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Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia.Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL).Hospitals.Hospitalized adults with severe COVID-19 pneumonia.Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28.The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active.Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

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

Objectives:To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.Design:Randomize

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

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

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

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

To identify circumstances in which repeated measures of organ failure would improve mortality prediction in ICU patients.Retrospective cohort study, with external validation in a deidentified ICU database.Eleven ICUs in three university hospitals within an academic healthcare system in 2014.Adults (18 yr old or older) who satisfied the following criteria: 1) two of four systemic inflammatory response syndrome criteria plus an ordered blood culture, all within 24 hours of hospital admission; and 2) ICU admission for at least 2 calendar days, within 72 hours of emergency department presentation.NoneMEASUREMENTS AND MAIN RESULTS:: Data were collected until death, ICU discharge, or the seventh ICU day, whichever came first. The highest Sequential Organ Failure Assessment score from the ICU admission day (ICU day 1) was included in a multivariable model controlling for other covariates. The worst Sequential Organ Failure Assessment scores from the first 7 days after ICU admission were incrementally added and retained if they obtained statistical significance (p0.05). The cohort was divided into seven subcohorts to facilitate statistical comparison using the integrated discriminatory index. Of the 1,290 derivation cohort patients, 83 patients (6.4%) died in the ICU, compared with 949 of the 8,441 patients (11.2%) in the validation cohort. Incremental addition of Sequential Organ Failure Assessment data up to ICU day 5 improved the integrated discriminatory index in the validation cohort. Adding ICU day 6 or 7 Sequential Organ Failure Assessment data did not further improve model performance.Serial organ failure data improve prediction of ICU mortality, but a point exists after which further data no longer improve ICU mortality prediction of early sepsis.

To investigate the effects of the administration of 4% albumin on lactated Ringer's, when compared with lactated Ringer's alone, in the early phase of sepsis in cancer patients.Single-center, randomized, double-blind, controlled-parallel trial.A tertiary care university cancer hospital.Cancer patients with severe sepsis or septic shock.Between October 2014 and December 2016, patients were randomly assigned to receive either bolus of albumin in a lactated Ringer's solution or lactated Ringer's solution alone during the first 6 hours of fluid resuscitation after intensive care medicine (ICU) admission. Primary outcome was defined as death from any cause at 7 days. Secondary outcomes were defined as death from any cause within 28 days, change in Sequence Organ Failure Assessment scores from baseline to day 7, days alive and free of mechanical ventilation, days alive and free of vasopressor, renal replacement therapy during ICU stay, and length of ICU and hospital stay.A total of 360 patients were enrolled in the trial. At 7 days, 46 of 180 patients (26%) died in the albumin group and 40 of 180 (22%) died in the lactated Ringer's group (p = 0.5). At 28 days, 96 of 180 patients (53%) died in the albumin group and 83 of 180 (46%) died in the lactated Ringer's group (p = 0.2). No significant differences in secondary outcomes were observed.Adding albumin to early standard resuscitation with lactated Ringer's in cancer patients with sepsis did not improve 7-day survival.

Sepsis-3 defines organ dysfunction as an increase in the Sequential Organ Failure Assessment score by greater than or equal to 2 points. However, some Sequential Organ Failure Assessment score components are not routinely recorded in all hospitals' electronic health record systems, limiting its utility for wide-scale sepsis surveillance. The Centers for Disease Control and Prevention recently released the Adult Sepsis Event surveillance definition that includes simplified organ dysfunction criteria optimized for electronic health records (eSOFA). We compared eSOFA versus Sequential Organ Failure Assessment with regard to sepsis prevalence, overlap, and outcomes.Retrospective cohort study.One hundred eleven U.S. hospitals in the Cerner HealthFacts dataset.Adults hospitalized in 2013-2015.None.We identified clinical indicators of presumed infection (blood cultures and antibiotics) concurrent with either: 1) an increase in Sequential Organ Failure Assessment score by 2 or more points (Sepsis-3) or 2) 1 or more eSOFA criteria: vasopressor initiation, mechanical ventilation initiation, lactate greater than or equal to 2.0 mmol/L, doubling in creatinine, doubling in bilirubin to greater than or equal to 2.0 mg/dL, or greater than or equal to 50% decrease in platelet count to less than 100 cells/μL (Centers for Disease Control and Prevention Adult Sepsis Event). We compared area under the receiver operating characteristic curves for discriminating in-hospital mortality, adjusting for baseline characteristics. Of 942,360 patients in the cohort, 57,242 (6.1%) had sepsis by Sequential Organ Failure Assessment versus 41,618 (4.4%) by eSOFA. Agreement between sepsis by Sequential Organ Failure Assessment and eSOFA was good (Cronbach's alpha 0.81). Baseline characteristics and infectious diagnoses were similar, but mortality was higher with eSOFA (17.1%) versus Sequential Organ Failure Assessment (14.4%; p0.001) as was discrimination for mortality (area under the receiver operating characteristic curve, 0.774 vs 0.759; p0.001). Comparisons were consistent across subgroups of age, infectious diagnoses, and comorbidities.The Adult Sepsis Event's eSOFA organ dysfunction criteria identify a smaller, more severely ill sepsis cohort compared with the Sequential Organ Failure Assessment score, but with good overlap and similar clinical characteristics. Adult Sepsis Events may facilitate wide-scale automated sepsis surveillance that tracks closely with the more complex Sepsis-3 criteria.

OBJECTIVES This study examines the relationships between hospitals' annual acute respiratory distress syndrome case volume with hospitals' acute respiratory distress syndrome case fatality rates and individuals' odds of acute respiratory distress syndrome hospital mortality. DESIGN Retrospective cohort study. SETTING The U.S. Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, 2002-2011. PATIENTS Acute respiratory distress syndrome discharges defined by the presence of an acute respiratory distress syndrome International Classification of Diseases, 9th revision, Clinical Modification diagnosis code (518.82 or 518.5) and a mechanical ventilation procedure code (96.70, 96.71 or 96.72) on the discharge diagnosis and procedure lists. If the procedure code 96.71 was on the discharge record (mechanical ventilation < 96 hr duration), the patient also needed to be classified as deceased. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We analyzed 2,686 hospitals and 117,204 cases of acute respiratory distress syndrome. Average annual hospital acute respiratory distress syndrome in-hospital mortality was 47%. Acute respiratory distress syndrome case volume was categorized as low (1-9), medium (10-49), and high (50-423 cases per year). In a hospital-level Poisson regression adjusting for hospital characteristics, when compared with low-volume acute respiratory distress syndrome hospitals, high- and medium-volume acute respiratory distress syndrome hospitals had lower annual acute respiratory distress syndrome case fatality (rate ratio, 0.75; 99% CI, 0.71-0.79 and rate ratio, 0.86; 99% CI, 0.82-0.90, respectively; p ≤ 0.001 for both). In an individual-level, multivariable model adjusting for hospital and individual characteristics, high and medium acute respiratory distress syndrome volume hospitals were associated with lower odds of acute respiratory distress syndrome mortality compared with low-volume hospitals (odds ratio, 0.85 [99% CI, 0.74-0.99]; p = 0.006 and odds ratio, 0.89 [99% CI 0.79-1.00]; p = 0.01, respectively). CONCLUSIONS In this cohort, at both an individual- and hospital-level, higher acute respiratory distress syndrome hospital case volume is associated with lower acute respiratory distress syndrome hospital mortality.

Objective: Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. Design: Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. Patients: A total of 6,179 critically ill patients. Setting: Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Interventions: None. Measurements and Main Results: The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15–21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). Conclusions: Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality.

OBJECTIVES Although highly active antiretroviral therapy has led to improved survival in HIV-infected individuals, outcomes for HIV-infected patients with sepsis in the post-highly active antiretroviral therapy era are conflicting. Access to highly active antiretroviral therapy and healthcare disparities continue to affect outcomes. We hypothesized that HIV-infected patients with severe sepsis would have worse outcomes compared with their HIV-uninfected counterparts in a large safety-net hospital where access to healthcare is low and delivery of critical care is delayed. DESIGN Secondary analysis of an ongoing prospective observational study between 2006 and 2010. SETTING Three adult ICUs (medical ICU, surgical ICU, and neurologic ICU) at Grady Memorial Hospital, Atlanta, GA. PATIENTS Adult patients with severe sepsis in the ICU. INTERVENTIONS Baseline patient characteristics and clinical outcomes were collected. HIV-infected and HIV-uninfected patients with sepsis were compared using t tests, chi-square tests, and logistic regression; p values less than 0.05 indicated significance. MEASUREMENTS AND MAIN RESULTS Of 1,095 patients with severe sepsis enrolled, 165 (15%) were positive for HIV, with a median CD4 count of 41 (8-167). Twenty-two percent of HIV-infected patients were on highly active antiretroviral therapy prior to admission, and 80% had a CD4 count less than 200. HIV-infected patients had a greater hospital mortality (50% vs 38%; p < 0.01). HIV infection (odds ratio = 1.78; p = 0.005) was an independent predictor of mortality by multivariate regression modeling after adjusting for age, history of pneumonia, history of hospital-acquired infection, and history of sepsis. CONCLUSIONS HIV-infected patients with severe sepsis continue to suffer worse outcomes compared with HIV-uninfected patients in a large urban safety-net hospital caring for patients with limited access to medical care. Further studies need to be done to investigate the effect of socioeconomic status and mitigate healthcare disparities among critically ill HIV-infected patients.

Objectives Multiple training pathways are recognized by the Accreditation Council for Graduate Medical Education (ACGME) for internal medicine (IM) physicians to certify in critical care medicine (CCM) via the American Board of Internal Medicine. While each involves 1 year of clinical fellowship training in CCM, substantive differences in training requirements exist among the various pathways. The Critical Care Societies Collaborative convened a task force to review these CCM pathways and to provide recommendations for unified and coordinated training requirements for IM-based physicians.

Objective:Hospital-level variations in structure and process may affect clinical outcomes in ICUs. We sought to characterize the organizational structure, processes of care, use of protocols, and standardized outcomes in a large sample of U.S. ICUs.Design:We surveyed 69 ICUs about organization, size

Sepsis generates significant global acute illness burden. The international variations in sepsis epidemiology (illness burden) have implications for region specific health policy. We hypothesised that there have been changes over time in the sepsis definitional elements (infection and organ dysfunction), and these may have impacted on hospital mortality.Cohort study.We evaluated a high quality, nationally representative, clinical ICU database including data from 181 adult ICUs in England.Nine hundred sixty-seven thousand five hundred thirty-two consecutive adult ICU admissions from January 2000 to December 2012.None.To address the proposed hypothesis, we evaluated a high quality, nationally representative, clinical, ICU database of 967,532 consecutive admissions to 181 adult ICUs in England, from January 2000 to December 2012, to identify sepsis cases in a robust and reproducible way. Multinomial logistic regression was used to report unadjusted trends in sepsis definitional elements and in mortality risk categories based on organ dysfunction combinations. We generated logistic regression models and assessed statistical interactions with acute hospital mortality as outcome and cohort characteristics, sepsis definitional elements, and mortality risk categories as covariates. Finally, we calculated postestimation statistics to illustrate the magnitude of clinically meaningful improvements in sepsis outcomes over the study period. Over the study period, there were 248,864 sepsis admissions (25.7%). Sepsis mortality varied by infection sources (19.1% for genitourinary to 43.0% for respiratory; p0.001), by number of organ dysfunctions (18.5% for 1 to 69.9% for 5; p0.001), and organ dysfunction combinations (18.5% for risk category 1 to 58.0% for risk category 4). The rate of improvement in adjusted hospital mortality was significant (odds ratio, 0.939 [0.934-0.945] per year; p0.001), but showed different secular trends in improvement between infection sources.Within a sepsis cohort, we illustrate case-mix heterogeneity using definitional elements (infection source and organ dysfunction). In the context of improving outcomes, we illustrate differential secular trends in impact of these variables on adjusted mortality and propose this as a valid reason for international variations in sepsis epidemiology. Our article highlights the need to determine standardized reporting elements for optimal comparisons of international sepsis epidemiology.

To summarize the current literature on racial and gender disparities in critical care and the mechanisms underlying these disparities in the course of acute critical illness.MEDLINE search on the published literature addressing racial, ethnic, or gender disparities in acute critical illness, such as sepsis, acute lung injury, pneumonia, venous thromboembolism, and cardiac arrest.Clinical studies that evaluated general critically ill patient populations in the United States as well as specific critical care conditions were reviewed with a focus on studies evaluating factors and contributors to health disparities.Study findings are presented according to their association with the prevalence, clinical presentation, management, and outcomes in acute critical illness.This review presents potential contributors for racial and gender disparities related to genetic susceptibility, comorbidities, preventive health services, socioeconomic factors, cultural differences, and access to care. The data are organized along the course of acute critical illness.The literature to date shows that disparities in critical care are most likely multifactorial involving individual, community, and hospital-level factors at several points in the continuum of acute critical illness. The data presented identify potential targets as interventions to reduce disparities in critical care and future avenues for research.

OBJECTIVE Research supports the efficacy and safety of restrictive transfusion protocols to reduce avoidable RBC transfusions, but evidence of their effectiveness in practice is limited. This study assessed whether admission to an ICU with an restrictive transfusion protocol reduces the likelihood of transfusion for adult patients. DESIGN Observational study using data from the multicenter, cohort Critical Illness Outcomes Study. Patient-level analyses were conducted with RBC transfusion on day of enrollment as the outcome and admission to an ICU with a restrictive transfusion protocol as the exposure of interest. Covariates included demographics, hospital course (e.g., lowest hematocrit, blood loss), severity of illness (e.g., Sequential Organ Failure Assessment score), interventions (e.g., sedation/analgesia), and ICU characteristics (e.g., size). Multivariable logistic regression modeling assessed the independent effects of restrictive transfusion protocols on transfusions. SETTING Fifty-nine U.S. ICUs. PATIENTS A total of 6,027 adult ICU patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of the 59 study ICUs, 24 had an restrictive transfusion protocol; 2,510 patients (41.6%) were in an ICU with an restrictive transfusion protocol. The frequency of RBC transfusion among patients with severe (hematocrit, 30%) anemia in restrictive transfusion protocol ICUs was 67%, 19%, and 4%, respectively, compared with 60%, 14%, and 2% for those in ICUs without an restrictive transfusion protocol. Only 27% of transfusions were associated with a hematocrit less than 21%. Adjusting for confounding factors, restrictive transfusion protocols independently reduced the odds of transfusion in moderate anemia with an odds ratio of 0.59 (95% CI, 0.36-0.96) while demonstrating no effect in mild (p = 0.93) or severe (p = 0.52) anemia. CONCLUSIONS In this sample of ICU patients, transfusions often occurred outside evidence-based guidelines, but admission to an ICU with an restrictive transfusion protocol did reduce the risk of transfusion in moderately anemic patients controlling for patient and ICU factors. This study supports the effectiveness of restrictive transfusion protocols for influencing transfusions in clinical practice.

Improved means to monitor and guide interventions could be useful in the intensive care unit. Metabolomic analysis with bioinformatics is used to understand mechanisms and identify biomarkers of disease development and progression. This pilot study evaluated plasma proton nuclear magnetic resonance spectroscopy as a means to monitor metabolism following albumin administration in acute lung injury patients.This study was conducted on plasma samples from six albumin-treated and six saline-treated patients from a larger double-blind trial. The albumin group was administered 25 g of 25% human albumin in 0.9% saline every 8 hrs for a total of nine doses over 72 hrs. A 0.9% concentration of saline was used as a placebo. Blood samples were collected immediately before, 1 hr after, and 4 hrs after the albumin/saline administration for the first, fourth, and seventh doses (first dose of each day for 3 days). Samples were analyzed by proton nuclear magnetic resonance spectroscopy, and spectra were analyzed by principal component analysis and biostatistical methods.None.After 1 day of albumin therapy, changes in small molecules, including amino acids and plasma lipids, were evident with principal component analysis. Differences remained 3 days after the last albumin administration. Analysis of data along with spectra from healthy controls showed that spectra for patients receiving albumin had a trajectory toward the spectra observed for healthy individuals while those of the placebo controls did not.The data suggest that metabolic changes detected by proton nuclear magnetic resonance spectroscopy and the bioinformatics tool may be a useful approach to clinical research, especially in acute lung injury.

Sepsis, the tenth leading cause of death in the United States, is a significant public health problem. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), severe forms of hypoxemic respiratory failure and frequent complications of sepsis (1), often result in prolonged mechanical ventilatory support with a mortality of approximately 30 –50% (1). Despite years of research and recent advances in therapeutic strategies for these two diseases (2– 4), morbidity, mortality, and healthcare expenditures remain high (1, 5). Considerable research has identified several of the pathophysiological responses that occur when a host responds to a systemic infection. Proinflammatory cytokines such as tumor necrosis factor-α3 and interleukin-6 (IL-6) characterize sepsis (6, 7) and ALI/ARDS (8 –10), whereas coexisting anti-inflammatory pathways modulate the inflammatory response (11). An improved understanding of this pathophysiology has resulted in aggressive attempts to identify pathogenetically important biomarkers and new therapies. Both embryonic and adult tissue-derived stem cells have shown remarkable potential to repair and regenerate various organs, including the lungs (12–14). For the purposes of this review, we will only discuss adult tissue-derived stem cells. Additionally, stem cells are able to mitigate injury and inflammation through paracrine mechanisms (12, 15, 16), and detecting their presence may help prognosticate survival (17, 18). These findings suggest that stem cells may offer novel approaches for both prognosis and cell-based therapies in sepsis and ALI/ARDS.

Better understanding of the pathophysiology of critical illness has led to an increase in clinical trials designed to improve the clinical care and outcomes of patients with life-threatening illness. Knowledge of basic principles of clinical trial design and interpretation will assist the clinician in better applying the results of these studies into clinical practice.We review selected clinical trials to highlight important design features that will improve understanding of the results of critical care clinical trials designed to improve clinical care of the critically ill.Trial design features such as patient selection, bias, sample size calculation, selection of subjects and controls, and primary outcome measure may influence the results of a critical care clinical trial designed to test a therapy targeting improved clinical care. In conjunction with trial design knowledge, understanding the size of the anticipated treatment effect, the importance of any clinical end point achieved, and whether patients in the trial are representative of typical patients with the illness will assist the reader in determining whether the results should be applied to specific patients or usual clinical practice.Better understanding of important aspects of trial design and interpretation, such as whether patients enrolled in both intervention arms were comparable and whether the primary outcome of the trial is clinically important, will assist the bedside clinician in determining whether to apply the findings from the clinical study into clinical practice.

We sought to investigate seasonal and regional variability in the epidemiology of sepsis and to identify underlying associations based on geography and seasonal viral infections. Understanding seasonal or regional variations may improve knowledge of sepsis epidemiology and pathophysiology and could affect healthcare planning and resource allocation.Retrospective cohort study using the National Hospital Discharge Survey to identify cases of sepsis, severe sepsis, influenza, and viral pneumonia using ICD-9-CM codes. Incidence rates are reported as mean cases frequencies per season per 100,000 as calculated by normalization to the 2000 U.S. Census.Acute-care nonfederal U.S. hospitals.Patients hospitalized between 1979 and 2003 in acute-care nonfederal U.S. hospitals with a diagnosis of sepsis or viral respiratory infection.None.The seasonal incidence rate of sepsis increased 16.5% from a low of 41.7 in the fall to a high of 48.6 cases per 100,000 in the winter (p.05). Similarly, seasonal rates for severe sepsis statistically increased 17.7% from fall to winter at 13.0 and 15.3 cases per 100,000, respectively. The greatest change in sepsis incidence occurred with respiratory sources, increasing 40% during the winter compared with the fall (p.05). Seasonal variations in viral respiratory infections paralleled changes in sepsis incidence but did not fully account for the changes. The greatest seasonal change in sepsis rates occurred in the Northeast (+30%). Sepsis case-fatality rates were 13% greater in the winter compared with the summer (p.05) despite similar severity of illness.The incidence and mortality of sepsis and severe sepsis are seasonal and consistently highest during the winter, predominantly related to respiratory sepsis. Seasonal changes in sepsis incidence vary according to geographic region. The mechanisms underlying these differences require further investigation.

Hypoproteinemia, fluid retention, and weight gain are associated with development of acute lung injury and mortality in critically ill patients, without proof of cause and effect. We designed a clinical trial to determine whether diuresis and colloid replacement in hypoproteinemic patients with acute lung injury would improve pulmonary physiology.Prospective, randomized, double-blind, placebo-controlled trial.All adult intensive care units from two university hospitals.Thirty-seven mechanically-ventilated patients with acute lung injury and serum total protein/=5.0 g/dL.Five-day protocolized regimen of 25 g of human serum albumin every 8 hrs with continuous infusion furosemide, or dual placebo, targeted to diuresis, weight loss, and serum total protein.Measured outcomes included change in weight, serum total protein, fluid balance, hemodynamics, respiratory system compliance, and oxygenation. Baseline characteristics were similar between groups (treatment, n = 19; control, n = 18), with trauma being the major cause of acute lung injury. Diuresis and weight loss over 5 days (5.3 kg more in the treatment group, p =.04) was accompanied by improvements in the Pao2/Fio2 ratio in the treatment group within 24 hrs (from 171 to 236, p =.02). Respiratory mechanics were unchanged. Mean arterial pressure increased from 80 to 88 mm Hg (p =.10), and heart rate decreased from 110 to 95 beats/min (p =.008) over time in the treatment group. No difference in mortality was observed, with favorable trends in measures of intensive care.Albumin and furosemide therapy improves fluid balance, oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. Determining the effect of this simple therapy on cost, outcomes, and other patient populations requires further study.

Objective: To describe the impact of novel pH1N1 virus in Atlanta, GA, for inpatient and intensive care services, including lung lavage data and determinants of disease outcome, from the earliest group of infected US population after initial cases. Design: An observational review of all patients with laboratory-confirmed pH1N1 disease hospitalized in four Atlanta hospitals from August 1 through October 31, 2009. Data reviewed included demographics, anthropometrics, clinical laboratory, and respiratory physiology. Setting: Four hospitals in urban Atlanta, Georgia. Patients: Consecutively admitted patients between August 1 and October 31, 2009 with laboratory confirmed pH1N1 infection. Interventions: None. Measurements and Main Results: A total of 109 patients were admitted during the surveillance period and intensive care unit care was required in 23 patients (21%) among which there were six deaths (26%). Only eight of the 109 (7%) patients were without medical comorbidity; 34% of the 65 female patients were pregnant and none died or required intensive care unit care. Patients with respiratory failure undergoing bronchoalveolar lavage exhibited neutrophilic predominance (average 64%) and negative bacterial cultures. Body mass index was >30 kg/m2 in 35 of 81 (43%) of patients with anthropometric data and 16 of 23 (70%) patients requiring intensive care unit care (p = .03). The 16 patients who required mechanical ventilation (70% of intensive care unit patients) were characterized by severe hypoxemia (requiring high levels of inspired oxygen and positive end-expiratory pressures), reduced lung compliance, and high lung injury scores. Conclusions: This first report of the second wave of US pH1N1 disease from Atlanta, GA, shares epidemiologic characteristics of earlier cohorts but differs by having an even greater prevalence of obesity and fewer patients who were free from chronic medical conditions. Importantly, lung lavage fluid in severe pH1N1 disease is predominantly neutrophilic and culture-negative. Further reports are needed to validate these new findings regarding pH1N1 disease in the United States.

To characterize variation in the institutional review board application process of a multicenter, observational critical care study.Survey analysis of 36 investigators who applied for participation in the United States Critical Illness and Injury Trials Group: Critical Illness and Outcomes Study, an observational study of 69 adult ICUs.None.Analysis of investigator-specific characteristics, institutional review board process, application and approval dates, and level of difficulty in obtaining approval. Surveys were analyzed from 36 sites (95%) that applied for institutional review board approval. Level of review ranged from full board, expedited, to exempt. Seventy-five percent of applications were submitted by an experienced investigator while 25% were submitted by a less experienced investigator. Median time to institutional review board approval was 30 days (interquartile range, 14-54) and ranged from 5 days to 5.5 months. Time to approval was 29 days (interquartile range, 17-48) for applications submitted by an experienced investigator compared with 97 days (interquartile range, 25-159) for those submitted by a less experienced investigator (p = 0.08). Subjective level of difficulty was significantly higher for less experienced investigators (4 of 10; interquartile range, 2-8) vs experienced investigators (2 of 10; interquartile range, 1-3) (p = 0.04). Four sites cited institutional review board concern regarding waiver of consent as a major barrier to approval and were required to perform revisions or participate in board meetings regarding this concern.In a multicenter, observational critical care study, significant variation was observed between sites in all aspects of the institutional review board evaluation and approval process. The level of difficulty was significantly higher for less experienced investigators with a trend toward longer time to institutional review board approval. Variation in institutional review board interpretation of waiver of informed consent regulations was cited as a major barrier to approval.

ObjectiveStarling’s equation indicates that reduced oncotic pressure gradients will favor edema formation, and the current consensus definition of acute respiratory distress syndrome (ARDS) excludes only the hydrostatic pressure contribution. We hypothesized that low serum total protein levels might

Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients.Individual patient data analysis.ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation.Mechanical ventilation with low tidal volume.The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (7 and10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p0.01) and an increased hospital mortality (49.5% vs 35.6%; p0.01).Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.

Sepsis is among the most common conditions encountered in adult critical care, occurring in approximately 2% of all hospitalizations and in some hospitals occurring in more than 50% of all ICU admissions.1,2 The past three decades have seen tremendous advances in understanding the pathophysiology of sepsis. However, some core elements of sepsis pathophysiology that remain unchanged include the general processes of oxidative stress, inflammation, endothelial dysfunction, among other factors that advance along a common pathway towards multiple organ dysfunction.3 These contributors are most apparent in critically ill patients with severe sepsis and septic shock, where multiple organ dysfunction is the major cause of death.4,5 The underlying instigators of reactive oxygen species and endothelial injury are myriad and unlikely to be from a single cause in all patients. Hemolysis occurs in many diseases, producing cell-free hemoglobin (CFH) as a result. Increased quantities of circulating CFH have been reported in a variety of diseases, including sickle cell disease, blood transfusion, malaria and sepsis, among other conditions. Two of the predominant effects of CFH are depletion of nitric oxide (NO) and generation of reactive oxygen species (ROS).6 A primary effector for NO is reduced oxyhemoglobin that rapidly reacts with it to form methemoglobin and nitrate. This reaction accounts for the vasoconstrictor response known to occur with CFH and hemoglobin-based oxygen carriers (i.e. one class of artificial blood substitutes). In addition, oxidation reactions are catalyzed by hemoglobin, heme, and iron to generate ROS, subsequently leading to lipid peroxidation and cellular injury.7 While free heme can amplify some innate immune responses in sepsis, free iron can amplify a deleterious inflammatory response. Fortunately, there is an efficient biological system to scavenge hemoglobin and heme, using haptoglobin, CD163 and hemopexin, which effectively sequesters these redox-active molecules to prevent them from interacting with NO or generating ROS. However, in conditions such as sepsis the normal biological mechanisms are insufficient to prevent CFH from inciting at least a local if not a systemic inflammatory reaction. It has been well established that patients with severe sepsis often have circulating CFH. Furthermore, acetaminophen has been shown to reduce the iron protoporphyrin radical in CFH and inhibit lipid peroxidation.8 In this study 9, a group of clinical and translational scientists studied oral acetaminophen in patients with severe sepsis. They sought to replicate some of the beneficial effects of acetaminophen demonstrated in animal models (reducing oxidative stress and renal injury) and observational human studies (reduced markers of oxidative stress). In this randomized study of patients with severe sepsis and circulating CFH, 40 subjects completed the treatment protocol. Those who received acetaminophen had reduced levels of F2-isoprostanes on day 2, lower serum creatinine on day 3 (even after adjusting for imbalances in baseline creatinine) and lower maximum body temperature on day 3. However, there were no significant differences in day 3 F2-isoprostane levels, heart rate, blood pressure or measures of organ failure. Overall, there were no significant safety concerns with study drug administration in terms of hospital mortality and adverse effects. The authors well described the limitations of this study: its small size, single center nature, surrogate endpoints, limited safety assessments and baseline imbalances between groups. These are real and valid concerns, and they restrict our ability to draw conclusions from the study. This is compounded by the few positive results that withstood statistical scrutiny, which ultimately becomes even fewer when the multiple comparisons are taken into consideration. However, this study stands as a significant achievement in testing a new therapeutic for a condition where no effective pharmacological therapy exists. Furthermore, the correlation of CFH and creatinine support an underlying mechanism thought to cause kidney injury and produced a similar response to acetaminophen in preclinical models. This study sets the stage for further clinical trials in patients with severe sepsis. Larger trials are needed to better characterize the molecular and biochemical responses from acetaminophen therapy in these patients, and to further characterize the tissue responses and additional outcomes that predict clinical benefits. Subsequent studies would also need to consider the optimal dose for a given response, better define the patients most likely to respond, and consider sepsis subgroups that have not been studied as well (e.g. surgical patients). These subsequent trials will allow us to gain more confidence with potential adverse effects, particularly those that are less common and would not have been expected to occur in a small population. Where do we go from here? This distinguished group deserves credit for considering the existing armamentarium of treatment possibilities rather than narrowly considering only the newly discovered pathways and novel targeted therapies that have become popular. It reminds us that much of the gains we have made in the past years improving the care of critically ill patients is from optimizing the utilization of existing therapies and redoubling our efforts to ensure timely, high quality care. This study proves once more, what's old is new again.