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IMPORTANCE: Physical functional impairment is one of three components of postintensive care syndrome (PICS) that affects up to 60% of ICU survivors. OBJECTIVES: To explore the prevalence of objective physical functional impairment among a diverse cohort of ICU survivors, both at discharge and longitudinally, and to highlight sociodemographic factors that might be associated with the presence of objective physical functional impairment. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of 37 patients admitted to the ICU in New Orleans, Louisiana, and Denver, Colorado between 2016 and 2019 who survived with longitudinal follow-up data. MAIN OUTCOMES AND MEASURES: Our primary outcome of physical functional impairment was defined by handgrip strength and the short physical performance battery. We explored associations between functional impairment and sociodemographic factors that included race/ethnicity, sex, primary language, education status, and medical comorbidities. RESULTS: More than 75% of ICU survivors were affected by physical functional impairment at discharge and longitudinally at 3- to 6-month follow-up. We did not see a significant difference in the proportion of patients with physical functional impairment by race/ethnicity, primary language, or education status. Impairment was relatively higher in the follow-up period among women, compared with men, and those with comorbidities. Among 18 patients with scores at both time points, White patients demonstrated greater change in handgrip strength than non-White patients. Four non-White patients demonstrated diminished handgrip strength between discharge and follow-up. CONCLUSIONS AND RELEVANCE: In this exploratory analysis, we saw that the prevalence of objective physical functional impairment among ICU survivors was high and persisted after hospital discharge. Our findings suggest a possible relationship between race/ethnicity and physical functional impairment. These exploratory findings may inform future investigations to evaluate the impact of sociodemographic factors on functional recovery.
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Unidades de Cuidados Intensivos , Sobrevivientes , Humanos , Masculino , Femenino , Persona de Mediana Edad , Unidades de Cuidados Intensivos/estadística & datos numéricos , Sobrevivientes/estadística & datos numéricos , Anciano , Factores Sociodemográficos , Fuerza de la Mano/fisiología , Estudios Longitudinales , Rendimiento Físico Funcional , Colorado/epidemiología , Adulto , Alta del Paciente/estadística & datos numéricos , Louisiana/epidemiología , Enfermedad CríticaRESUMEN
BACKGROUND: Alcohol misuse is overlooked frequently in hospitalized patients, but is common among patients with pneumonia and acute hypoxic respiratory failure. Investigations in hospitalized patients rely heavily on self-report surveys or chart abstraction, which lack sensitivity. Therefore, our understanding of the prevalence of alcohol misuse before and during the COVID-19 pandemic is limited. RESEARCH QUESTION: In critically ill patients with respiratory failure, did the proportion of patients with alcohol misuse, defined by the direct biomarker phosphatidylethanol, vary over a period including the COVID-19 pandemic? STUDY DESIGN AND METHODS: Patients with acute hypoxic respiratory failure receiving mechanical ventilation were enrolled prospectively from 2015 through 2019 (before the pandemic) and from 2020 through 2022 (during the pandemic). Alcohol use data, including Alcohol Use Disorders Identification Test (AUDIT)-C scores, were collected from electronic health records, and phosphatidylethanol presence was assessed at ICU admission. The relationship between clinical variables and phosphatidylethanol values was examined using multivariable ordinal regression. Dichotomized phosphatidylethanol values (≥ 25 ng/mL) defining alcohol misuse were compared with AUDIT-C scores signifying misuse before and during the pandemic, and correlations between log-transformed phosphatidylethanol levels and AUDIT-C scores were evaluated and compared by era. Multiple imputation by chained equations was used to handle missing phosphatidylethanol data. RESULTS: Compared with patients enrolled before the pandemic (n = 144), patients in the pandemic cohort (n = 92) included a substantially higher proportion with phosphatidylethanol-defined alcohol misuse (38% vs 90%; P < .001). In adjusted models, absence of diabetes, positive results for COVID-19, and enrollment during the pandemic each were associated with higher phosphatidylethanol values. The correlation between health care worker-recorded AUDIT-C score and phosphatidylethanol level was significantly lower during the pandemic. INTERPRETATION: The higher prevalence of phosphatidylethanol-defined alcohol misuse during the pandemic suggests that alcohol consumption increased during this period, identifying alcohol misuse as a potential risk factor for severe COVID-19-associated respiratory failure. Results also suggest that AUDIT-C score may be less useful in characterizing alcohol consumption during high clinical capacity.
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Alcohol use is associated with an increased incidence of negative health outcomes in burn patients due to biological mechanisms that include a dysregulated inflammatory response and increased intestinal permeability. This study used phosphatidylethanol (PEth) in blood, a direct biomarker of recent alcohol use, to investigate associations between a recent history of alcohol use and the fecal microbiota, short chain fatty acids, and inflammatory markers in the first week after a burn injury for nineteen participants. Burn patients were grouped according to PEth levels of low or high and differences in the overall fecal microbial community were observed between these cohorts. Two genera that contributed to the differences and had higher relative abundance in the low PEth burn patient group were Akkermansia, a mucin degrading bacteria that improves intestinal barrier function, and Bacteroides, a potentially anti-inflammatory bacteria. There was no statistically significant difference between levels of short chain fatty acids or intestinal permeability across the two groups. To our knowledge, this study represents the first report to evaluate the effects of burn injury and recent alcohol use on early post burn microbiota dysbiosis, inflammatory response, and levels of short chain fatty acids. Future studies in this field are warranted to better understand the factors associated with negative health outcomes and develop interventional trials.
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Consumo de Bebidas Alcohólicas , Quemaduras , Heces , Microbioma Gastrointestinal , Glicerofosfolípidos , Humanos , Quemaduras/microbiología , Masculino , Adulto , Femenino , Microbioma Gastrointestinal/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , Persona de Mediana Edad , Heces/microbiología , Glicerofosfolípidos/sangre , Ácidos Grasos Volátiles/metabolismo , Disbiosis , Biomarcadores/sangre , Adulto JovenRESUMEN
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.
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Hipnóticos y Sedantes , Ventilación no Invasiva , Humanos , Ventilación no Invasiva/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estados Unidos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/uso terapéutico , Insuficiencia Respiratoria/terapia , Insuficiencia Respiratoria/mortalidad , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Adulto , Analgesia/métodos , Analgesia/estadística & datos numéricos , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/mortalidad , Benzodiazepinas/uso terapéutico , Benzodiazepinas/administración & dosificaciónRESUMEN
Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols using this procedure in critically ill patients, no recent document encapsulates the important safety considerations and downstream applications of this procedure in this setting. The objectives were to identify safe practices for patient selection and protection of hospital staff, provide recommendations for sample procurement to standardize studies, and give guidance on sample preparation for novel research technologies. Seventeen international experts in the management of critically ill patients, bronchoscopy in clinical and research settings, and experience in patient-oriented clinical or translational research convened for a workshop. Review of relevant literature, expert presentations, and discussion generated the findings presented herein. The committee concludes that research bronchoscopy with bronchoalveolar lavage in critically ill patients on mechanical ventilation is valuable and safe in appropriately selected patients. This report includes recommendations on standardization of this procedure and prioritizes the reporting of sample management to produce more reproducible results between laboratories. This document serves as a resource to the community of researchers who endeavor to include bronchoscopy as part of their research protocols and highlights key considerations for the inclusion and safety of research participants.
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Broncoscopía , Enfermedad Crítica , Humanos , Lavado Broncoalveolar , Dimercaprol , Selección de PacienteRESUMEN
Rationale: In patients with pneumonia requiring intensive care unit (ICU) admission, alcohol misuse is associated with increased mortality, but the relationship between other commonly misused substances and mortality is unknown. Objectives: We sought to establish whether alcohol misuse, cannabis misuse, opioid misuse, stimulant misuse, or misuse of more than one of these substances was associated with differences in mortality among ICU patients with pneumonia. Methods: This was a retrospective cohort study of hospitals participating in the Premier Healthcare Database between 2010 and 2017. Patients were included if they had a primary or secondary diagnosis of pneumonia and received antibiotics or antivirals within 1 day of admission. Substance misuse related to alcohol, cannabis, stimulants, and opioids, or more than one substance, were identified from the International Classification of Diseases (Ninth and Tenth Editions). The associations between substance misuse and in-hospital mortality were the primary outcomes of interest. Secondary outcomes included the measured associations between substance misuse disorders and mechanical ventilation, as well as vasopressor and continuous paralytic administration. Analyses were conducted with multivariable mixed-effects logistic regression modeling adjusting for age, comorbidities, and hospital characteristics. Results: A total of 167,095 ICU patients met inclusion criteria for pneumonia. Misuse of alcohol was present in 5.0%, cannabis misuse in 0.6%, opioid misuse in 1.5%, stimulant misuse in 0.6%, and misuse of more than one substance in 1.2%. No evidence of substance misuse was found in 91.1% of patients. In unadjusted analyses, alcohol misuse was associated with increased in-hospital mortality (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.19), whereas opioid misuse was associated with decreased in-hospital mortality (OR, 0.46; 95% CI, 0.39-0.53) compared with no substance misuse. These findings persisted in adjusted analyses. Although cannabis, stimulant, and more than one substance misuse (a majority of which were alcohol in combination with another substance) were associated with lower odds for in-hospital mortality in unadjusted analyses, these relationships were not consistently present after adjustment. Conclusions: In this study of ICU patients hospitalized with severe pneumonia, substance misuse subtypes were associated with different effects on mortality. Although administrative data can provide epidemiologic insight regarding substance misuse and pneumonia outcomes, biases inherent to these data should be considered when interpreting results.
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Alcoholismo , Trastornos Relacionados con Opioides , Neumonía , Humanos , Alcoholismo/epidemiología , Estudios Retrospectivos , Hospitalización , Neumonía/epidemiologíaRESUMEN
Burn-injured patients with alcohol use disorder (AUD) have increased morbidity and mortality compared to alcohol-abstaining individuals with similar injuries. It is hypothesized that this is due, in part, to alcohol-induced dysregulation of the systemic inflammatory response, leading to worsened clinical outcomes, including increased susceptibility to infection, and heightened cognitive impairment. To examine the effects of alcohol on inflammatory markers after burn injury, we used multiplex assays to measure a panel of 48 cytokines, chemokines, and growth factors in the plasma of burn patents within 24 h of admission to the University of Colorado Burn Center. Thirty patients were enrolled between July 2018 to February 2020 and were stratified based on presence of AUD and total body surface area (TBSA) burn of ≥20% into four groups: [AUD-, TBSA <20%, N = 12], [AUD+, TBSA <20%, N = 3], [AUD-, TBSA ≥20%, N = 8], [AUD+, TBSA ≥20%, N = 7]. In addition, Confusion Assessment Method (CAM) scores were collected to evaluate patient delirium during the course of hospitalization. Multivariate statistical analysis demonstrated a number of cytokines and other factors that were significantly different between the groups. For example, the anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1ra) was dampened in the AUD+, TBSA ≥20% cohort with a 75.2% decrease compared to AUD-, TBSA ≥20%, and an 83.9% decrease compared to AUD-, TBSA <20% (p = 0.008). Additionally, plasma levels of the pro-inflammatory mediator CXCL12 (C-X-C motif chemokine ligand 12, also known as stromal cell-derived factor 1, SDF-1) was higher in the AUD + groups (p = 0.03) and similarly, IL-18 levels were greater in AUD+, TBSA ≥20% (p = 0.009). Eotaxin (also known as cytokine CC motif ligand 11, CCL11) was markedly elevated in the AUD+, TBSA ≥20% cohort with a 2.4-fold increase over the AUD-, TBSA ≥20%, and a 1.7-fold rise compared to the AUD-, TBSA <20% cohorts (p = 0.04). Interestingly, there was also a marked rise in CAM + delirium scores (85.7%) among the AUD + patients with TBSA ≥20% (p = 0.02). Not surprisingly, we found that hospital stays increased with AUD+ and larger burns (p = 0.0009). Our findings reveal that burn patients who misuse alcohol have aberrant inflammatory responses that may lead to greater immune dysregulation and worse clinical outcomes.
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Alcoholismo , Delirio , Humanos , Ligandos , Citocinas , Análisis Multivariante , Cognición , Estudios RetrospectivosRESUMEN
Alcohol misuse has been associated with increased morbidity in the setting of pulmonary infections, including the need for critical care resource utilization and development of delirium. How alcohol misuse impacts morbidity and outcomes among patients admitted with COVID-19 pneumonia is not well described. We sought to determine if alcohol misuse was associated with an increased need for critical care resources and development of delirium among patients hospitalized with COVID-19 pneumonia. DESIGN: Retrospective cohort study. SETTING: Twelve University of Colorado hospitals between March 2020 and April 2021. PATIENTS: Adults with a COVID-19 diagnosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was admission to the ICU. Secondary outcomes included need for mechanical ventilation, development of delirium, and in-hospital mortality. Alcohol misuse was defined by International Classification of Diseases, 10th Revision codes. Of 5,979 patients hospitalized with COVID-19, 26% required ICU admission and 15.4% required mechanical ventilation. Delirium developed in 4.5% and 10.5% died during hospitalization. Alcohol misuse was identified in 4%. In analyses adjusted for age, sex, body mass index, diabetes, and liver disease, alcohol misuse was associated with increased odds of ICU admission (adjusted odds ratio [aOR], 1.46; p < 0.01), mechanical ventilation (aOR, 1.43; p = 0.03), and delirium (aOR, 5.55; p < 0.01) compared with patients without misuse. Mortality rates were not associated with alcohol misuse alone, although the presence of both alcohol misuse and in-hospital delirium significantly increased odds of in-hospital death (aOR, 2.60; p = 0.04). CONCLUSIONS: Among patients hospitalized with COVID-19, alcohol misuse was associated with increased utilization of critical care resources including ICU admission and mechanical ventilation. Delirium was an important modifiable risk factor associated with worse outcomes in hospitalized patients with alcohol misuse, including increased odds of death.
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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.
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Cardiología , Docentes Médicos , Humanos , Femenino , Estados Unidos/epidemiología , Masculino , Estudios Transversales , Oncología Médica , Liderazgo , BecasRESUMEN
BACKGROUND: Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed. RESEARCH QUESTION: Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care? STUDY DESIGN AND METHODS: This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age < 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs. RESULTS: The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P < .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation. INTERPRETATION: ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials.
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Asma , COVID-19 , Oxigenación por Membrana Extracorpórea , Insuficiencia Respiratoria , Humanos , Adolescente , Estudios Retrospectivos , Asma/complicaciones , Asma/terapia , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Resultado del TratamientoRESUMEN
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.
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Agotamiento Profesional , COVID-19 , Médicos , Adulto , Masculino , Humanos , Niño , Estados Unidos/epidemiología , Femenino , Estudios Transversales , Pandemias , Agotamiento Profesional/epidemiología , Unidades de Cuidados Intensivos , Adaptación Psicológica , Encuestas y Cuestionarios , América del NorteRESUMEN
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.
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Alcoholismo , Trastornos Relacionados con Opioides , Adulto , Alcoholismo/tratamiento farmacológico , Alcoholismo/epidemiología , Colorado/epidemiología , Atención a la Salud , Etanol/uso terapéutico , Femenino , Humanos , Naltrexona/uso terapéuticoRESUMEN
INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04488081.
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COVID-19 , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Teorema de Bayes , Humanos , Pandemias , SARS-CoV-2 , Resultado del TratamientoRESUMEN
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.
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Lesión Pulmonar Aguda , Fibrosis Pulmonar , Proteínas Tirosina Fosfatasas Clase 4 Similares a Receptores , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Pulmón/metabolismo , Ratones , Monoéster Fosfórico Hidrolasas/metabolismo , Fibrosis Pulmonar/patología , Proteínas Tirosina Fosfatasas Clase 4 Similares a Receptores/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
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.
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Fibrosis Pulmonar Idiopática , Bleomicina/toxicidad , Cilios/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Fibrosis Pulmonar Idiopática/patología , Transducción de SeñalRESUMEN
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.
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Alcoholismo , COVID-19 , Adulto , Alcoholismo/epidemiología , Hospitalización , Humanos , Estudios Retrospectivos , SARS-CoV-2Asunto(s)
Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Cannabis/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Uso de la Marihuana/patología , Líquido del Lavado Bronquioalveolar/química , Estudios de Casos y Controles , Humanos , Uso de la Marihuana/genética , Uso de la Marihuana/inmunología , Uso de la Marihuana/metabolismo , RNA-SeqRESUMEN
Clinical studies have demonstrated that age 50 years or older is an independent risk factor associated with poor prognosis after burn injury, the second leading cause of traumatic injuries in the aged population. While mechanisms driving age-dependent postburn mortality are perplexing, changes in the intestinal microbiome, may contribute to the heightened, dysregulated systemic response seen in aging burn patients. The fecal microbiome from 22 patients admitted to a verified burn center from July 2018 to February 2019 was stratified based on the age of 50 years and total burn surface area (TBSA) size of ≥10%. Significant differences (P = .014) in overall microbiota community composition (ie, beta diversity) were measured across the four patient groups: young <10% TBSA, young ≥10% TBSA, older <10% TBSA, and older ≥10% TBSA. Differences in beta diversity were driven by %TBSA (P = .013) and trended with age (P = .087). Alpha diversity components, richness, evenness, and Shannon diversity were measured. We observed significant differences in bacterial species evenness (P = .0023) and Shannon diversity (P = .0033) between the groups. There were significant correlations between individual bacterial species and levels of short-chain fatty acids. Specifically, levels of fecal butyrate correlated with the presence of Enterobacteriaceae, an opportunistic gut pathogen, when elevated in burn patients lead to worsen outcomes. Overall, our findings reveal that age-specific changes in the fecal microbiome following burn injuries may contribute to immune system dysregulation in patients with varying TBSA burns and potentially lead to worsened clinical outcomes with heightened morbidity and mortality.
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Quemaduras , Disbiosis , Anciano , Superficie Corporal , Unidades de Quemados , Quemaduras/complicaciones , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
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.
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Choque Séptico , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Norepinefrina/uso terapéutico , Estudios Retrospectivos , Vasoconstrictores/uso terapéutico , Vasopresinas/uso terapéuticoRESUMEN
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.