Analgesia and Sedation Use During Noninvasive Ventilation for Acute Respiratory Failure.

OBJECTIVES: To describe U.S. practice regarding administration of sedation and analgesia to patients on noninvasive ventilation (NIV) for acute respiratory failure (ARF) and to determine the association of this practice with odds of intubation or death. DESIGN: A retrospective multicenter cohort study. SETTING: A total of 1017 hospitals contributed data between January 2010 and September 2020 to the Premier Healthcare Database, a nationally representative healthcare database in the United States. PATIENTS: Adult (≥ 18 yr) patients admitted to U.S. hospitals requiring NIV for ARF. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 433,357 patients on NIV of whom (26.7% [95% CI] 26.3%-27.0%) received sedation or analgesia. A total of 50,589 patients (11.7%) received opioids only, 40,646 (9.4%) received benzodiazepines only, 20,146 (4.6%) received opioids and benzodiazepines, 1.573 (0.4%) received dexmedetomidine only, and 2,639 (0.6%) received dexmedetomidine in addition to opioid and/or benzodiazepine. Of 433,357 patients receiving NIV, 50,413 (11.6%; 95% CI, 11.5-11.7%) patients underwent invasive mechanical ventilation on hospital days 2-5 or died on hospital days 2-30. Intubation was used in 32,301 patients (7.4%; 95% CI, 7.3-7.6%). Further, death occurred in 24,140 (5.6%; 95% CI, 5.5-5.7%). In multivariable analysis adjusting for relevant covariates, receipt of any medication studied was associated with increased odds of intubation or death. In inverse probability weighting, receipt of any study medication was also associated with increased odds of intubation or death (average treatment effect odds ratio 1.38; 95% CI, 1.35-1.40). CONCLUSIONS: The use of sedation and analgesia during NIV is common. Medication exposure was associated with increased odds of intubation or death. Further investigation is needed to confirm this finding and determine whether any subpopulations are especially harmed by this practice.

Association of Women Leaders with Women Program Director and Trainee Representation Across US Academic Internal Medicine.

BACKGROUND: Women are underrepresented within internal medicine (IM). Whether women leaders attract women trainees is not well explored. OBJECTIVE: To characterize leader and trainee gender across US academic IM and to investigate the association of leader gender with trainee gender. DESIGN: Cross-sectional study. PARTICIPANTS: Leaders (chairs, chiefs, program directors (PDs)) in 2018 and trainees (residents, fellows) in 2012-2016 at medical school-affiliated IM and seven IM fellowship programs. EXPOSURE: Leadership (chair/chief and program director; and, for resident analyses, fellow) gender. MAIN MEASURES: Our primary outcome was percent women trainees (IM residents and, separately, subspecialty fellows). We used standard statistics to describe leadership and trainee gender. We created separate multivariable linear regressions to evaluate associations of leader gender and percent women fellows with percent women IM residents. We then created separate multivariable multilevel models (site as a random effect) to evaluate associations of leader gender with percent women subspecialty fellows. KEY RESULTS: Our cohort consisted of 940 programs. Women were 13.4% of IM chairs and <25% of chiefs in each fellowship subspecialty (cardiology: 2.6%; gastroenterology: 6.6%; pulmonary and critical care: 10.7%; nephrology: 14.4%; endocrinology: 20.6%; hematology-oncology: 23.2%; infectious diseases: 24.3%). IM PDs were 39.7% women; fellowship PDs ranged from nearly 25% (cardiology and gastroenterology) to nearly 50% (endocrinology and infectious disease) women. Having more women fellows (but not chairs or PDs) was associated with having more women residents (0.3% (95% CI: 0.2-0.5%) increase per 1% fellow increase, p<0.001); this association remained after adjustment (0.3% (0.1%, 0.4%), p=0.001). In unadjusted analyses, having a woman PD (increase of 7.7% (4.7%, 10.6%), p<0.001) or chief (increase of 8.9% (4.6%, 13.1%), p<0.001) was associated with an increase in women fellows; after adjustment, these associations were lost. CONCLUSIONS: Women held a minority of leadership positions in academic IM. Having women leaders was not independently associated with having more women trainees.

Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis.

We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene MUC5B, and KRT5 marker of basal cell airway progenitors. Here we show the association of MUC5B and cilia gene expression in human IPF airway epithelial cells, providing further rationale for examining the role of cilium genes in the pathogenesis of IPF. We demonstrate increased multiciliogenesis and changes in motile cilia structure of multiciliated cells both in IPF and bleomycin lung fibrosis models. Importantly, conditional deletion of a cilium gene, Ift88 (intraflagellar transport 88), in Krt5 basal cells reduces Krt5 pod formation and lung fibrosis, whereas no changes are observed in Ift88 conditional deletion in club cell progenitors. Our findings indicate that aberrant injury-activated primary ciliogenesis and Hedgehog signaling may play a causative role in Krt5 pod formation, which leads to aberrant multiciliogenesis and lung fibrosis. This implies that modulating cilium gene expression in Krt5 cell progenitors is a potential therapeutic target for IPF.

PTPα promotes fibroproliferative responses after acute lung injury.

The acute respiratory distress syndrome (ARDS) is a major healthcare problem, accounting for significant mortality and long-term disability. Approximately 25% of patients with ARDS will develop an overexuberant fibrotic response, termed fibroproliferative ARDS (FP-ARDS) that portends a poor prognosis and increased mortality. The cellular pathological processes that drive FP-ARDS remain incompletely understood. We have previously shown that the transmembrane receptor-type tyrosine phosphatase protein tyrosine phosphatase-α (PTPα) promotes pulmonary fibrosis in preclinical murine models through regulation of transforming growth factor-ß (TGF-ß) signaling. In this study, we examine the role of PTPα in the pathogenesis of FP-ARDS in a preclinical murine model of acid (HCl)-induced acute lung injury. We demonstrate that although mice genetically deficient in PTPα (Ptpra-/-) are susceptible to early HCl-induced lung injury, they exhibit markedly attenuated fibroproliferative responses. In addition, early profibrotic gene expression is reduced in lung tissue after acute lung injury in Ptpra-/- mice, and stimulation of naïve lung fibroblasts with the BAL fluid from these mice results in attenuated fibrotic outcomes compared with wild-type littermate controls. Transcriptomic analyses demonstrate reduced extracellular matrix (ECM) deposition and remodeling in mice genetically deficient in PTPα. Importantly, human lung fibroblasts modified with a CRISPR-targeted deletion of PTPRA exhibit reduced expression of profibrotic genes in response to TGF-ß stimulation, demonstrating the importance of PTPα in human lung fibroblasts. Together, these findings demonstrate that PTPα is a key regulator of fibroproliferative processes following acute lung injury and could serve as a therapeutic target for patients at risk for poor long-term outcomes in ARDS.

Internal and External Validation of an Alcohol Biomarker for Screening in Trauma.

OBJECTIVE: We aimed to examine biomarkers for screening unhealthy alcohol use in the trauma setting. SUMMARY AND BACKGROUND DATA: Self-report tools are the practice standard for screening unhealthy alcohol use; however, their collection suffers from recall bias and incomplete collection by staff. METHODS: We performed a multi-center prospective clinical study of 251 adult patients who arrived within 24 hours of injury with external validation in another 60 patients. The Alcohol Use Disorders Identification Test served as the reference standard. The following biomarkers were measured: (1) PEth; (2) ethyl glucuronide; (3) ethyl sulfate; (4) gamma-glutamyl-transpeptidase; (5) carbohydrate deficient transferrin; and (6) blood alcohol concentration (BAC). Candidate single biomarkers and multivariable models were compared by considering discrimination (AUROC). The optimal cutpoint for the final model was identified using a criterion for setting the minimum value for specificity at 80% and maximizing sensitivity. Decision curve analysis was applied to compare to existing screening with BAC. RESULTS: PEth alone had an AUROC of 0.93 [95% confidence interval (CI): 0.92-0.93] in internal validation with an optimal cutpoint of 25 ng/mL. A 4- variable biomarker model and the addition of any single biomarker to PEth did not improve AUROC over PEth alone ( P > 0.05). Decision curve analysis showed better performance of PEth over BAC across most predicted probability thresholds. In external validation, sensitivity and specificity were 76.0% (95% CI: 53.0%-92.0%) and 73.0% (95% CI: 56.0%-86.0%), respectively.Conclusion and Relevance: PEth alone proved to be the single best biomarker for screening of unhealthy alcohol use and performed better than existing screening systems with BAC. PEth may overcome existing screening barriers.

Association Between Vasopressin Rebranding and Utilization in Patients With Septic Shock.

OBJECTIVES: Vasopressin is suggested as an adjunct to norepinephrine in patients with septic shock. However, after vasopressin was rebranded in November 2014, its cost exponentially increased. Utilization patterns of vasopressin after its rebranding are unclear. The objective of this study was to determine if there is an association between the rebranding of vasopressin in November 2014 and its utilization in vasopressor-dependent patients with severe sepsis or septic shock. DESIGN: Retrospective, multicenter, database study between January 2010 and March 2017. SETTING: Premier Healthcare Database hospitals. PATIENTS: Adult patients admitted to an ICU with severe sepsis or septic shock, who received at least one vasoactive agent for two or more calendar days were included. INTERVENTIONS: The proportion of patients who received vasopressin and vasopressin cost was assessed before and after rebranding, and evaluated with segmented regression. MEASUREMENTS AND MAIN RESULTS: Among 294,733 patients (mean age, 66 ± 15 yr), 27.8% received vasopressin, and ICU mortality was 26.5%. The proportion of patients receiving vasopressin was higher after rebranding (31.2% postrebranding vs 25.8% prerebranding). Before vasopressin rebranding, the quarterly proportion of patients who received vasopressin had an increasing slope (prerebranding slope 0.41% [95% CI, 0.35-0.46%]), with no difference in slope detected after vasopressin rebranding (postrebranding slope, 0.47% [95% CI, 0.29-0.64%]). After vasopressin rebranding, mean vasopressin cost per patient was higher ($527 ± 1,130 vs $77 ± 160), and the quarterly slope of vasopressin cost was higher (change in slope $77.18 [95% CI, $75.73-78.61]). Total vasopressin billed cost postrebranding continually increased by ~$294,276 per quarter from less than $500,000 in Q4 2014 to over $3,000,000 in Q1 2017. CONCLUSIONS: After vasopressin rebranding, utilization continued to increase quarterly despite a significant increase in vasopressin cost. Vasopressin appeared to have price inelastic demand in septic shock.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Malondialdehyde-Acetaldehyde Adduct Formation Decreases Immunoglobulin A Transport across Airway Epithelium in Smokers Who Abuse Alcohol.

Alcohol misuse and smoking are risk factors for pneumonia, yet the impact of combined cigarette smoke and alcohol on pneumonia remains understudied. Smokers who misuse alcohol form lung malondialdehyde-acetaldehyde (MAA) protein adducts and have decreased levels of anti-MAA secretory IgA (sIgA). Transforming growth factor-ß (TGF-ß) down-regulates polymeric Ig receptor (pIgR) on mucosal epithelium, resulting in decreased sIgA transcytosis to the mucosa. It is hypothesized that MAA-adducted lung protein increases TGF-ß, preventing expression of epithelial cell pIgR and decreasing sIgA. Cigarette smoke and alcohol co-exposure on sIgA and TGF-ß in human bronchoalveolar lavage fluid and in mice instilled with MAA-adducted surfactant protein D (SPD-MAA) were studied herein. Human bronchial epithelial cells (HBECs) and mouse tracheal epithelial cells were treated with SPD-MAA and sIgA and TGF-ß was measured. Decreased sIgA and increased TGF-ß were observed in bronchoalveolar lavage from combined alcohol and smoking groups in humans and mice. CD204 (MAA receptor) knockout mice showed no changes in sIgA. SPD-MAA decreased pIgR in HBECs. Conversely, SPD-MAA stimulated TGF-ß release in both HBECs and mouse tracheal epithelial cells, but not in CD204 knockout mice. SPD-MAA stimulated TGF-ß in alveolar macrophage cells. These data show that MAA-adducted surfactant protein stimulates lung epithelial cell TGF-ß, down-regulates pIgR, and decreases sIgA transcytosis. These data provide a mechanism for the decreased levels of sIgA observed in smokers who misuse alcohol.

Medication prescribing for alcohol use disorders during alcohol-related encounters in a Colorado regional healthcare system.

RATIONALE: Investigations show that medications for alcohol use disorders (MAUD) reduce heavy drinking and relapses. However, only 1.6% of individuals with alcohol use disorders (AUD) receive MAUD across care settings. The epidemiology of MAUD prescribing in the acute care setting is incompletely described. We hypothesized that MAUD would be under prescribed in inpatient acute care hospital settings compared to the outpatient, emergency department (ED), and inpatient substance use treatment settings. METHODS: We evaluated electronic health record (EHR) data from adult patients with an International Classification of Diseases, 10th revision (ICD-10) alcohol-related diagnosis in the University of Colorado Health (UCHealth) system between January 1, 2016 and 31 December, 2019. Data from patients with an ICD-10 diagnosis code for opioid use disorder and those receiving MAUD prior to their first alcohol-related episode were excluded. The primary outcome was prescribing of MAUD, defined by prescription of naltrexone, acamprosate, and/or disulfiram. We performed bivariate and multivariate analyses to identify independent predictors of MAUD prescribing at UCHealth. RESULTS: We identified 48,421 unique patients with 136,205 alcohol-related encounters at UCHealth. Encounters occurred in the ED (42%), inpatient acute care (17%), inpatient substance use treatment (18%), or outpatient primary care (12%) settings. Only 2270 (5%) patients received MAUD across all settings. Female sex and addiction medicine consults positively predicted MAUD prescribing. In contrast, encounters outside inpatient substance use treatment, Hispanic ethnicity, and black or non-white race were negative predictors of MAUD prescribing. Compared to inpatient substance use treatment, inpatient acute care hospitalizations for AUD was associated with a 93% reduced odds of receiving MAUD. CONCLUSIONS: AUD-related ED and inpatient acute care hospital encounters in our healthcare system were common. Nevertheless, prescriptions for MAUD were infrequent in this population, particularly in inpatient settings. Our findings suggest that the initiation of MAUD for patients with alcohol-related diagnoses in acute care settings deserves additional evaluation.

COVID-19 patients with documented alcohol use disorder or alcohol-related complications are more likely to be hospitalized and have higher all-cause mortality.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) has affected every country globally, with hundreds of millions of people infected with the SARS-CoV-2 virus and over 6 million deaths to date. It is unknown how alcohol use disorder (AUD) affects the severity and mortality of COVID-19. AUD is known to increase the severity and mortality of bacterial pneumonia and the risk of developing acute respiratory distress syndrome. Our objective is to determine whether individuals with AUD have increased severity and mortality from COVID-19. METHODS: We utilized a retrospective cohort study of inpatients and outpatients from 44 centers participating in the National COVID Cohort Collaborative. All were adult COVID-19 patients with and without documented AUDs. RESULTS: We identified 25,583 COVID-19 patients with an AUD and 1,309,445 without. In unadjusted comparisons, those with AUD had higher odds of hospitalization (odds ratio [OR] 2.00, 95% confidence interval [CI] 1.94 to 2.06, p < 0.001). After adjustment for age, sex, race/ethnicity, smoking, body mass index, and comorbidities, individuals with an AUD still had higher odds of requiring hospitalization (adjusted OR [aOR] 1.51, CI 1.46 to 1.56, p < 0.001). In unadjusted comparisons, individuals with AUD had higher odds of all-cause mortality (OR 2.18, CI 2.05 to 2.31, p < 0.001). After adjustment as above, individuals with an AUD still had higher odds of all-cause mortality (aOR 1.55, CI 1.46 to 1.65, p < 0.001). CONCLUSION: This work suggests that AUD can increase the severity and mortality of COVID-19 infection. This reinforces the need for clinicians to obtain an accurate alcohol history from patients hospitalized with COVID-19. For this study, our results are limited by an inability to quantify the daily drinking habits of the participants. Studies are needed to determine the mechanisms by which AUD increases the severity and mortality of COVID-19.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Effects of acetate on cerebral blood flow, systemic inflammation, and behavior in alcohol use disorder.

BACKGROUND: Alcohol use disorders (AUDs) are associated with altered regulation of physiological processes in the brain. Acetate, a metabolite of ethanol, has been implicated in several processes that are disrupted in AUDs including transcriptional regulation, metabolism, inflammation, and neurotransmission. To further understand the effects of acetate on brain function in AUDs, we investigated the effects of acetate on cerebral blood flow (CBF), systemic inflammatory cytokines, and behavior in AUD. METHODS: Sixteen participants with AUD were recruited from a nonmedical, clinically managed detoxification center. Each participant received acetate and placebo in a randomly assigned order of infusion and underwent 3T MR scanning using quantitative pseudo-continuous arterial spin labeling. Participants and the study team were blinded to the infusion. CBF values (ml/100 g/min) extracted from thalamus were compared between placebo and acetate using a mixed effect linear regression model accounting for infusion order. Voxel-wise CBF comparisons were set at threshold of p < 0.05 cluster-corrected for multiple comparisons, voxel-level p < 0.0001. Plasma cytokine levels and behavior were also assessed between infusions. RESULTS: Fifteen men and 1 woman were enrolled with Alcohol Use Disorders Identification Test (AUDIT) scores between 13 and 38 with a mean of 28.3 ± 9.1. Compared to placebo, acetate administration increased CBF in the thalamus bilaterally (Left: 51.2 vs. 68.8, p < 0.001; Right: 53.7 vs. 69.6, p = 0.001), as well as the cerebellum, brainstem, and cortex. Older age and higher AUDIT scores were associated with increases in acetate-induced thalamic blood flow. Cytokine levels and behavioral measures did not differ between placebo and acetate infusions. CONCLUSIONS: This pilot study in AUD suggests that during the first week of abstinence from alcohol, the brain's response to acetate differs by brain region and this response may be associated with the severity of alcohol dependence.

Noninvasive Ventilation Use in Critically Ill Patients with Acute Asthma Exacerbations.

Rationale: Noninvasive ventilation decreases the need for invasive mechanical ventilation and mortality among patients with chronic obstructive pulmonary disease but has not been well studied in asthma.Objectives: To assess the association between noninvasive ventilation and subsequent need for invasive mechanical ventilation and in-hospital mortality among patients admitted with asthma exacerbation to the ICU.Methods: We performed a retrospective cohort study using administrative data collected during 2010-2017 from 682 hospitals in the United States. Outcomes included receipt of invasive mechanical ventilation and in-hospital mortality. Generalized estimating equations, propensity-matched models, and marginal structural models were used to assess the association between noninvasive ventilation and outcomes.Measurements and Main Results: The study population included 53,654 participants with asthma exacerbation. During the study period, 13,540 patients received noninvasive ventilation (25.2%; 95% confidence interval [CI], 24.9-25.6%), 14,498 underwent invasive mechanical ventilation (27.0%; 95% CI, 26.7-27.4%), and 1,291 died (2.4%; 95% CI, 2.3-2.5%). Among those receiving noninvasive ventilation, 3,013 patients (22.3%; 95% CI, 21.6-23.0%) required invasive mechanical ventilation after first receiving noninvasive ventilation, 136 of whom died (4.5%; 95% CI, 3.8-5.3%). Across all models, the use of noninvasive ventilation was associated with a lower odds of receiving invasive mechanical ventilation (adjusted generalized estimating equation odds ratio, 0.36; 95% CI, 0.32-0.40) and in-hospital mortality (odds ratio, 0.48; 95% CI 0.40-0.58). Those who received noninvasive ventilation before invasive mechanical ventilation were more likely to have comorbid pneumonia and severe sepsis.Conclusions: Noninvasive ventilation use during asthma exacerbation was associated with improved outcomes but should be used cautiously with acute comorbid conditions.

Harnessing the Power of Hospitalists in Operational Disaster Planning: COVID-19.

Hospitalists are well poised to serve in key leadership roles and in frontline care in particular when facing a pandemic such as the SARS-CoV-2 (COVID-19) infection. Much of the disaster planning in hospitals around the country addresses overcrowded emergency departments and decompressing these locations; however, in the case of COVID-19, intensive care units, emergency departments, and medical wards ran the risk of being overwhelmed by a large influx of patients needing high-level medical care. In a matter of days, our Division of Hospital Medicine, in partnership with our hospital, health system, and academic institution, was able to modify and deploy existing disaster plans to quickly care for an influx of medically complex patients. We describe a scaled approach to managing hospitalist clinical operations during the COVID-19 pandemic.

Alcohol Use Disorders Are Associated With a Unique Impact on Airway Epithelial Cell Gene Expression.

BACKGROUND: Alcohol use disorders (AUDs) and cigarette smoking both increase risk for the development of community-acquired pneumonia (CAP), likely through adverse effects on proximal airway mucociliary clearance and pathogen recognition. Smoking-related alterations on airway gene expression are well described, but little is known about the impact of AUDs. We measured gene expression in human airway epithelial cells (AECs), hypothesizing that AUDs would be associated with novel differences in gene expression that could alter risk for CAP. METHODS: Bronchoscopy with airway brushings was performed in participants with AUDs and controls to obtain AECs. An AUD Identification Test was used to define AUD. RNA was extracted from AECs, and mRNA expression data were collected on an Agilent micro-array. Differential expression analyses were performed on the filtered and normalized data with correction for multiple testing. Enrichment analyses were performed using clusterProfiler. RESULTS: Expression data from 19 control and 18 AUD participants were evaluated. After adjustment for smoking, AUDs were associated with significant differential expression of 520 AEC genes, including genes for ribosomal proteins and genes involved in protein folding. Enrichment analyses indicated significant differential expression of 24 pathways in AUDs, including those implicated in protein targeting to membrane and viral gene expression. Smoking-associated AEC gene expression differences mirrored previous reports, but differed from those associated with AUDs. CONCLUSIONS: AUDs have a distinct impact on AEC gene expression that may influence proximal airway function independent of smoking. Alcohol-associated alterations may influence risk for CAP through modifying key mechanisms important in protecting proximal airway integrity.

Injury Characteristics and von Willebrand Factor for the Prediction of Acute Respiratory Distress Syndrome in Patients With Burn Injury: Development and Internal Validation.

OBJECTIVE: To derive and validate a prediction model for the development of ARDS in burn-injured patients. SUMMARY BACKGROUND DATA: Burn injury carries the highest incidence of acute respiratory distress syndrome (ARDS) among all predisposing conditions, but few studies exist on risk factors in these patients. Studies employing biomarkers and clinical risk factors for predicting ARDS mortality have recently been examined but none exist for onset of ARDS nor in patients with burn injury. METHODS: This was a prospective multicenter study of 113 patients with isolated burn injury or inhalation injury. Clinical variables and plasma biomarkers representative of endothelial injury, epithelial injury, or inflammation were collected within 24 hours of admission. The most parsimonious model was chosen by considering discrimination, calibration, and model fit. RESULTS: Among the biomarkers measured in patients with burn injuries, a one-standard deviation increase in log-transformed levels of the A2 domain of von Willebrand factor in the first 24 hours was most strongly associated with the development of ARDS (OR 7.72; 95% CI: 1.64-36.28, P = 0.03). Of candidate models, a 3-variable model with %TBSA, inhalation injury, and von Willebrand factor-A2 had comparable discrimination to more complex models (area under the curve: 0.90; 95% CI 0.85-0.96). The 3-variable model had good model fit by Hosmer-Lemeshow test (P = 0.74) and maintained similar discrimination after accounting for performance optimism (Bootstrapped area under the curve: 0.90; 95% CI: 0.84-0.95). CONCLUSIONS: The 3-variable model with %TBSA, inhalation injury, and von Willebrand factor could be used to better identify at-risk patients for both the study and prevention of ARDS in patients with burn injury.

Effects of Alcohol and Acetate on Cerebral Blood Flow: A Pilot Study.

BACKGROUND: Acute alcohol produces effects on cerebral metabolism and blood flow. Alcohol is converted to acetate, which serves as a source of energy for the brain and is an agonist at G protein-coupled receptors distributed in different cell types in the body including neurons. Acetate has been hypothesized to play a role in the cerebral blood flow (CBF) response after alcohol ingestion. We tested whether administration of acetate would alter CBF in a pattern similar to or different from that of alcohol ingestion in healthy individuals. METHODS: Twenty-four healthy participants were assigned by convenience to receive either 0.6 g/kg alcohol orally (n = 12) or acetate intravenously (n = 12). For each participant, CBF maps were acquired using an arterial spin labeling sequence on a 3T magnetic resonance scanner after placebo and after drug administration. Whole-brain CBF maps were compared between placebo and drug using a paired t-test, and set at a threshold of p < 0.05 corrected for multiple comparisons (k ≥ 142 voxels, ≥3.78 cm3 ), voxel-level p < 0.005. Intoxication was measured after placebo and drug administration with a Subjective High Assessment Scale (SHAS-7). RESULTS: Compared to placebo, alcohol and acetate were associated with increased CBF in the medial thalamus. Alcohol, but not acetate, was associated with increased CBF in the right orbitofrontal, medial prefrontal and cingulate cortex, and hippocampus. Plasma acetate levels increased following administration of alcohol and acetate and did not differ between the 2 arms. Alcohol, but not acetate, was associated with an increase in SHAS-7 scores (p < 0.001). CONCLUSIONS: Increased thalamic CBF associated with either alcohol or acetate administration suggests that the thalamic CBF response after alcohol could be mediated by acetate. Compared to other brain regions, thalamus may differ in its ability to metabolize acetate or expression of receptors responsive to acetate. Increased prefrontal and limbic CBF associated with alcohol may be linked to alcohol's behavioral effects.

Patterns of utilization and effects of hospital-specific factors on physical, occupational, and speech therapy for critically ill patients with acute respiratory failure in the USA: results of a 5-year sample.

BACKGROUND: Timely initiation of physical, occupational, and speech therapy in critically ill patients is crucial to reduce morbidity and improve outcomes. Over a 5-year time interval, we sought to determine the utilization of these rehabilitation therapies in the USA. METHODS: We performed a retrospective cohort study utilizing a large, national administrative database including ICU patients from 591 hospitals. Patients over 18 years of age with acute respiratory failure requiring invasive mechanical ventilation within the first 2 days of hospitalization and for a duration of at least 48 h were included. RESULTS: A total of 264,137 patients received invasive mechanical ventilation for a median of 4.0 [2.0-8.0] days. Overall, patients spent a median of 5.0 [3.0-10.0] days in the ICU and 10.0 [7.0-16.0] days in the hospital. During their hospitalization, 66.5%, 41.0%, and 33.2% (95% CI = 66.3-66.7%, 40.8-41.2%, 33.0-33.4%, respectively) received physical, occupational, and speech therapy. While on mechanical ventilation, 36.2%, 29.7%, and 29.9% (95% CI = 36.0-36.4%, 29.5-29.9%, 29.7-30.1%) received physical, occupational, and speech therapy. In patients receiving therapy, their first physical therapy session occurred on hospital day 5 [3.0-8.0] and hospital day 6 [4.0-10.0] for occupational and speech therapy. Of all patients, 28.6% (95% CI = 28.4-28.8%) did not receive physical, occupational, or speech therapy during their hospitalization. In a multivariate analysis, patients cared for in the Midwest and at teaching hospitals were more likely to receive physical, occupational, and speech therapy (all P < 0.05). Of patients with identical covariates receiving therapy, there was a median of 61%, 187%, and 70% greater odds of receiving physical, occupational, and speech therapy, respectively, at one randomly selected hospital compared with another (median odds ratio 1.61, 2.87, 1.70, respectively). CONCLUSIONS: Physical, occupational, and speech therapy are not routinely delivered to critically ill patients, particularly while on mechanical ventilation in the USA. The utilization of these therapies varies according to insurance coverage, geography, and hospital teaching status, and at a hospital level.

An Observational Study of the Efficacy of Cisatracurium Compared with Vecuronium in Patients with or at Risk for Acute Respiratory Distress Syndrome.

RATIONALE: The neuromuscular blocking agent cisatracurium may improve mortality for patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Other neuromuscular blocking agents, such as vecuronium, are commonly used and have different mechanisms of action, side effects, cost, and availability in the setting of drug shortages. OBJECTIVES: To determine whether cisatracurium is associated with improved outcomes when compared with vecuronium in patients at risk for and with ARDS. METHODS: Using a nationally representative database, patients who were admitted to the ICU with a diagnosis of ARDS or an ARDS risk factor, received mechanical ventilation, and were treated with a continuous infusion of neuromuscular blocking agent for at least 2 days within 2 days of hospital admission were included. Patients were stratified into two groups: those who received cisatracurium or vecuronium. Propensity matching was used to balance both patient- and hospital-specific factors. Outcomes included hospital mortality, duration of mechanical ventilation, ICU and hospital duration, and discharge location. MEASUREMENTS AND MAIN RESULTS: Propensity matching successfully balanced all covariates for 3,802 patients (1,901 per group). There was no significant difference in mortality (odds ratio, 0.932; P = 0.40) or hospital days (-0.66 d; P = 0.411) between groups. However, patients treated with cisatracurium had fewer ventilator days (-1.01 d; P = 0.005) and ICU days (-0.98 d; P = 0.028) but were equally likely to be discharged home (odds ratio, 1.19; P = 0.056). CONCLUSIONS: When compared with vecuronium, cisatracurium was not associated with a difference in mortality but was associated with improvements in other clinically important outcomes. These data suggest that cisatracurium may be the preferred neuromuscular blocking agent for patients at risk for and with ARDS.

The respiratory tract microbial biogeography in alcohol use disorder.

Individuals with alcohol use disorders (AUDs) are at an increased risk of pneumonia and acute respiratory distress syndrome. Data of the lung microbiome in the setting of AUDs are lacking. The objective of this study was to determine the microbial biogeography of the upper and lower respiratory tract in individuals with AUDs compared with non-AUD subjects. Gargle, protected bronchial brush, and bronchoalveolar lavage specimens were collected during research bronchoscopies. Bacterial 16S gene sequencing and phylogenetic analysis was performed, and the alterations to the respiratory tract microbiota and changes in microbial biogeography were determined. The microbial structure of the upper and lower respiratory tract was significantly altered in subjects with AUDs compared with controls. Subjects with AUD have greater microbial diversity [ P < 0.0001, effect size = 16 ± 1.7 observed taxa] and changes in microbial species relative abundances. Furthermore, microbial communities in the upper and lower respiratory tract displayed greater similarity in subjects with AUDs. Alcohol use is associated with an altered composition of the respiratory tract microbiota. Subjects with AUDs demonstrate convergence of the microbial phylogeny and taxonomic communities between distinct biogeographical sites within the respiratory tract. These results support a mechanistic pathway potentially explaining the increased incidence of pneumonia and lung diseases in patients with AUDs.