ALCOHOL CONSUMPTION AND MISUSE AMONG PATIENTS WITH RESPIRATORY FAILURE BEFORE AND DURING THE COVID-19 PANDEMIC

Alcohol misuse is associated with the development of respiratory failure, including the acute respiratory distress syndrome (ARDS), with attendant poorer outcomes. Epidemiologic data suggest that alcohol consumption increased during the COVID-19 pandemic;however, consumption habits among critically ill patients are not well-described. We hypothesized that the prevalence of alcohol consumption and misuse among patients with respiratory failure would be greater during the pandemic relative to years prior. Patients with respiratory failure requiring mechanical ventilation in a single academic hospital were enrolled from 2015-19 (pre-pandemic) and 2020-21 (pandemic). Data regarding demographics and alcohol use were obtained from the medical record. Phosphatidylethanol (PEth) was measured in a subset of patients in red blood cells collected within 48 hours of intubation. Patients were characterized as follows: (1) likely drinking: patient or proxy endorsed any drinking on the Alcohol Use Disorders Identification Test (AUDIT) or in social history;or patient was admitted for an alcohol-related diagnosis;or patient had detectable blood alcohol or PEth;(2) likely alcohol misuse: PEth ≥ 250;or AUDIT-C ≥3 (women) or ≥4 (men);or AUDIT ≥5 (women) or ≥ 8 (men);or patient was admitted for an alcohol-related diagnosis;(3) likely severe alcohol misuse: PEth ≥400. Univariable statistics were utilized as appropriate (Fisher's Exact Test, Kruskal- Wallis Test). The prevalence of likely drinking in the study population (n = 195) varied over time (p <0.0001). When pandemic (n = 67) and pre-pandemic patients (n = 128) were compared, the prevalence of likely drinking (93% vs 58%, p <0.0001), likely alcohol misuse (49% vs 33%, p <0.03) and likely severe alcohol misuse (32% vs 10%, p <0.003) were all greater during the pandemic. Among likely drinking patients with available PEth data (n = 97), median PEth was significantly higher during the pandemic compared to pre-pandemic years (251 [135-702] versus 87 [16-374], p = 0.002). Among the subset of patients enrolled during the pandemic, the prevalence of likely current drinking was 100% in those with COVID-19 compared to 76% among non-COVID patients (p = 0.002), but alcohol misuse did not differ. We conclude that alcohol consumption, and alcohol misuse, have increased during the pandemic in this patient cohort. These changes in drinking patterns are concerning and warrant additional research regarding their impact on susceptibility and outcomes for respiratory failure.

IN-HOSPITAL DELIRIUM IS ASSOCIATED WITH INCREASED MORTALITY RISK IN PATIENTS WITH ADMITTED WITH COVID-19 AND A HISTORY OF ALCOHOL MISUSE

Introduction: In-hospital delirium is a risk factor for worse critical care outcomes. Alcohol misuse contributes to increased risk of critical illness and greater pneumonia severity. We sought to determine if alcohol misuse was associated with increased risk of critical illness or complications of critical illness including delirium amongst hospitalized COVID-19 patients. Methods: Retrospective study across 12 University of Colorado hospitals (March 2020-April 2021). Adults with a COVID-19 diagnosis were included. Alcohol misuse was defined by validated ICD-10 codes (F10.1∗, F10.2∗, F10.9∗). Multivariable, mixed effects logistic regression models were used to estimate effects of alcohol misuse adjusting for age, sex, body mass index, diabetes and liver disease. Results: We included 6,454 hospitalized COVID-19 patients aged 60 (SD 18 years) with 53% male. Twenty-four percent (n = 1561) required ICU admission, 14.4% (n = 927) endotracheal intubation with a median ICU stay of 6 days [IQR 2 to 15] and duration of mechanical ventilation of 10 days [IQR 5 to 18]. Ten percent of the cohort (n = 644) died in hospital. Delirium was identified in 4% (n = 254) and 257 patients (4%) had alcohol misuse. Patients with misuse were younger (52 vs 60 p < 0.01), men (77 vs 52%, p < 0.01), had more co-morbid liver disease (p-value < 0.01) and received less remdesivir (29 vs 50%, p < 0.01). There was no difference in dexamethasone or vasopressor use. In adjusted analyses, alcohol misuse was associated with 54% increased odds of ICU admission (aOR, 1.54, 95%CI 1.13 to 2.09, p < 0.01) and 46% increased odds of mechanical ventilation (aOR. 1.46, 95% CI 1.03 to 2.08, p < 0.01) compared to patients without misuse. There was a significant interaction between misuse and in-hospital delirium on in-hospital death with odds of death highest amongst patients with both alcohol misuse and identified delirium. Conclusions: Alcohol misuse was associated with increased need for critical care including ICU admission and mechanical ventilation. Delirium was an important modifiable risk factor for worse outcomes in hospitalized patients with alcohol misuse, and the odds of in-hospital death were significantly increased in the presence of bothmisuse and delirium.

Outcomes Associated with Asthma Exacerbations with Respiratory Failure Treated with Extracorporeal Membrane Oxygenation

Rationale: Asthma affects 20 million adults in the United States resulting in up to 500,000 hospitalizations each year. Patients admitted to the intensive care unit (ICU) for asthma exacerbations requiring invasive ventilation have a mortality of ∼7%. Extracorporeal membrane oxygenation (ECMO) is a salvage technique used in patients with respiratory failure to increase delivery of oxygen, remove CO2 and allow time for recovery. Case series and uncontrolled registry studies have examined benefits of ECMO for asthma exacerbations with respiratory failure, but no studies have examined outcomes associated with use of ECMO for asthma exacerbations compared to standard care. Objective: To assess outcomes associated with use of ECMO during asthma exacerbations requiring invasive ventilation compared to standard care. Methods: Patients were extracted from the Premier Database from 2010-2020 if they had a primary diagnosis of asthma, or a primary diagnosis of respiratory failure with a secondary diagnosis of asthma, and were treated with invasive ventilation. Patients were excluded for age < 18y, no ICU admission, chronic lung disease other than asthma, COVID-19, or if they were not treated with corticosteroids. Hospital mortality was the primary study outcome. Key secondary outcomes included ICU length of stay (LOS), hospital LOS, length of invasive ventilation and hospital costs. Differences in outcomes were assessed using propensity score matching at a 1:2 ratio of ECMO versus no ECMO, and by covariate adjustment of the entire study group. Results: A total of 20,494 patients with asthma exacerbations requiring invasive ventilation were included in the study, of which 130 were treated with ECMO and 20,364 were not. After propensity matching, ECMO (N=103) versus no ECMO (N=206) was associated with reduced mortality (11.4% vs. 23.3%, p = 0.017) and increased hospital costs, but no difference in ICU LOS, hospital LOS or length of mechanical ventilation (Table). The covariate-adjusted model replicated these findings (Table). When individual patients were assigned a probability of being treated with ECMO equal to the hospital rate where they were admitted, each 10% increase in the hospital rate of ECMO was associated with no change in the odds of mortality (OR, 1.12: 95% CI, 0.82-1.52), p=0.48). ECMO was also associated with increased renal replacement therapy (P = 0.02), shock (P=0.02) and 30-day all-cause readmission (P = 0.01). Conclusion: ECMO was associated with reduced mortality at the cost of increased morbidity in asthmatics requiring invasive ventilation, indicating that ECMO has the potential to save thousands of lives.

PTPα Is a Regulator of Fibroproliferation during ARDS

Rationale: Acute Respiratory Distress Syndrome (ARDS) is a major healthcare issue resulting in high morbidity and mortality. Up to 25% of patients with ARDS will develop pathological fibrosis, termed Fibroproliferative ARDS (FP-ARDS). In this subset of patients, ongoing injury and dysregulated repair results in persistence of inflammatory infiltrates, myofibroblast differentiation, and dysregulated deposition of extracellular matrix. The consequences of this pathologic fibroproliferation include increased mortality, prolonged ventilator dependence, and diminished quality of life for survivors. This is especially relevant in the context of the COVID-19 pandemic, during which fibroproliferation following ARDS is an increasingly recognized entity. We demonstrate that a tyrosine phosphatase, PTPα, plays an important role in promoting fibroproliferation following ARDS. Methods: Mice deficient in PTPα and littermate controls were treated with intratracheal hydrochloric acid;histological, biochemical, and gene expression endpoint analyses were performed. NIH 3T3 (murine) fibroblasts or normal human lung fibroblasts (NLHFs) were stimulated with BAL fluid from these mice, or from ARDS patients and healthy controls, respectively. Human lung fibroblasts in which PTPα was deleted via CRISPR-cas9 targeted guide RNA were treated with exogenous TGF-β. Analysis of gene expression by qPCR was performed. Results: Mice deficient in PTPα demonstrated reduced fibrotic outcomes after lung injury. A fibrosis-focused qPCR array showed significant attenuation of key pro-fibrotic genes in PTPα-null mice, even at early timepoints during which inflammatory outcomes were unchanged. BAL fluid from PTPα-null mice treated with HCl induced less fibroproliferative gene expression in murine fibroblasts than BAL fluid from littermate controls. Human fibroblasts lacking PTPα (generated via CRISPR-cas9 deletion) showed reduced pro-fibrotic gene expression responses following stimulation with exogenous TGF-β. NHLFs stimulated with ARDS patient BAL fluid demonstrated increased pro-fibrotic gene expression as compared to BAL fluid from control patients. Conclusions: We conclude that absence of PTPα is protective in a model of FP-ARDS, through mechanisms that result in reduced TGF-β-dependent gene expression. The alveolar milieu of mice lacking PTPα has reduced fibroproliferative potential than those that express PTPα. Similarly, human fibroblasts that have been genetically modified to delete PTPα are less responsive to stimulation with TGF-β, suggesting that this pathway is relevant to human pathology. Since human ARDS BAL fluid induces the same changes in normal human lung fibroblasts that are attenuated by the absence of PTPα in experimental models, this suggests that targeting of this protein could be a strategy to alleviate pathologic fibroproliferation following lung injury.