretation of the data. For information regarding this article, E-mail: henry.wang@osumc.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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

Objectives: Rapid delivery of antibiotics is a cornerstone of sepsis therapy, although time targets for specific components of antibiotic delivery are unknown. We quantified time intervals comprising the task of antibiotic delivery and evaluated the association between interval delays and hospital mortality among patients treated in the emergency department for suspected sepsis. Design: Retrospective cohort. Setting: Twelve hospitals in Southeastern United States from 2014 to 2017. Patients: Twenty-four thousand ninety-three encounters among 20,026 adults with suspected sepsis in 12 emergency departments. Measurements and Main Results: We divided antibiotic administration into two intervals: time from emergency department triage to antibiotic order (recognition delay) and time from antibiotic order to infusion (administration delay). We used generalized linear mixed models to evaluate associations between these intervals and hospital mortality. Median time from emergency department triage to antibiotic administration was 3.4 hours (interquartile range, 2.0–6.0 hr), separated into a median recognition delay (time from emergency department triage to antibiotic order) of 2.7 hours(interquartile range, 1.5–4.7 hr) and median administration delay (time from antibiotic order to infusion) of 0.6 hours (0.3–1.2 hr). Adjusting for other risk factors, both recognition delay and administration delay were associated with mortality, but pairwise comparison with a no-delay reference group was not significant for up to 6 hours of recognition delay or up to 1.5 hours of administration delay. Conclusions: Both recognition delays and administration delays were associated with increased hospital mortality, but only for longer delays. These results suggest that both metrics may be important to measure and improve for patients with suspected sepsis but do not support targets less than 1 hour. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Presented, in part, at the annual meeting of the Society Critical Care Medicine, San Antonio, TX, February 2018. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Stephanie.p.taylor@atriumhealth.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Transfusions of blood products are common in critically ill patients and have a potential for immunomodulation. The aim of this study is to address the impact of transfusion of blood products on the susceptibility to ICU-acquired infections in the high-risk patients with septic shock. Design: A single-center retrospective study over a 10-year period (2008–2017). Setting: A medical ICU of a tertiary-care center. Patients: All consecutive patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients who were discharged or died within the first 48 hours were excluded. Interventions: RBC, platelet, and fresh frozen plasma transfusions collected up to 24 hours prior to the onset of ICU-acquired infection. Measurements and Main Results: During the study period, 1,152 patients were admitted for septic shock, with 893 patients remaining alive in the ICU after 48 hours of management. A first episode of ICU-acquired infection occurred in 28.3% of the 48-hour survivors, with a predominance of pulmonary infections (57%). Patients with ICU-acquired infections were more likely to have received RBC, platelet, and fresh frozen plasma transfusions. In a multivariate Cox cause-specific analysis, transfusions of platelets (cause-specific hazard ratio = 1.55 [1.09–2.20]; p = 0.01) and fresh frozen plasma (cause-specific hazard ratio = 1.38 [0.98–1.92]; p = 0.05) were independently associated with the further occurrence of ICU-acquired infections. Conclusions: Transfusions of platelets and fresh frozen plasma account for risk factors of ICU-acquired infections in patients recovering from septic shock. The occurrence of ICU-acquired infections should be considered as a relevant endpoint in future studies addressing the indications of transfusions in critically ill patients. Dr. Pène is the guarantor of the content of the article, including the data and analysis. Drs. Péju, Llitjos and Pène designed the study, collected and analyzed the data, and drafted the article. Drs. Jamme and Lambert performed the statistical analysis. Drs. Charpentier, François, Marin, Cariou, Chiche, and Mira collected the data, contributed to data interpretation and analysis, and revised the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Presented, in part, at the congress “Réanimation 2020”, Paris, France, February 05–07, 2020. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: frederic.pene@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Septic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy. Design: Retrospective cohort study. SETTING: Adult ICU. PATIENTS: Adult ICU patients with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Left ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was –16.8% (interquartile range, –20.4% to –12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5. Conclusions: Among patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The Intermountain Institutional Review Board approved this study with waiver of informed consent. Drs Beesley, Tonna, Paine, Grissom, and Brown designed the study. Drs. Beesley, Sorensen, Tonna, Paine, and Brown analyzed and interpreted the data. Dr. Beesley drafted the report, and all other authors revised it. All authors gave final approval of the report to be published. Supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001067. Dr. Walkey received funding from UptoDate. Dr. Tonna’s institution received funding from National Heart, Lung, and Blood Institute (NHLBI), National Center for Advancing Translational Sciences, and LivaNova; he received funding from Philips Healthcare; he received support for article research from National Institutes of Health; and he was supported by a career development award (K23HL141596) from the NHLBI of the National Institutes of Health. Dr. Burk received funding from Intermountain Research and Medical Foundation. Dr. Paine’s institution received funding from NHLBI and the Department of Veterans Affairs. The remaining authors have disclosed that they do not have any potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. For information regarding this article, E-mail: Sarah.beesley@imail.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. Methods: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. Results: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? Conclusions: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019. Drs. Coopersmtih and De Backer are cochairs of the committee who contributed equally to the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Coopersmith is past president of the Society of Critical Care Medicine. Dr. Antonelli is immediate past president of European Society of Intensive Care Medicine and received consulting fees from Toray, Intersurgical, and Fisher & Paykel and unrestricted research grants from GE and Estor. Dr. Bauer is a consultant for Wolters Kluwer, and he received funding from Wolters Kluwer. Dr. Deutschman is past president of the Society of Critical Care Medicine scientific editor for Critical Care Medicine, consultant for Enlivex and Lowell Therapeutics; his institution received funding from National Institute of General Medical Sciences; he received funding from the Society of Critical Care Medicine, Elsevier, Enlivex, Sage Therapeutics, and La Jolla Pharmaceuticals; and he received support for article research from the National Institutes of Health (NIH). Dr. Evans disclosed that she serves as the cochair of the Surviving Sepsis Committee and as the adult Surviving Sepsis Campaign Guidelines for the management of sepsis and septic shock. Dr. Ferrer received funding from MSD, Pfizer, and Gilead. Dr. Kesecioglu is president of the European Society of Intensive Care Medicine. Dr. Kissoon is the pediatrics guidelines cochair of the Surviving Sepsis Committee. Dr. Martin-Loeches received honoraria from MSD, Gilead, and Aspen. Dr. Nunnally is Treasurer of the Society of Critical Care Anesthesiologists. Dr. Prescott is the sepsis lead for a Michigan statewide sepsis quality improvement initiative sponsored by Blue Cross Blue Shield of Michigan, and his institution received funding from Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and the NIH, and she disclosed government work. Dr. Rhodes is the adult guidelines cochair of the Surviving Sepsis Committee and a member of the Executive Committee. Dr. Talmor received speaking fees from Hamilton Medical, Clew, and Mindray. Dr Tissieres is president of the European Society of Pediatric and Neonatal Intensive Care, is the pediatrics guidelines cochair of the Surviving Sepsis Committee, and has received consulting fees or research grant from Baxter, bioMerieux, Sanofi. Dr. DeBacker is past president of the European Society of Intensive Care Medicine and has received consulting fees from Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Cirrhosis is associated with hemodynamic and vascular disorders. However, microvascular reactivity of cirrhotic patients in the context of sepsis has poorly been investigated. Design: Prospective observational study. Setting: Medical ICU in a tertiary teaching hospital. Patients: We prospectively included adult patients admitted in the ICU for septic shock with and without cirrhosis. After initial resuscitation, global hemodynamic parameters were recorded and skin microvascular reactivity to local acetylcholine iontophoresis was measured. Interventions: None. Measurements and Main Results: Thirty patients with septic shock were included (60% male), 10 with cirrhosis and 20 without, with a median age of 61 years (54–74 yr). Cirrhotic patients were mainly classed as Child-Pugh C (80%) and all of them had ascites. Sequential Organ Failure Assessment score and ICU mortality of cirrhotic patients were higher than the noncirrhotic patients, respectively (6.5 [5.0–8.3] vs 11.5 [9.0–14.0]; p < 0.01; 15% vs 70%; p < 0.01). Peripheral tissue perfusion and global hemodynamic parameters were not different between the cirrhotic and noncirrhotic patients but arterial lactate level was three times higher in patients with cirrhosis (6.0 mmol/L [3.9–8.0 mmol/L] vs 2.0 mmol/L [0.9–3.5 mmol/L]; p < 0.01). Basal skin microvascular blood flow was not statistically different between the groups (4.94 perfusion units [3.45–8.73 perfusion units] vs 6.95 perfusion units [5.24–8.38 perfusion units]; p = 0.29). After acetylcholine simulation, skin microvascular blood flow increased more in cirrhotic patients than in noncirrhotic patients (644% [217–966%] vs 169% [73–505%], p = 0.03). Global microvascular reactivity was seven times higher in cirrhotic patients (area under the curve, 16,412 perfusion units [13,898–19,041 perfusion units] vs 2,664 perfusion units [969–4,604 perfusion units]; p < 0.001). Conclusions: We identified an exaggerated vasodilating microvascular response in cirrhotic patients with septic shock. Such a result may explain vasopressor resistance and paves the way for future therapeutic trials, targeting nitric oxide pathway specifically in this population. All authors are involved in study concept and design, and critical revision of article. Drs. Hariri, Urbina, Lavillegrand, and Ait-Oufella helped in acquisitions of data. Drs. Hariri, Urbina, Gasperment, Guidet, Maury, and Ait-Oufella drafted of the article. Drs. Hariri and Ait-Oufella are involved in statistical analysis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hafid.aitoufella@aphp.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The SEPSISPAM trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. Design: Post hoc analysis of the SEPSISPAM trial. Setting: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. Patients: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. Measurements and Main Results: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09–0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. Conclusions: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence. Drs. Demiselle and Asfar designed the study. Drs. Demiselle and Lemerle collected data in hospitalization reports. Drs. Demiselle and Seegers performed statistical analysis. Drs. Demiselle, Seegers, Guitton, Ricard, Radermacher, and Asfar drafted the article. Drs. Meziani, Grelon, Megarbane, Anguel, Mira, Dequin, Gergaud, Weiss, Legay, Le Tulzo, Conrad, Robert, Gonzalez, Guitton, Tamion, Tonnelier, Bédos, Van Der Linden, Vieillard-Baron, Mariotte, Pradel, Lesieur, Ricard, Hervé, du Cheyron, and Helms included patients in the SEPSISPAM trial and helped to have access to hospitalization reports. All the authors have revised and approved the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The SEPSISPAM trial was supported by the French Ministry of Health. Dr. Weiss perceived consultant fees from Med-Day Pharmaceuticals outside of the scope of this article. Dr. Dequin’s institution received funding from Angers University Hospital, the French Ministry of Health, Abionic, Atox Bio, Sphingotec GMBH, Adrenomed, Medspace, Aridis, Merck, Combioxin, GSK, Med-Immune, Genentech INH, Rev-Immune, Faron, Kenta, and Tigenix, and he received support for article research from the French Ministry of Health. Dr. Gonzalez disclosed work for hire. Dr. Teboul received funding from Getinge/Pulsion. Dr. Radermacher’s institution received funding from Deutsche Forschungsgemeinschaft and the German Ministry of Defense. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: piasfar@chu-angers.fr Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Assess the impact of heterogeneity among established sepsis criteria (Sepsis-1, Sepsis-3, Centers for Disease Control and Prevention Adult Sepsis Event, and Centers for Medicare and Medicaid severe sepsis core measure 1) through the comparison of corresponding sepsis cohorts. Design: Retrospective analysis of data extracted from electronic health record. Setting: Single, tertiary-care center in St. Louis, MO. Patients: Adult, nonsurgical inpatients admitted between January 1, 2012, and January 6, 2018. Interventions: None. Measurements and Main Results: In the electronic health record data, 286,759 encounters met inclusion criteria across the study period. Application of established sepsis criteria yielded cohorts varying in prevalence: Centers for Disease Control and Prevention Adult Sepsis Event (4.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (4.8%), International Classification of Disease code (7.2%), Sepsis-3 (7.5%), and Sepsis-1 (11.3%). Between the two modern established criteria, Sepsis-3 (n = 21,550) and Centers for Disease Control and Prevention Adult Sepsis Event (n = 12,494), the size of the overlap was 7,763. The sepsis cohorts also varied in time from admission to sepsis onset (hr): Sepsis-1 (2.9), Sepsis-3 (4.1), Centers for Disease Control and Prevention Adult Sepsis Event (4.6), and Centers for Medicare and Medicaid severe sepsis core measure 1 (7.6); sepsis discharge International Classification of Disease code rate: Sepsis-1 (37.4%), Sepsis-3 (40.1%), Centers for Medicare and Medicaid severe sepsis core measure 1 (48.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (54.5%); and inhospital mortality rate: Sepsis-1 (13.6%), Sepsis-3 (18.8%), International Classification of Disease code (20.4%), Centers for Medicare and Medicaid severe sepsis core measure 1 (22.5%), and Centers for Disease Control and Prevention Adult Sepsis Event (24.1%). Conclusions: The application of commonly used sepsis definitions on a single population produced sepsis cohorts with low agreement, significantly different baseline demographics, and clinical outcomes. Washington University in St. Louis, St. Louis, MO. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Michelson received funding as a shareholder of Pfizer. Dr. Lai received funding as a shareholder of Altria Group, Apple, Berkshire Hathaway, Barnes Group, Carnival Corp, Citigroup, Johnson & Johnson, Verizon Communications, Walt Disney, Royal Caribbean Cruises, Caterpillar, McDonald’s Corp, Ubiquiti, Westinghouse Air Brake Technologies, and Yum! Brands. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: amichels@wustl.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Listeriosis is a foodborne infection causing significant morbidity and mortality (>20%) in immunocompromised patients or those at extreme age (Allerberger and Listeriosis, 2010; Charlier et al., 2017). Underlying conditions associated with none-perinatal listeriosis include ongoing malignancies, diabetes mellitus, advanced age (>65-year-old), receiving immunosuppressive agents, dialysis, and liver cirrhosis (Allerberger and Listeriosis, 2010; Charlier et al., 2017; Goulet et al., 2012). Disease manifestations varied from self-limited gastroenteritis in patients without underlying diseases, bacteremia, or neurolisteriosis in those with comorbidities to septic abortion in pregnant women (Allerberger and Listeriosis, 2010; Charlier et al., 2017).

by Jesús Díez-Manglano, Marta Nataya Solís-Marquínez, Andrea Álvarez García, Nicolás Alcalá-Rivera, Irene Maderuelo Riesco, Martín Gericó Aseguinolaza, José Luis Beato Pérez, Manuel Méndez Bailón, Ane-Elbire Labirua-Iturburu Ruiz, Miriam García Gómez, Carmen Martínez Cilleros, Paula María Pesqueira Fontan, Lucy Abella Vázquez, Julio César Blázquez Encinar, Ramon Boixeda, Ricardo Gil Sánchez, Andrés de la Peña Fernández, José Loureiro Amigo, Joaquín Escobar Sevilla, Marcos Guzmán Garcia, María Dolores Martín Escalante, Jeffrey Oskar Magallanes Gamboa, Ángel Luis Martínez González, Carlos Lumbreras Bermejo, Juan Miguel Antón Santos, for the SEMI-COVID-19 Network Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20–65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067–0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality.

New England Journal of Medicine, Ahead of Print.

Abstract Background The association between blood culture status and mortality among sepsis patients remains controversial hence we conducted a tri-center retrospective cohort study to compare the early and late mortality of culture-negative versus culture-positive sepsis using the inverse probability of treatment weighting (IPTW) method. Methods Adult patients with suspected sepsis who completed the blood culture and procalcitonin tests in the emergency department or hospital floor were eligible for inclusion. Early mortality was defined as 30-day mortality, and late mortality was defined as 30- to 90-day mortality. IPTW was calculated from propensity score and was employed to create two equal-sized hypothetical cohorts with similar covariates for outcome comparison. Results A total of 1405 patients met the inclusion criteria, of which 216 (15.4%) yielded positive culture results and 46 (21.3%) died before hospital discharge. The propensity score model showed that diabetes mellitus, urinary tract infection, and hepatobiliary infection were independently associated with positive blood culture results. There was no significant difference in early mortality between patients with positive or negative blood culture results. However, culture-positive patients had increased late mortality as compared with culture-negative patients in the full cohort (IPTW-OR, 1.95, 95%CI: 1.14–3.32) and in patients with severe sepsis or septic shock (IPTW-OR, 1.92, 95%CI: 1.10–3.33). After excluding Staphylococcal bacteremia patients, late mortality difference became nonsignificant (IPTW-OR, 1.78, 95%CI: 0.87–3.62). Conclusions Culture-positive sepsis patients had comparable early mortality but worse late mortality than culture-negative sepsis patients in this cohort. Persistent Staphylococcal bacteremia may have contributed to the increased late mortality.

For skin antisepsis, chlorhexidine plus alcohol provides greater protection of peripheral venous catheter-related infectious complications than does povidone iodine plus alcohol. Use of innovative devices extends the catheter complication-free dwell time.

Peripheral venous catheters are the most frequently used invasive devices in health care.1 A French prevalence survey found that peripheral venous catheters account for 80% of all intravascular catheters.2 Although peripheral venous catheters are considered low risk to the patient, they rarely can cause substantial adverse events, including mechanical, vascular, and infectious complications.3 However, little research has been done on strategies and interventions focused on decreasing the risk of complications related to peripheral venous catheters.

Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Tang et al. reveal that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1-LPS interaction.

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 for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s websitehttp://journals.lww.com/ccmjournal). Dr. Evans has disclosed that she is a PI on a multi-center observational cohort study of hospitalized patients with severe acute respiratory infection, funded by the CDC Foundation. Drs. Prescott, Chertow, and Mammen disclosed government work. Dr. Fan received funding from Lung Technologies, MC3 Cardiopulmonary, and Fresenius Medical Care. Dr. Derde’s institution received funding from ZonMw (Den Haag, Europe) grant number 10150062010003, the Canadian Institutes of Health Research (CIHR), and from Rapid European COVID-19 Emergency Research response (RECOVER) (Europe, H2020) grant agreement No 101003589, and her institution has agreements with Faron (interferon), SOBI (anakinra), and Abbvie (lopinavir/r) to supply drugs for the above-funded studies. Dr. Du’s institution received funding from the Ministry of Science and Technology for a COVID-19–related study (NCT04244591). Dr. Crowther received funding from Servier Canada, Asahi Kasei, Precision Biologicals, Hemostasis Reference Laboratory, Pfizer, CSL Behring, Diagnostica Stago, and he disclosed that he undertakes significant amounts of both medical malpractice and product work in the general areas of hematology and thromboembolism. Dr. Belley-Cote received funding from CIHR, Roche, and Bayer as a principal investigator for the ACT trial that evaluates hydroxychloroquine, interferon beta, colchicine, aspirin, and rivaroxaban in patients with COVID-19. Dr. Zarychanski received operating grants from CIHR, LifeArc Foundation, Thistledown Foundation, and Research Manitoba for grants related to anticoagulation in COVID-19. Dr. McGreer’s institution received funding from Appili Therapeutics. Dr. Hayden disclosed he is a nonpaid consultant for multiple companies involved in developing COVID-19 countermeasures (Arcturus, Cidara, Gilead, GSK, resTORbio, Regeneron, SAB Biotherapeutics, Takeda, Vir), and he is a DSMB member for CytoDyn. Dr. Martin received funding from serving on a clinical trial data monitoring board. Dr. Antonelli received funding from consulting for Intersurgical and ESTOR. Dr. Waleed Alhazzani is the principal investigator on awake proning trial in COVID-19 COVI-PRONE. Dr. Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). He is a co-investigator on the REMAP-CAP trial and on an awake proning trial in COVID-19 (COVI-PRONE). Dr. Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical: Dr. Lennie Derde is an investigator on REMAP-CAP trial, the NVIC (Dutch National ICU society) chair of Taskforce Infectious Diseases (standing committee), member of ESICM Coronavirus Taskforce (started with this outbreak), and chair of the ESICM Clinical Training Committee; all are unpaid positions. Dr. Laura Evans is the team leader for the critical care section of the NIH COVID-19 management guideline. Dr. Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Dr. Frederick Hayden is a noncompensated consultant to Gilead Sciences, Regeneron, Cidara, Fujifilm, Ridgeback, Merck, Roche/Genentech, GSK, Vir, resTORbio, and SAB Biotherapeutics, and he is a DSMB member for CytoDyn therapeutic clinical trial: Dr. Manoj J. Mammen is an investigator for the U.S. NIH PASSive Immunity Trial for Our Nation (PassItOn) trial: Dr. Greg Martin is a member of the NIH COVID-19 treatment guidelines, principal investigator for COVID-19 diagnostic testing (U.S. NIH RADx program) and has served as a research consultant to Genentech, Grifols, Regeneron and Siemens. Dr. Massimo Antonelli declared consultancy with Toray/Estor and Fisher and Pykel and research grant from GE. Dr. Flavia Machado is member of the executive committee for the CODEX study. Dr. Sheila Nainan Myatra is on the steering committee of the COVID Steroid 2 Trial (ClinicalTrials.gov Identifier: NCT04509973) and the HydrOxychloroquine Prophylaxis Evaluation (HOPE) Trial (CTRI registration No.CTRI/2020/05/025067). Dr Naomi Hammond is on the steering committee of the COVID Steroid 2 Trial (ClinicalTrials.gov Identifier: NCT04509973) and the HydrOxychloroquine Prophylaxis Evaluation (HOPE) Trial (CTRI registration No.CTRI/2020/05/025067). Dr. Emilie Belley-Cote reports grants from Bayer, grants from Roche outside the submitted work. She is a principal investigator for the ACT trial: The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: andrewrhodes@nhs.net Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Catecholaminergic vasopressors are the cornerstone of circulatory shock management. Nevertheless, catecholamines have problematic side effects, arousing a growing interest in noncatecholaminergic agents such as vasopressin or angiotensin-II. However, their respective effects on sepsis-associated microvascular endothelial dysfunction such as permeability or inflammation remain elusive. We investigated the role of catecholamines and other vasopressors on Toll-like receptor agonists-induced microvascular endothelial permeability and inflammation. Setting: University research laboratory/cell research. Subjects: Human pulmonary microvascular endothelial cells from multiple donors. Intervention: Confluent monolayers of human pulmonary microvascular endothelial cell were treated with Toll-like receptor agonists (lipopolysaccharide, Poly[I:C], or tripalmitoyl-S-glyceryl cysteine) in the presence or absence of epinephrine, norepinephrine, vasopressin, and angiotensin-II. Permeability was inferred from transendothelial resistance, measured using electrical cell impedance sensing, where decreased transendothelial resistance is consistent with increased permeability. Cell-cell junction molecule expression was assessed via immunofluorescence microscopy and flow cytometry. We quantified cytokines in supernatants of Toll-like receptor agonist-treated human pulmonary microvascular endothelial cell. Measurements and Main Results: Epinephrine and norepinephrine both ameliorate lipopolysaccharide, polyinosinic:polycytidylic acid, or tripalmitoyl-S-glyceryl cysteine–induced reductions in transendothelial resistance, a surrogate for endothelial permeability. In contrast, the noncatecholaminergic agents, vasopressin, and angiotensin-II did not affect Toll-like receptor agonist-induced reductions in transendothelial resistance. β1- and β2-adrenergic receptor antagonists reduced the effects of the catecholamines on transendothelial resistance, whereas α-adrenergic receptor antagonists did not. We observed that epinephrine and norepinephrine induced actin cytoskeletal rearrangement and normalized the membrane expression of proteins involved with adherens-junctions (vascular endothelial-cadherin) and tight-junctions (zona occludens-1). Despite having a substantial effect on endothelial permeability, epinephrine and norepinephrine did not affect human pulmonary microvascular endothelial cell survival or production of interleukin-8, interleukin-6, or monocyte chemoattractant protein-1 (CCL-2) induced by Toll-like receptor agonists, suggesting that these functions are regulated separately from permeability. Conclusions: Our findings demonstrate that treatment with epinephrine or norepinephrine strongly reduces endothelial permeability induced by agonists of multiple Toll-like receptors (Toll-like receptor-2, Toll-like receptor-3, Toll-like receptor-4) in vitro. Our studies suggest that both β1- and β2-adrenergic receptor mediate the stabilizing effects of epinephrine and norepinephrine on the endothelial barrier. Drs. Joffre and Lloyd participated in the study concept and design, acquisitions of data, statistical analysis, drafting, and revision of the article. Drs. Wong, Chung-Yeh, Nguyen, and Xu participated in cell culture, stimulation, and immunoassays. Drs. Legrand and Hellman provided input on the design and critical comments and edits to the article. The study was performed in Dr. Hellman’s laboratory. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by awards from the University of California, San Francisco (UCSF) Department of Anesthesia and Perioperative Care and the San Francisco Foundation (to Dr. Hellman). The UCSF Flow Cytometry Facility acknowledges Diabete research center Center Grant National Institutes of Health P30 DK063720. Dr. Joffre is supported by a fellowship from SRLF (French Society of Intensive Care) and Amicale des Anciens Internes en medicine des Hopitaux de Paris and Assistance Publique—Hopitaux de Paris. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Jeremie.joffre@ucsf.edu This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To assess whether Black race is associated with a higher rate of all-cause readmission compared with White race following community-onset sepsis. Design: Retrospective cohort study. Setting: One-thousand three-hundred bed urban academic medical centers. Patients: Three-thousand three-hundred ninety patients hospitalized with community-onset sepsis between January 1, 2010, and December 31, 2017. Interventions: Community-onset sepsis was defined as patients admitted through the emergency department with an International Classification of Disease, ninth revision, Clinical Modification code for either severe sepsis (995.92) or septic shock (785.52). Beginning in 2015, we used International Classification of Disease, Tenth Revision, Clinical Modification codes R65.20 (severe sepsis) and R65.21 (septic shock). We excluded those individuals hospitalized at another acute care facility that were transferred to our facility. Race was abstracted electronically, and patients who expired or self-identified as a race other than Black or White race were excluded. Patients who experienced a subsequent hospitalization at our facility were considered to be readmitted. Measurements and Main Results: Compared with White race, Black race demonstrated a significantly higher rate of all-cause readmission (60.8% vs 71.1%; p < 0.001), including a higher rate of readmission for sepsis (14.0% vs 19.8%; p < 0.001). Black patients also resided in zip codes with a lower median household income and were more likely to use public insurance compared with White race. Similar rates of comorbid diseases and disease burden were observed between the two groups, but vasopressors were less likely to be administered to Black patients. Multivariable analysis showed that Black race was associated with a 50% increased odds (odds ratio, 1.52, 99% CI, 1.25–1.84) in all-cause readmission risk compared with White race. Conclusions: Black race was associated with a higher rate of all-cause and sepsis readmission, possibly as a result of unaddressed health disparities, compared with White race. Programs addressing healthcare disparities should use readmission as another marker of equity. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http:/journals.lww.com/ccmjournal). Dr. Betthauser received funding from La Jolla Pharmaceutical Company. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: bryan.lizza@bjc.org Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children. Design: Post hoc analysis of a Bayesian phase 2b randomized clinical trial. Setting: Seven PICUs. Patients: Children less than 18 years old with newly inserted central venous catheter. Interventions: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2–0.5 international units/mL versus usual care. Measurements and Main Results: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37–2.44) in infants and 0.24 (95% credible interval, 0.04–0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78–437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7–74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17–61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count. Conclusions: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Faustino and Spinella received funding to conduct the Catheter-Related Early Thromboprophylaxis with Enoxaparin Trial. Dr. Faustino’s institution received funding from National Institutes of Health (NIH) and the American Heart Association to conduct the trial (16RNT31180018). Drs. Faustino and Spinella received funding from the NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to conduct the trial (R21HD089131). Drs. Faustino, Hanson, Pinto, Shabanova, and McPartland received support for article research from the NIH. Drs. Faustino, Raffini, Hanson, Kandil, McPartland, and Spinella disclosed off-label product use of enoxaparin (investigational new drug approval from the U.S. Food and Drug Administration was received). Dr. Raffini received funding from Bayer, Genetech, Xa-Tek, and HemaBiologics. Dr. Hanson’s institution received funding from the NIH. Dr. Kandil received funding from Children’s Hospital Collaborative, Improving Pediatric Sepsis Outcomes. Dr. Shabanova’s institution received funding from Prevention of Central Venous Catheter-Associated Thrombosis in Critically Ill Children NICHD: R21HD089131; she received funding through the Clinical and Translational Science Award Grant Number UL1 RR024139 from the National Center for Research Resources and the National Center for Advancing Translational Science, components of the NIH, and NIH Roadmap for Medical Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. The CRETE Trial Investigators are listed in the Appendix. ClinicalTrials.gov Identifier: NCT03003390. For information regarding this article, E-mail: vince.faustino@yale.edu Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care. Design: Retrospective, international, Sapphire study. Setting: Academic Medical Center. Patients: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment. Interventions: None. Measurements and Main Results: We stratified patients enrolled in the Sapphire study into three groups—those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2–3 acute kidney injury within the first 3 days compared with 14% without stage 2–3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53–11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2–3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8–34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury. Conclusions: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria. A complete list of Sapphire Investigators is provided in the Appendix (Supplemental Digital Content 1, http://links.lww.com/CCM/G111). Clinical Trial Registration: NCT01209169. The parent study was designed by Drs. Kellum, Kampf, McPherson and Chawla and was conducted by Drs. Artigas, Gunnerson, Honore, Nguyen, Rimmel,o Shapiro, and Vincent. Dr. Kellum conceived of the current study and drafted the article. Dr. Shi performed the statistical analysis. Drs. Kellum, Kampf, Kwan, and McPherson interpreted the results, and all authors reviewed and revised the article. Dr. Kellum takes responsibility for the content of the article, including the data and analysis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The study sponsor (Astute Medical) was primarily responsible for design of the parent study and data collection; the current study was designed and interpreted by the authors. Dr. Kellum’s institution received funding from Astute Medical and bioMerieux. Drs. Kellum, Rimmelé, Shi, and Chawla received funding from Astute Medical. Drs. Kampf, Kwan, and McPherson are employees of Astute Medical/bioMerieux; Drs. Kellum, Rimmelé, Shi, and Chawla are paid consultants of Astute Medical/bioMerieux; and Dr. Kellum has received grant support from Astute Medical/ bioMerieux apart from the current work. Dr. Artigas’s institution received funding from Lilly Foundation, and he received funding from Grifols, Fisher & Paykel. Drs. Kampf, Kwan, and McPherson received funding from Astute Medical (employee). Drs. Nguyen’s and Shapiro’s institutions received funding from Astute Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kellum@pitt.edu This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. Design: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. Setting: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. Conclusions: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019. COVID-19-Core Outcomes Set Investigators are listed in Appendix 1. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Tong and Ms. Baumgart are co-first authors. Supported, in part, by the Flinders University and the National COVID-19 Clinical Evidence Taskforce, convened by the Australian Living Evidence Consortium, hosted by Cochrane Australia, School of Public Health and Preventive Medicine, Monash University supported by the Australian Government, Victorian Department of Health and Human Services, Ian Potter Foundation, Walter Cottman Endowment Fund (managed by Equity Trustees), and the Lord Mayor’s Charitable Foundation). Dr. Tong is supported by The University of Sydney Robinson Fellowship. Dr. Morris is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Dr. Douglas is the principal investigator of clinical and translational research studies of acute respiratory distress syndrome, sepsis, and coronavirus disease 2019 from National Institutes of Health, Roche Pharmaceuticals, and Genentech. Research grants are to his institution, Denver Health Medical Center. Dr. Povoa had received lecture fees from Orion, Pfizer, and Technofage. Dr. Azevedo received funding from Halex Istar and Baxter. Dr. Marshall received funding from AM Pharma, and he disclosed he is Cochair of the World Health Organization Working Group on Clinical Characterization and Management. Dr. Mer received funding from honoraria for serving on speakers bureaus and advisory boards as an invited “key opinion leader,” including from Pfizer, MSD, Astellas, and Sun. Dr. Morris received support from WT/Charity Open Access Fund. Dr. Morris’ institution received funding from WT. Dr. Smyth’s institution received funding from Vertex outside the submitted work; he disclosed having a patent “Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof”; and he received funding from Teva, Novartis, and Vertex, outside the submitted work. Dr. Simpson disclosed he is a coapplicant on independent grants with Becton Dickinson Biosciences and he is the Director of a National Institute for Health Research In Vitro Diagnostics Co-operative, which works with companies across the diagnostics industry. Dr. Turner’s institution received funding from Burnet Institute and United States Agency for International Development, and she received funding from World Health Organization. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: allison.tong@sydney.edu.au This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Objectives: To describe the infrastructure and resources for pediatric emergency and critical care delivery in resource-limited settings worldwide. Design: Cross-sectional survey with survey items developed through literature review and revised following piloting. Setting: The electronic survey was disseminated internationally in November 2019 via e-mail directories of pediatric intensive care societies and networks and using social media. PATIENTS: Healthcare providers who self-identified as working in resource-limited settings. Interventions: None. Measurements and Main Results: Results were summarized using descriptive statistics and resource availability was compared across World Bank country income groups. We received 328 responses (238 hospitals, 60 countries), predominantly in Latin America and Sub-Saharan Africa (n = 161, 67.4%). Hospitals were in low-income (28, 11.7%), middle-income (166, 69.5%), and high-income (44, 18.4%) countries. Across 174 PICU and adult ICU admitting children, there were statistically significant differences in the proportion of hospitals reporting consistent resource availability (“often” or “always”) between country income groups (p < 0·05). Resources with limited availability in lower income countries included advanced ventilatory support, invasive and noninvasive monitoring, central venous access, renal replacement therapy, advanced imaging, microbiology, biochemistry, blood products, antibiotics, parenteral nutrition, and analgesic/sedative drugs. Seventy-seven ICUs (52.7%) were staffed 24/7 by a pediatric intensivist or anesthetist. The nurse-to-patient ratio was less than 1:2 in 71 ICUs (49.7%). Conclusions: Contemporary data demonstrate significant disparity in the availability of essential and advanced human and material resources for the care of critically ill children in resource-limited settings. Minimum standards for essential pediatric emergency and critical care in resource-limited settings are needed. The PALISI Global Health Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) are as follows: Jonah Attebery, MD; Adnan T. Bhutta, MBBS; Alden Blair, PhD, MS; Timothy Thomas Cornell, MD; Ericka Fink, MD, MS; Adrian J. Holloway, MD; Shubhada Hooli, MD, MPH; Teresa Kortz, MD, MS; Niranjan (Tex) Kissoon, MD; Katie Nielsen, MD, MPH; Kenneth E. Remy, MD, MHSc, MSCI; and Amelie von Saint Andre-von Arnim, MD. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Muttalib received research fellowship funding from the Centre for Global Child Health (Hospital for Sick Children). The Hospital for Sick Children had no role in the design, conduct, or analysis of the study, or the decision to publish. Dr. Lee received funding from KK Women’s and Children’s Hospital. Dr. Agulnik’s institution received funding from Conquer Cancer Foundation Global Oncology Young Investigator Award. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Fiona.muttalib@mail.utoronto.ca Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

No abstract available…

Objectives: To define the characteristic of bacteremia in the patients with acute pancreatitis and determine its possible association with the disease severity. Design: A prospective controlled study. Setting: ICU of Jinling Hospital, China. Patients: A total of 48 patients with mild or severe acute pancreatitis were enrolled in this study. Interventions: None. Measurements and Main Results: Samples of peripheral blood were collected from the patients at 4 or 5 and 9 or 10 days after acute pancreatitis was definitely diagnosed. Resulting DNA from the blood was analyzed using denaturing gradient gel electrophoresis, and separated fragments were sequenced for identification of bacterial species. Bacterial DNA was detected in peripheral blood from 68.8% of patients with acute pancreatitis, and more than half (60.4%) of the patients encountered polymicrobial flora. Translocated bacteria in patients with acute pancreatitis were primarily constituted of opportunistic pathogens derived from the gut, including Escherichia coli, Shigella flexneri, Enterobacteriaceae bacterium, Acinetobacter lwoffii, Bacillus coagulans, and Enterococcus faecium. And the species of circulating bacteria shifted remarkably among the patients with different severity. The presence of the bacteremia correlated positively with the Acute Physiology and Chronic Health Evaluation-II scores of patients with acute pancreatitis (r = 0.7918, p < 0.0001). Conclusions: This study provides a detailed description on the prevalence of bacteremia and characteristic of bacterial species in patients with acute pancreatitis. We demonstrate an association between the bacteremia and the disease severity, which enables us to better understand a potential role of bacterial translocation in the pathogenesis of septic complication in acute pancreatitis. Drs. Qiurong Li and Jieshou Li conceived and designed the study. Mr. Wang, Ms. Tang, Ms. He, and Dr. Ning Li performed the experiments. Dr. Qiurong Li and Mr. Wang analyzed the data and wrote and revised the manuscript. All authors approved the final version. Supported, in part, by the National Basic Research Program (97 Program) in China (201CB5140 and 2009CB522405), National High-tech R&D Program (86 Program) of China (2012AA021007), National Natural Science Foundation in China (8107075), and Scientific Research Fund in Jiangsu Province (BK200917). Dr. Qiurong Li is thankful for receiving the Deutscher Akademischer Austauschdienst Researcher Fellowship (Bioscience Special Program, Germany). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: liqiurong@yahoo.com, or lijieshounj@16.com Copyright © by 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Purpose of review Neisseria meningitidis (Nm) is primarily associated with asymptomatic nasopharyngeal carriage and invasive meningococcal disease (sepsis and meningitis), but like N. gonorrhoea (Ng), Nm can colonize urogenital and rectal mucosal surfaces and cause disease. First noted in 2015, but with origins in 2011, male urethritis clusters caused by a novel Nm clade were reported in the USA (the US_NmUC). This review describes research developments that characterize this urogenital-tropic Nm. Recent findings The US_NmUC evolved from encapsulated Nm serogroup C strains. Loss of capsule expression, lipooligosaccharide (LOS) sialylation, genetic acquisition of gonococcal alleles (including the gonococcal anaerobic growth aniA/norB cassette), antimicrobial peptide heteroresistance and high surface expression of a unique factor-H-binding protein, can contribute to the urethra-tropic phenotype. Loss-of-function mutations in mtrC are overrepresented in clade isolates. Similar to Ng, repeat US_NmUC urethritis episodes can occur. The US_NmUC is now circulating in the UK and Southeast Asia. Genomic sequencing has defined the clade and rapid diagnostic tests are being developed for surveillance. Summary The US_NmUC emerged as a cause of urethritis due to acquisition of gonococcal genetic determinants and phenotypic traits that facilitate urogenital tract infection. The epidemiology and pathogenesis of this urogenital-tropic pathogen continues to be defined.

Journal of Medical Virology, Volume 93, Issue 3, Page 1532-1537, March 2021.