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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.

The role of early, serial measurements of protein biomarkers in sepsis-induced acute respiratory distress syndrome (ARDS) is not clear.To determine the differences in soluble receptor for advanced glycation end-products (sRAGEs), angiopoietin-2, and surfactant protein-D (SP-D) levels and their changes over time between sepsis patients with and without ARDS.Prospective observational cohort study of adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis.Plasma sRAGE, angiopoietin-2, and SP-D levels were measured for 3 consecutive days after enrollment. The primary outcome was ARDS development, and the secondary outcome of 28-day mortality. The biomarker levels and their changes over time were compared between ARDS and non-ARDS patients and between nonsurvivors and survivors.We enrolled 111 patients, and 21 patients (18.9%) developed ARDS. The three biomarker levels were not significantly different between ARDS and non-ARDS patients on all 3 days of measurement. Nonsurvivors had higher levels of all three biomarkers than did survivors on multiple days. The changes of the biomarker levels over time were not different between the outcome groups. Logistic regression analyses showed association between day 1 SP-D level and mortality (odds ratio, 1.52; 95% CI, 1.03-2.24;Among critically ill patients with sepsis, sRAGE, angiopoietin-2, and SP-D levels were not significantly different between ARDS and non-ARDS patients but were higher in nonsurvivors compared with survivors. The trend toward higher levels of sRAGE and SP-D, but not of angiopoietin-2, in ARDS patients may indicate the importance of epithelial injury in sepsis-induced ARDS. Changes of the biomarker levels over time were not different between the outcome groups.

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 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.

OBJECTIVES:. Patients with infection can develop sepsis, and their mortality can be high. An important aspect in the treatment of sepsis is adequate management of the infection. DATA SOURCES:. Using a modified Delphi approach, the Surviving Sepsis Campaign research committee recently published a series of 26 priorities for sepsis and septic shock. STUDY SELECTION:. Task force members with specific expertise were tasked with generating expanded reviews for all infection questions and a subset of adjunctive therapy questions from the larger list of sepsis priorities. Each question was addressed by one of the six task force members. DATA EXTRACTION:. In-depth reviews were then edited by the group as a whole, with added input from the committee cochairs. DATA SYNTHESIS:. Six questions were addressed: 1) should empiric antibiotic combination therapy be used in sepsis or septic shock? 2) does optimization of antimicrobial pharmacokinetics and pharmacodynamics impact patient outcomes in sepsis? 3) should viral reactivation resulting from sepsis-induced immunosuppression be treated with antiviral therapy in critically ill septic patients? 4) should rapid diagnostic tests be implemented in clinical practice? 5) what is the role of lung-protective ventilation in sepsis patients without acute respiratory distress syndrome? and 6) how do we determine the efficacy of “blood purification” therapies such as endotoxin absorbers, cytokine absorbers, and plasmapheresis. CONCLUSIONS:. The research committee members for the Surviving Sepsis Campaign aimed to explore research questions in order to provide existing evidence and highlight areas of uncertainty and future directions.

Rationale: We investigated aging of human endogenous reparative capacity and aimed to clarify whether it is affected by presence of cardiovascular disease or its risk factors (RFs). Objective: Circulating progenitor cell (PC) levels reflect endogenous regenerative potential. The effect on PC of healthy aging compared with aging with RFs or cardiovascular disease (CVD) is unknown. We examined whether exposure to RF and CVD leads to an accelerated decline in circulating PC with increasing age. Methods and Results: In 2792 adult subjects, 498 were free of RFs (smoking, diabetes mellitus, hypertension, or hyperlipidemia), 1036 subjects had 1 to 2 RF, and 1253 had ≥3 RFs or CVD. PC were enumerated by flow cytometry as CD45 med+ mononuclear cells expressing CD34 and subsets coexpressing CD133, CXCR4, and vascular endothelial growth factor receptor-2 epitopes. Younger age, male sex, and larger body size correlated with higher PC counts ( P P P ≤0.005), such that for younger subjects (60 years), RFs and CVD were associated with lower PC counts. Conclusions: Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization, whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.

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.

Background— Food deserts (FD), neighborhoods defined as low-income areas with low access to healthy food, are a public health concern. We evaluated the impact of living in FD on cardiovascular risk factors and subclinical cardiovascular disease (CVD) with the hypothesis that people living in FD will have an unfavorable CVD risk profile. We further assessed whether the impact of FD on these measures is driven by area income, individual household income, or area access to healthy food. Methods and Results— We studied 1421 subjects residing in the Atlanta metropolitan area who participated in the META-Health study (Morehouse and Emory Team up to Eliminate Health Disparities; n=712) and the Predictive Health study (n=709). Participants’ zip codes were entered into the United States Food Access Research Atlas for FD status. Demographic data, metabolic profiles, hs-CRP (high-sensitivity C-reactive protein) levels, oxidative stress markers (glutathione and cystine), and arterial stiffness were evaluated. Mean age was 49.4 years, 38.5% male and 36.6% black. Compared with those not living in FD, subjects living in FD (n=187, 13.2%) had a higher prevalence of hypertension and smoking, higher body mass index, fasting glucose, and 10-year risk for CVD. They also had higher hs-CRP ( P =0.014), higher central augmentation index ( P =0.015), and lower glutathione level ( P =0.003), indicative of increased oxidative stress. Area income and individual income, rather than food access, were associated with CVD risk measures. In a multivariate analysis that included food access, area income and individual income, both low-income area and low individual household income, were independent predictors of a higher 10-year risk for CVD. Only low individual income was an independent predictor of higher hs-CRP and augmentation index. Conclusions— Although living in FD is associated with a higher burden of cardiovascular risk factors and preclinical indices of CVD, these associations are mainly driven by area income and individual income rather than access to healthy food.

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

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.

Background Lifestyle modifications are first‐line measures for cardiovascular disease prevention. Whether lifestyle intervention also preserves cardiovascular health is less clear. Our study examined the role of a Health Partner–administered lifestyle intervention on metrics of ideal cardiovascular health. Methods and Results A total of 711 university employees (48±11 years; 66% women, 72% Caucasian/22.5% African Americans) enrolled in a program that promoted healthier lifestyles at Emory University (Atlanta, GA). Anthropometric, laboratory, and physical activity measurements were performed at baseline and at 6 months, 1 year, and 2 years of follow‐up. Results were utilized by the Health Partner to generate a personalized plan aimed at meeting ideal health metrics. Compared to baseline, at each of the 6‐month, 1‐year, and 2‐year follow‐up visits, systolic blood pressure was lower by 3.6, 4.6, and 3.3 mm Hg ( P P 2 ( P P Conclusions A personalized, goal‐directed Health Partner intervention significantly improved the cardiometabolic risk profile and metrics of cardiovascular health. These effects were evident at 6 months following enrollment and were sustained for 2 years. Whether the Health Partner intervention improves long‐term morbidity and mortality and is cost‐effective needs further investigation.

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.

This review provides an overview of sepsis as a prototypical critical illness and discusses the role of the endothelium in the pathophysiology of sepsis and sepsis-related organ dysfunction, the characterization and functions of endothelial progenitor cells, and investigates these cells both as a prognostic and therapeutic strategy in critically ill patients.Sepsis continues to be a major cause of morbidity and mortality worldwide. Preclinical and clinical sepsis studies have shown that the acute systemic inflammatory and procoagulant response results in structural and functional alterations in the endothelium, which may lead to organ failure and ultimately, death. In the last decade, the concept of postnatal vasculogenesis has been revolutionized to include angiogenesis by mature endothelial cells and vasculogenesis by endothelial progenitor cells. These cells are recruited from the bone marrow to areas of endothelial injury, at which point they differentiate and promote revascularization of the endothelium, which has been shown to have significant prognostic and therapeutic implications in a variety of ischemic vascular disorders.Circulating endothelial progenitor cells may be an important mechanism of vascular repair, and thus shows significant promise for prognostic and therapeutic strategies in critical illness, namely sepsis and sepsis-related organ dysfunction.

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.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) affect hundreds of thousands of people each year worldwide, resulting in a significant healthcare burden. Over the past four decades, much has been discovered regarding the pathophysiology of lung injury, yet little progress has been made in advancing effective treatment strategies. In this article, we discuss the current knowledge as to fluid balance in the pathophysiology of ALI/ARDS and the recent innovations that have been described related to manipulations of hydrostatic or oncotic pressure in this condition.Hypoproteinemia is a clear marker for ALI/ARDS and may play a pathophysiologic role given its independent prognostic value. Fluid balance and oncotic pressure alterations induced by diuretic and colloid therapy improve respiratory physiology and likely alter net flux of fluid across the injured capillary-alveolar membrane. Chest radiographs serve as a useful adjunctive tool in monitoring longitudinal fluid balance manipulations in ALI/ARDS.Manipulation of Starling forces in established ALI/ARDS produces significant physiologic benefit and may influence outcome. Future research should focus on determining a mortality benefit with this readily available intervention.

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.

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.