Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Oxygen-Free Days as an Outcome Measure in Clinical Trials of Therapies for COVID-19 and Other Causes of New-Onset Hypoxemia.

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

A non-invasive, automated diagnosis of Menière's disease using radiomics and machine learning on conventional magnetic resonance imaging: A multicentric, case-controlled feasibility study.

PURPOSE: This study investigated the feasibility of a new image analysis technique (radiomics) on conventional MRI for the computer-aided diagnosis of Menière's disease. MATERIALS AND METHODS: A retrospective, multicentric diagnostic case-control study was performed. This study included 120 patients with unilateral or bilateral Menière's disease and 140 controls from four centers in the Netherlands and Belgium. Multiple radiomic features were extracted from conventional MRI scans and used to train a machine learning-based, multi-layer perceptron classification model to distinguish patients with Menière's disease from controls. The primary outcomes were accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the classification model. RESULTS: The classification accuracy of the machine learning model on the test set was 82%, with a sensitivity of 83%, and a specificity of 82%. The positive and negative predictive values were 71%, and 90%, respectively. CONCLUSION: The multi-layer perceptron classification model yielded a precise, high-diagnostic performance in identifying patients with Menière's disease based on radiomic features extracted from conventional T2-weighted MRI scans. In the future, radiomics might serve as a fast and noninvasive decision support system, next to clinical evaluation in the diagnosis of Menière's disease.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Supply Chain Delays in Antimicrobial Administration After the Initial Clinician Order and Mortality in Patients With Sepsis.

OBJECTIVES: There is mounting evidence that delays in appropriate antimicrobial administration are responsible for preventable deaths in patients with sepsis. Herein, we examine the association between potentially modifiable antimicrobial administration delays, measured by the time from the first order to the first administration (antimicrobial lead time), and death among people who present with new onset of sepsis. DESIGN: Observational cohort and case-control study. SETTING: The emergency department of an academic, tertiary referral center during a 3.5-year period. PATIENTS: Adult patients with new onset of sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 4,429 consecutive patients who presented to the emergency department with a new diagnosis of sepsis. We defined 0-1 hour as the gold standard antimicrobial lead time for comparison. Fifty percent of patients had an antimicrobial lead time of more than 1.3 hours. For an antimicrobial lead time of 1-2 hours, the adjusted odds ratio of death at 28 days was 1.28 (95% CI, 1.07-1.54; p = 0.007); for an antimicrobial lead time of 2-3 hours was 1.07 (95% CI, 0.85-1.36; p = 0.6); for an antimicrobial lead time of 3-6 hours was 1.57 (95% CI, 1.26-1.95; p < 0.001); for an antimicrobial lead time of 6-12 hours was 1.36 (95% CI, 0.99-1.86; p = 0.06); and for an antimicrobial lead time of more than 12 hours was 1.85 (95% CI, 1.29-2.65; p = 0.001). CONCLUSIONS: Delays in the first antimicrobial execution, after the initial clinician assessment and first antimicrobial order, are frequent and detrimental. Biases inherent to the retrospective nature of the study apply. Known biologic mechanisms support these findings, which also demonstrate a dose-response effect. In contrast to the elusive nature of sepsis onset and sepsis onset recognition, antimicrobial lead time is an objective, measurable, and modifiable process.

Web-Based Multidomain Lifestyle Programs for Brain Health: Comprehensive Overview and Meta-Analysis.

BACKGROUND: The number of people living with dementia is increasing worldwide, mainly because of aging of the population. To date, there is no pharmaceutical intervention to delay or treat cognitive decline or dementia. As an estimated one-third of dementia cases might be attributable to modifiable lifestyle factors (such as cognitive and physical activity), multidomain lifestyle interventions are a promising way to maintain or improve brain health. Offering programs online would enable large-scale implementation. An overview of multidomain Web-based lifestyle programs for brain health would facilitate comparison and improvement of such programs to develop effective and sustainable interventions. OBJECTIVE: This study aimed to (1) provide a comprehensive overview of Web-based multidomain lifestyle programs aimed at optimizing brain health in healthy adult populations and (2) describe the programs and targeted lifestyle factors, availability, and evaluation of adherence and user experience. In addition, a meta-analysis was performed to evaluate the effectiveness of these programs. METHODS: Electronic databases (PubMed, EMBASE, and PsycINFO) were searched for Web-based lifestyle programs that were included when the program (1) aimed to optimize brain health, (2) focused on multiple lifestyle factors, (3) was completely Web-based (website, Web application or mobile app), (4) consisted of multiple sessions, and (5) focused on a healthy adult population. Program characteristics (target population, duration, frequency, tailoring, platform, and availability) and results of program evaluations (effectiveness, user evaluations, and adherence) were extracted and compared. Studies using a controlled design were included in a random-effects meta-analysis on the effectiveness on brain health outcomes. Study quality was assessed using the physiotherapy evidence database (PEDro) scale. RESULTS: The electronic searches yielded 44 documents describing 14 Web-based lifestyle programs; physical and cognitive activities were targeted in all programs. Four programs (4/14, 29%) were publicly available and free of charge, whereas others were restricted to research settings (5/14, 36%), available after payment (1/14, 7%), or not available at all (2/14, 14%). User evaluations were reported for 8 (57%) of the 14 programs. Reported dropout of the intervention groups ranged from 2% to 52%. Overall, 3 studies evaluated the effectiveness of a program using a controlled design and were included in the meta-analysis (moderate-to-high quality). Pooled results showed a significant small-to-medium effect of the Web-based multidomain lifestyle interventions on outcome measures for brain health (global cognition score, subjective cognitive score, and lifestyle risk score; standard mean difference=0.45; 95% CI 0.12-0.78), with a high degree heterogeneity across studies (I2=75%; P=.02). CONCLUSIONS: In total, 14 Web-based multidomain lifestyle programs aimed at optimizing brain health were found. The programs showed heterogeneity in both characteristics and effectiveness evaluation. Despite this heterogeneity, this meta-analysis suggests that Web-based lifestyle programs can positively influence brain health outcomes and have the potential to contribute to the prevention of dementia.

Alcohol Use As a Risk Factor in Infections and Healing: A Clinician's Perspective.

Physicians have recognized for more than a century that alcohol use is associated with infections and that alcoholics are especially at risk for pneumonia. Clear evidence now indicates that alcohol has a systemic effect on every organ. This review first presents a clinical case to describe a patient with immunity issues complicated by alcohol use-a setting familiar to many clinicians. This is followed by a description of the molecular mechanisms that explain the secondary immune deficiency produced by alcohol in the host, focusing mostly on the gut and lower respiratory mucosal immunity. The goal of this review is to increase awareness of the new mechanisms being investigated to understand how alcohol affects the human immune system and the development of new strategies to attenuate adverse outcomes in the affected population.

Transforming growth factor-ß1 rise in pleural fluid after tunneled pleural catheter placement: pilot study.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) plays a major role in pleural fibrosis and chemical pleurodesis. Approximately 50% of patients with tunneled pleural catheters (TPCs) for malignant pleural effusions (MPEs) will have autopleurodesis. Pleural TGF-ß1 levels have never been measured in the setting of TPC drainage and may predict autopleurodesis. METHODS: Pleural fluid was collected prospectively in subjects with MPE and planned TPC insertion. Pleural fluid was collected at time 0 (T0, thoracentecis before TPC placement), time 1 (T1, TPC insertion), and time 2 (T2, 2 wk after TPC insertion). The MPE levels of TGF-ß1, vascular endothelial growth factor, and plasminogen activator inhibitor-1 were measured using ELISA. Lactate dehydrogenase levels were also measured at T0. Patients were followed up for autopleurodesis and TPC removal. RESULTS: Nineteen samples were collected from 9 patients with MPE who underwent TPC placement. Three patients died before the study completion. The median level of TGF-ß1 of 1243 pg/mL (range, 620 to 4547 pg/mL) at T1 in 6 patients showed a statistically significant rise to 2857 pg/mL (range, 2120 to 7160 pg/mL) after TPC placement (P=0.004, R=0.898). There was no statistically significant increase in TGF-ß1 levels from T0 to T1. There was a linear relationship between TGF-ß1 and lactate dehydrogenase at T0 (R=0.635). Plasminogen activator inhibitor-1 levels increased from T1 to T2, but was not statistically significant. There was no significant rise in vascular endothelial growth factor from T1 to T2. CONCLUSIONS: TPC insertion results in an independent increase in TGF-ß1 levels in MPE.

Alcohol use disorders and hospital-acquired infections in women undergoing cesarean delivery.

OBJECTIVE: To determine the risk of hospital-acquired infection in women with alcohol use disorders undergoing cesarean delivery. METHODS: Using the Nationwide Inpatient Sample, we conducted a retrospective cohort study of women undergoing cesarean delivery from 2002 to 2010. Women with a diagnosis of alcohol use disorder were compared with women without alcohol use disorders. Hospital-acquired infections include surgical site infection, endometritis, urinary tract infection, sepsis, and pneumonia. RESULTS: A total of 12,081 women with alcohol use disorders were identified and matched with 11,960 women without alcohol use disorders. Women with alcohol use disorders were more likely to have development of urinary tract infection and sepsis. By multivariable analyses, women with alcohol use disorders had higher odds of hospital-acquired infections (odds ratio 2.2, 95% confidence interval [CI] 1.9-2.7; P=2×10; 397 among those with alcohol use disorders and 179 among those without alcohol use disorders; number needed to harm 55). Length of stay was longer in women with alcohol use disorders, but this was unexplained by hospital-acquired infection (3.3 days; 95% CI 3.2-3.3 compared with 3.1 days; 95% CI 3.0-3.1; P=4×10). CONCLUSION: Women with alcohol use disorders undergoing cesarean delivery have increased risk of hospital-acquired infections. Interventions aimed at decreasing alcohol use disorders during pregnancy may reduce maternal and fetal complications. LEVEL OF EVIDENCE: II.

Health care-associated infections in surgical patients undergoing elective surgery: are alcohol use disorders a risk factor?

BACKGROUND: Health care-associated infections (HAI) result in 100,000 deaths/year. Alcohol use disorders (AUD) increase the risk of community-acquired infections and HAI. Small studies have shown that AUD increase the risk of HAI and surgical site infections (SSI). We sought to determine the risk of HAI and SSI in surgical patients undergoing elective inpatient joint replacement, coronary artery bypass grafting, laparoscopic cholecystectomy, colectomy, and hernia repair. STUDY DESIGN: The Nationwide Inpatient Sample was analyzed (years 2007 and 2008). HAI were defined as health care-associated pneumonia, sepsis, SSI, and urinary tract infection. Primary outcomes were risk of HAI and SSI in patients with AUD. Secondary outcomes were mortality and hospital length of stay in patients with HAI and SSI, alpha = 10(-6). RESULTS: There were 1,275,034 inpatient admissions analyzed; 38,335 (3.0%) cases of HAI were documented, and 5,756 (0.5%) cases of SSI were identified. AUD was diagnosed in 11,640 (0.9%) of cases. Multivariable analysis demonstrated that AUD was an independent predictor of developing HAI: odds ratio (OR) 1.70, p < 10(-6), and this risk was independent of type of surgery. By multivariable analysis, the risk of SSI in patients with AUD was also higher: OR 2.73, p < 10(-6). Hospital mortality in patients with HAI or SSI was not affected by AUD. However, hospital length of stay was longer in patients with HAI who had AUD (multivariable analysis 2.4 days longer, p < 10(-6)). Among patients with SSI, those with AUD did not have longer hospital length of stay. CONCLUSIONS: Patients with AUD who undergo a variety of elective operations have an increased risk of infectious postoperative morbidity.

Accuracy of previous estimates for adult prolonged acute mechanical ventilation volume in 2020: update using 2000-2008 data.

OBJECTIVES: Patients requiring prolonged acute mechanical ventilation (mechanical ventilation ≥ 96 hrs) have hospital survival rates similar to those requiring <96 hrs of mechanical ventilation and consume approximately two-thirds of hospital resources devoted to mechanical ventilation care. Using 2000-2005 data, we previously estimated that their volume will go from approximately 250,000 cases in 2000 to 605,898 by year 2020. With 2006-2008 data becoming available, we explored the precision of our previous formulas and estimates. DESIGN: We utilized National Inpatient Sample/Health Care Utilization Project of the Agency for Healthcare Research and Quality data from 2000 to 2008 to calculate historic annual age-adjusted prolonged acute mechanical ventilation incidence rates using estimated population statistics from the U.S. Census Bureau. To predict future growth by age group, we fit linear regression models to the historic incidence rate changes. Age-adjusted estimates were computed using population projections obtained from the U.S. Census Bureau. SETTING: U.S. hospitals. PATIENTS: Nationally representative sample of U.S. hospital discharges with prolonged acute mechanical ventilation (International Classification of Diseases version 9 code 96.72). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Formulas based on the 2000-2005 data predicted the 2008 prolonged acute mechanical ventilation volume within a 1.9% margin. The historic annualized increase in adult prolonged acute mechanical ventilation increased from 5.0% to 5.2% after incorporating the 2006-2008 data. Factoring in the 2006-2008 data altered our 2020 prolonged acute mechanical ventilation estimates from 605,898 (95% confidence interval 456,695-779,806) to 625,298 (95% confidence interval 552,168-698,838), an upward revision of 3.2%. CONCLUSION: Our original projections for growth of the adult prolonged acute mechanical ventilation population in the U.S. hospitals by the year 2020 are altered only slightly by adding the 2006-2008 data. Relatively precise prediction of the 2008 prolonged acute mechanical ventilation numbers by the original formulas lends internal validity to the methodology. By virtue of being a large, resource-intensive, and rapidly increasing population, this group of mechanical ventilation patients requires continued close monitoring over time to optimize our preparedness to meet their growing healthcare needs.

Outcomes of patients with alcohol use disorders experiencing healthcare-associated infections.

BACKGROUND: Healthcare-associated infections (HAI) affect 1.7 million patients annually in the United States, and patients with alcohol use disorders (AUD) are at increased risk of developing HAI. HAI have been shown to substantially increase the hospital length of stay, mortality, and cost. In a cohort of patients with HAI, we sought to determine mortality, cost, and hospital length of stay attributable to AUD. METHODS: Using the Nationwide Inpatient Sample for the year 2007, the largest all-payer database of hospitalized patients comprising approximately 1,000 hospitals, we performed a retrospective cohort study of all patients who developed healthcare-associated pneumonia or sepsis. We excluded patients who were transferred from another healthcare facility, who were diagnosed with community-acquired infections, immunosuppression, or cancer. Logistic regression was computed to calculate attributable mortality. Linear regression analyses were computed to determine cost and hospital length of stay α = 10(-10) . RESULTS: A total of 149,892 patients developed HAI, and 8,830 (5.9%) had a co-diagnosis of AUD. Patients with AUD were younger, more likely to be men, less likely to be Asian, and more likely to be Hispanic. Patients with AUD were more likely to have tobacco dependence, less likely to be electively admitted to the hospital, and less likely to undergo surgery. They also had lower severity of illness, lower income, and were more likely to be in academic medical centers. Logistic regression revealed that AUD was an independent predictor of increased mortality: Odds ratio = 1.71, 95% confidence interval (CI) [1.626; 1.799], p < 10(-10) . Linear regression demonstrated that AUD independently predicted increased hospital length of stay by 2 days: Patients with AUD had a length of stay of 13 days, 95% CI [12.4; 13.6] compared with 11 days, 95% CI [11.1; 11.4] for patients without AUD, p < 10(-10) . Linear regression also revealed that patients with AUD had a higher hospital cost: $34,826, 95% CI [32,415.71; 37,416.52] for patients with AUD compared with $27,167, 95% CI [25,703.18; 28,714.05] for patients without AUD, p < 10(-10) . CONCLUSIONS: Patients with AUD who experience HAI have worse outcomes compared with patients without AUD. Patients with AUD have higher mortality, longer hospital length of stay, and higher costs. Studies aimed at decreasing the morbidity and mortality of HAI in patients with AUD are warranted.

Monitoring of patient-ventilator interaction at the bedside.

Monitoring of patient-ventilator interactions at the bedside involves evaluation of patient breathing pattern on ventilator settings. One goal of mechanical ventilation is to have ventilator-assisted breathing coincide with patient breathing. The objectives of this goal are to have patient breath initiation result in ventilator triggering without undue patient effort, to match assisted-breath delivery with patient inspiratory effort, and to have assisted breathing cease when the patient terminates inspiration, thus avoiding ventilator-assisted inspiration during patient exhalation. Asynchrony can occur throughout the respiratory cycle, and this paper describes common asynchronies. The types of asynchronies discussed are trigger asynchrony (ie, breath initiation that may manifest as ineffective triggering, double-triggering, or auto-triggering); flow asynchrony (ie, breath-delivery asynchrony, which may manifest as assisted-breath delivery being faster or slower than what patient desires); and cycling asynchronies (ie, termination of assisted inspiration does not coincide with patient breath termination, which may manifest as delayed cycling or premature cycling). Various waveforms are displayed and graphically demonstrate asynchronies; basic principles of waveform interpretation are discussed.

Relationship between alcohol use disorders, cortisol concentrations, and cytokine levels in patients with sepsis.

INTRODUCTION: Patients with alcohol use disorders (AUD) are at increased risk of developing sepsis and have higher mortality. AUD are associated with higher cortisol and anti-inflammatory cytokine profile. Higher cortisol increases risk of death in septic patients. The relationship between AUD and cortisol in septic patients is unknown. We aimed to study this relationship and postulated that AUD would be associated with higher cortisol and anti-inflammatory cytokine profile. METHODS: This was a prospective cohort study of 40 medical intensive care unit (ICU) patients admitted with sepsis. Cortisol, anti-inflammatory interleukin (IL) 10, and pro-inflammatory IL1ß, IL6, tumor necrosis factor (TNF) α were measured. RESULTS: Thirteen (32%) out of 40 patients had AUD. AUD patients had higher cortisol by univariate (39 microg/dl versus 24, P = 0.04) and multivariable analyses (44 microg/dl versus 23, P = 0.004). By univariate analyses, AUD patients had higher IL10 (198 picog/dl versus 47, P = 0.02) and IL6 (527 picog/ml versus 156, P = 0.048), but similar IL1ß and TNFα. By multivariable analyses, AUD patients had higher IL10 (182 picog/dl versus 23, P = 0.049) but similar IL1ß, IL6, and TNFα. AUD patients had lower IL1ß/IL10 (univariate 0.01 versus 0.10, P = 0.04; multivariable 0.01 versus 0.03, P = 0.04), lower TNFα/IL10 (univariate 0.15 versus 0.52, P = 0.03; multivariable 0.11 versus 0.63, P = 0.01), but similar IL6/IL10. CONCLUSIONS: AUD are common diagnoses among medical ICU patients with sepsis. Patients with AUD have higher cortisol concentrations and have differences in cytokine expression. Future studies should seek to determine if these differences may explain the higher severity of illness seen in patients with sepsis and AUD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00615862.

Alcohol-use disorders in the critically ill patient.

Alcohol abuse and dependence, referred to as alcohol-use disorders (AUDs), affect 76.3 million people worldwide and account for 1.8 million deaths per year. AUDs affect 18.3 million Americans (7.3% of the population), and up to 40% of hospitalized patients have AUDs. This review discusses the development and progression of critical illness in patients with AUDs. In contrast to acute intoxication, AUDs have been linked to increased severity of illness in a number of studies. In particular, surgical patients with AUDs experience higher rates of postoperative hemorrhage, cardiac complications, sepsis, and need for repeat surgery. Outcomes from trauma are worse for patients with chronic alcohol abuse, whereas burn patients who are acutely intoxicated may not have worse outcomes. AUDs are linked to not only a higher likelihood of community-acquired pneumonia and sepsis but also a higher severity of illness and higher rates of nosocomial pneumonia and sepsis. The management of sedation in patients with AUDs may be particularly challenging because of the increased need for sedatives and opioids and the difficulty in diagnosing withdrawal syndrome. The health-care provider also must be watchful for the development of dangerous agitation and violence, as these problems are not uncommonly seen in hospital ICUs. Despite studies showing that up to 40% of hospitalized patients have AUDs, relatively few guidelines exist on the specific management of the critically ill patient with AUDs. AUDs are underdiagnosed, and a first step to improving patient outcomes may lie in systematically and accurately identifying AUDs.

Predictors for daily interruption of sedation therapy by nurses: a prospective, multicenter study.

PURPOSE: The aim of the study was to identify the nurse and patient-related factors predicting daily interruption of sedation (DIS) performance by nurses in the intensive care unit (ICU). METHODS: Nurses, caring for a mechanically ventilated patient receiving 24 hours or more of a continuously infused sedative, were interviewed at the bedside to determine their willingness to perform DIS on this patient and to determine the influence of 20 nurse- and 47 patient-related factors on DIS completion. RESULTS: The 57 (44%) of 130 of nurses willing to perform DIS had performed DIS at least once in the past (P < .0001) and were not targeting deep sedation (ie, Sedation Agitation Scale [SAS] ≤ 2 [P = .03]). The DIS performance was less likely with use of higher-dose continuous midazolam (P = .006), a fraction of inspired oxygen (Fio(2)) greater than 50% (P = .03), or positive end-expiratory pressure greater than 5 mm Hg (P = .006) and in patients either deeply sedated (SAS ≤ 2) (P = .05) or agitated (SAS ≥ 5) in the past 24 hours (P = .003). Prior DIS experience (odds ratio [OR], 2.54; P = .004), hours of sedation-related continuing education (OR, 1.13; P = .02), and a target of deep sedation (OR, 0.49; P = .02) were independent nurse-related factors for DIS performance. Nurse's willingness to conduct DIS ranged from 45% to 80% based on the interaction between patient sex, current Fio(2), and agitation in past 24 hours. CONCLUSIONS: Educational strategies and institutional protocols focused on improving use of DIS need to consider the various nurse- and patient-related factors that affect DIS performance by nurses in the ICU.

Ineffective triggering predicts increased duration of mechanical ventilation.

OBJECTIVES: To determine whether high rates of ineffective triggering within the first 24 hrs of mechanical ventilation (MV) are associated with longer MV duration and shorter ventilator-free survival (VFS). DESIGN: Prospective cohort study. SETTING: Medical intensive care unit (ICU) at an academic medical center. PATIENTS: Sixty patients requiring invasive MV. INTERVENTIONS: None. MEASUREMENTS: Patients had pressure-time and flow-time waveforms recorded for 10 mins within the first 24 hrs of MV initiation. Ineffective triggering index (ITI) was calculated by dividing the number of ineffectively triggered breaths by the total number of breaths (triggered and ineffectively triggered). A priori, patients were classified into ITI >or=10% or ITI <10%. Patient demographics, MV reason, codiagnosis of chronic obstructive pulmonary disease (COPD), sedation levels, and ventilator parameters were recorded. MEASUREMENTS AND MAIN RESULTS: Sixteen of 60 patients had ITI >or=10%. The two groups had similar characteristics, including COPD frequency and ventilation parameters, except that patients with ITI >or=10% were more likely to have pressured triggered breaths (56% vs. 16%, p = .003) and had a higher intrinsic respiratory rate (22 breaths/min vs. 18, p = .03), but the set ventilator rate was the same in both groups (9 breaths/min vs. 9, p = .78). Multivariable analyses adjusting for pressure triggering also demonstrated that ITI >or=10% was an independent predictor of longer MV duration (10 days vs. 4, p = .0004) and shorter VFS (14 days vs. 21, p = .03). Patients with ITI >or=10% had a longer ICU length of stay (8 days vs. 4, p = .01) and hospital length of stay (21 days vs. 8, p = .03). Mortality was the same in the two groups, but patients with ITI >or=10% were less likely to be discharged home (44% vs. 73%, p = .04). CONCLUSIONS: Ineffective triggering is a common problem early in the course of MV and is associated with increased morbidity, including longer MV duration, shorter VFS, longer length of stay, and lower likelihood of home discharge.

Perceived barriers to the use of sedation protocols and daily sedation interruption: a multidisciplinary survey.

BACKGROUND: Although use of sedation protocols and daily sedation interruption (DSI) improve outcome, their current use and barriers affecting their use are unclear. METHODS: We designed a multidisciplinary, Web-based survey to determine current use of sedation protocols and DSI and the perceived barriers to each, and administered it to members of the Society of Critical Care Medicine. RESULTS: The 904 responders were physicians (60%), nurses (14%), or pharmacists (12%); 45% worked in a university hospital. Of 64% having a sedation protocol, 78% used it for >or=50% of ventilated patients. Reasons for lack of protocol use included no physician order (35%), lack of nursing support (11%), and a fear of oversedation (7%). Daily sedation interruption was used by only 40%. Barriers to DSI included lack of nursing acceptance (22%), concern about risk of patient-initiated device removal (19%), and inducement of either respiratory compromise (26%) or patient discomfort (13%). Clinicians who prefer propofol were more likely to use DSI than those who prefer benzodiazepines (55% vs 40, P < .0001). CONCLUSIONS: Current intensive care unit sedation practices are heterogeneous, and the barriers preventing the use of both sedation protocols and DSI are numerous. These barriers should be addressed on an institutional basis to boost the use of these evidence-based practices.