Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant.

INTRODUCTION: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 µg [medium-strength BDP]; Study 2: 200/6/12.5 µg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %. RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies. CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Impact of ICU strain on outcomes.

PURPOSE OF REVIEW: Acute surge events result in health capacity strain, which can result in deviations from normal care, activation of contingencies and decisions related to resource allocation. This review discusses the impact of health capacity strain on patient centered outcomes. RECENT FINDINGS: This manuscript discusses the lack of validated metrics for ICU strain capacity and a need for understanding the complex interrelationships of strain with patient outcomes. Recent work through the coronavirus disease 2019 pandemic has shown that acute surge events are associated with significant increase in hospital mortality. Though causal data on the differential impact of surge actions and resource availability on patient outcomes remains limited the overall signal consistently highlights the link between ICU strain and critical care outcomes in both normal and surge conditions. SUMMARY: An understanding of ICU strain is fundamental to the appropriate clinical care for critically ill patients. Accounting for stain on outcomes in critically ill patients allows for minimization of variation in care and an ability of a given healthcare system to provide equitable, and quality care even in surge scenarios.

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.

Predictors of Respiratory Support Use in Emergency Department Patients With COVID-19-Related Respiratory Failure.

BACKGROUND: Given the known downstream implications of choice of respiratory support on patient outcomes, all factors influencing these decisions, even those not limited to the patient, warrant close consideration. We examined the effect of emergency department (ED)-specific system factors, such as work load and census, on the use of noninvasive versus invasive respiratory support. METHODS: We conducted a multi-center retrospective cohort study of all adult subjects with severe COVID-19 requiring an ICU admission from 5 EDs within a single urban health care system. Subject demographics, severity of illness, and the type of respiratory support used were obtained. Using continuous measures of ED census, boarding, and active management, we estimated ED work load for each subjects' ED stay. The subjects were categorized by type(s) of respiratory support used: low-flow oxygen, noninvasive respiratory support (eg, noninvasive ventilation [NIV] and/or high-flow nasal cannula [HFNC]), invasive mechanical ventilation, or invasive mechanical ventilation after trial of NIV/HFNC. We used multivariable logistic regression to examine system factors associated with the type of respiratory support used in the ED. RESULTS: A total of 634 subjects were included. Of these, 431 (70.0%) were managed on low-flow oxygen alone, 108 (17.0%) on NIV/HFNC, 54 (8.5%) on invasive mechanical ventilation directly, and 41 (6.5%) on NIV/HFNC prior to invasive mechanical ventilation in the ED. Higher severity of illness and underlying lung disease increased the odds of requiring invasive mechanical ventilation compared to low-flow oxygen (odds ratio 1.05 [95% CI 1.03-1.07] and odds ratio 3.47 [95% CI 1.37-8.78], respectively). Older age decreased odds of being on invasive mechanical ventilation compared to low-flow oxygen (odds ratio 0.96 [95% CI 0.94-0.99]). As ED work load increased, the odds for subjects to be managed initially with NIV/HFNC prior to invasive mechanical ventilation increased 6-8-fold. CONCLUSIONS: High ED work load was associated with higher odds on HFNC/NIV prior to invasive mechanical ventilation.

The Influence of the COVID-19 Pandemic on Intensivists' Well-Being: A Qualitative Study.

BACKGROUND: The COVID-19 pandemic has strained health care systems and has resulted in widespread critical care staffing shortages, negatively impacting the quality of care delivered. RESEARCH QUESTION: How have hospitals' emergency responses to the pandemic influenced the well-being of frontline intensivists, and do any potential strategies exist to improve their well-being and to help preserve the critical care workforce? STUDY DESIGN AND METHODS: We conducted semistructured interviews of intensivists at clusters of tertiary and community hospitals located in six regions across the United States between August and November 2020 using the "four S" framework of acute surge planning (ie, space, staff, stuff, and system) to organize the interview guide. We then used inductive thematic analysis to identify themes describing the influence of hospitals' emergency responses on intensivists' well-being. RESULTS: Thirty-three intensivists from seven tertiary and six community hospitals participated. Intensivists reported experiencing substantial moral distress, particularly because of restricted visitor policies and their perceived negative impacts on patients, families, and staff. Intensivists also frequently reported burnout symptoms as a result of their experiences with patient death, exhaustion over the pandemic's duration, and perceived lack of support from colleagues and hospitals. We identified several potentially modifiable factors perceived to improve morale, including the proactive provision of mental health resources, establishment of formal backup schedules for physicians, and clear actions demonstrating that clinicians are valued by their institutions. INTERPRETATION: Restrictive visitation policies contributed to moral distress as reported by intensivists, highlighting the need to reconsider the risks and benefits of these policies. We also identified several interventions as perceived by intensivists that may help to mitigate moral distress and to improve burnout as part of efforts to preserve the critical care workforce.

Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

Effects of Timing of Invasive Mechanical Ventilation in Patients with Shock. An Analysis of the Multicenter Prospective Observational VOLUME-CHASERS Cohort.

Objectives: Describe the variation in practice and identify predictors of invasive mechanical ventilation (IMV) use in shock. Explore the association between the timing of IMV initiation ("Early" vs. "Delayed") on shock duration. Design: Multicenter, prospective, observational cohort study between September 2017 and February 2018 Setting: 34 hospitals in the United States and Jordan. Patients: Consecutive, adult, critically ill patients with shock, defined as a systolic blood pressure less than or equal to 90mm Hg, mean arterial pressure less than or equal to 65mm Hg, or need for a vasopressor medication. Interventions: None. Measurements and Main Results: "Early" IMV was defined as starting IMV 0-6 hours of shock onset and "Delayed" IMV was defined as starting IMV between 6 and 48 hours of shock onset. The primary outcome was shock-free days, defined as the number of days without shock after the first 48 hours of shock onset. Variation and predictors of IMV use were examined within the whole cohort as well as the subgroup of those intubated within 0-48 hours of shock onset. Mixed effects modeling with hospital site as a random effect showed that there was 7% variation by site in the use and timing of IMV in this shock cohort. In a propensity-matched model for the timing of IMV, "Early" IMV after shock onset was associated with more shock-free days when compared to "Delayed" IMV in those intubated within 0-48 hours of shock onset (Beta coefficient 0.65 days, 95% CI 0.14-1.16 days). Conclusions: Timing of IMV initiation for patients in shock has potentially important implications for patient outcomes and merits further study.

Predictors of Delayed Recognition of Critical Illness in Emergency Department Patients and Its Effect on Morbidity and Mortality.

PURPOSE: Timely recognition of critical illness is associated with improved outcomes, but is dependent on accurate triage, which is affected by system factors such as workload and staffing. We sought to first study the effect of delayed recognition on patient outcomes after controlling for system factors and then to identify potential predictors of delayed recognition. METHODS: We conducted a retrospective cohort study of Emergency Department (ED) patients admitted to the Intensive Care Unit (ICU) directly from the ED or within 48 hours of ED departure. Cohort characteristics were obtained through electronic and standardized chart abstraction. Operational metrics to estimate ED workload and volume using census data were matched to patients' ED stays. Delayed recognition of critical illness was defined as an absence of an ICU consult in the ED or declination of ICU admission by the ICU team. We employed entropy-balanced multivariate models to examine the association between delayed recognition and development of persistent organ dysfunction and/or death by hospitalization day 28 (POD+D), and multivariable regression modeling to identify factors associated with delayed recognition. RESULTS: Increased POD+D was seen for those with delayed recognition (OR 1.82, 95% CI 1.13-2.92). When the delayed recognition was by the ICU team, the patient was 2.61 times more likely to experience POD+D compared to those for whom an ICU consult was requested and were accepted for admission. Lower initial severity of illness score (OR 0.26, 95% CI 0.12-0.53) was predictive of delayed recognition. The odds for delayed recognition decreased when ED workload is higher (OR 0.45, 95% CI 0.23-0.89) compared to times with lower ED workload. CONCLUSIONS: Increased POD+D is associated with delayed recognition. Patient and system factors such as severity of illness and ED workload influence the odds of delayed recognition of critical illness and need further exploration.

Characteristics and Outcomes of US Patients Hospitalized With COVID-19.

BACKGROUND: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation. OBJECTIVE: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic. METHODS: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020. RESULTS: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services. CONCLUSIONS: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.

The Influence of the COVID-19 Pandemic on ICU Organization, Care Processes, and Frontline Clinician Experiences: A Qualitative Study.

BACKGROUND: The COVID-19 pandemic resulted in unprecedented adjustments to ICU organization and care processes globally. RESEARCH QUESTIONS: Did hospital emergency responses to the COVID-19 pandemic differ depending on hospital setting? Which strategies worked well to mitigate strain as perceived by intensivists? STUDY DESIGN AND METHODS: Between August and November 2020, we carried out semistructured interviews of intensivists from tertiary and community hospitals across six regions in the United States that experienced early or large surges of COVID-19 patients, or both. We identified themes of hospital emergency responses using the four S framework of acute surge planning: space, staff, stuff, system. RESULTS: Thirty-three intensivists from seven tertiary and six community hospitals participated. Clinicians across both settings believed that canceling elective surgeries was helpful to increase ICU capabilities and that hospitals should establish clearly defined thresholds at which surgeries are limited during future surge events. ICU staff was the most limited resource; staff shortages were improved by the use of tiered staffing models, just-in-time training for non-ICU clinicians, designated treatment teams, and deployment of trainees. Personal protective equipment (PPE) shortages and reuse were widespread, causing substantial distress among clinicians; hands-on PPE training was helpful to reduce clinicians' anxiety. Transparency and involvement of frontline clinicians as stakeholders were important components of effective emergency responses and helped to maintain trust among staff. INTERPRETATION: We identified several strategies potentially to mitigate strain as perceived by intensivists working in both tertiary and community hospital settings. Our study also demonstrated the importance of trust and transparency between frontline staff and hospital leadership as key components of effective emergency responses during public health crises.

Variation in Initial U.S. Hospital Responses to the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: The coronavirus disease 2019 pandemic has strained many healthcare systems. In response, U.S. hospitals altered their care delivery systems, but there are few data regarding specific structural changes. Understanding these changes is important to guide interpretation of outcomes and inform pandemic preparedness. We sought to characterize emergency responses across hospitals in the United States over time and in the context of local case rates early in the coronavirus disease 2019 pandemic. DESIGN: We surveyed hospitals from a national acute care trials group regarding operational and structural changes made in response to the coronavirus disease 2019 pandemic from January to August 2020. We collected prepandemic characteristics and changes to hospital system, space, staffing, and equipment during the pandemic. We compared the timing of these changes with county-level coronavirus disease 2019 case rates. SETTING AND PARTICIPANTS: U.S. hospitals participating in the Prevention and Early Treatment of Acute Lung Injury Network Coronavirus Disease 2019 Observational study. Site investigators at each hospital collected local data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-five sites participated (94% response rate). System-level changes (incident command activation and elective procedure cancellation) occurred at nearly all sites, preceding rises in local case rates. The peak inpatient census during the pandemic was greater than the prior hospital bed capacity in 57% of sites with notable regional variation. Nearly half (49%) expanded ward capacity, and 63% expanded ICU capacity, with nearly all bed expansion achieved through repurposing of clinical spaces. Two-thirds of sites adapted staffing to care for patients with coronavirus disease 2019, with 48% implementing tiered staffing models, 49% adding temporary physicians, nurses, or respiratory therapists, and 30% changing the ratios of physicians or nurses to patients. CONCLUSIONS: The coronavirus disease 2019 pandemic prompted widespread system-level changes, but front-line clinical care varied widely according to specific hospital needs and infrastructure. Linking operational changes to care delivery processes is a necessary step to understand the impact of the coronavirus disease 2019 pandemic on patient outcomes.

The Intersection of Work and Home Challenges Faced by Physician Mothers During the Coronavirus Disease 2019 Pandemic: A Mixed-Methods Analysis.

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has presented extreme challenges for health care workers. This study sought to characterize challenges faced by physician mothers, compare differences in challenges by home and work characteristics, and elicit specific needs and potential solutions. Methods: We conducted a mixed-methods online survey of the Physician Moms Group (PMG) and PMG COVID19 Subgroup on Facebook from April 18th to 29th, 2020. We collected structured data on personal and professional characteristics and qualitative data on home and work concerns. We analyzed qualitative data thematically and used bivariate analyses to evaluate variation in themes by frontline status and children's ages. Results: We included 1,806 participants in analysis and identified 10 key themes. The most frequently identified need/solution was for Community and Government Support (n = 545, 47.1%). When comparing frontline and nonfrontline physicians, those on the frontline more frequently raised concerns about Personal Health and Safety (67.8% vs. 48.4%, p < 0.001), Organizational Communication and Relationships (31.8% vs. 23.8%, p < 0.001), and Family Health and Safety (27.2 vs. 16.6, p < 0.001), while nonfrontline physicians more frequently addressed Patient Care and Safety (56.4% vs. 48.2%, p < 0.001) and Financial/Job Security (33.8% vs. 46.9%, p < 0.001). Participants with an elementary school-aged child more frequently raised concerns about Parenting/Homeschooling (44.0% vs. 31.1%, p < 0.001) and Work/Life Balance (28.4 vs. 13.7, p < 0.001), and participants with a preschool-aged child more frequently addressed Access to Childcare (24.0 vs. 7.7, p < 0.001) and Spouse/Partner Relationships (15.8 vs. 9.5, p < 0.001), when compared to those without children in these age groups. Conclusions: The physician workforce is not homogenous. Health care and government leaders need to understand these diverse challenges in order to meet physicians' professional and family needs during the pandemic.

Cardiovascular Disease and Severe Hypoxemia Are Associated With Higher Rates of Noninvasive Respiratory Support Failure in Coronavirus Disease 2019 Pneumonia.

Acute hypoxemic respiratory failure is the major complication of coronavirus disease 2019, yet optimal respiratory support strategies are uncertain. We aimed to describe outcomes with high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation in coronavirus disease 2019 acute hypoxemic respiratory failure and identify individual factors associated with noninvasive respiratory support failure. DESIGN: Retrospective cohort study to describe rates of high-flow oxygen delivered through nasal cannula and/or noninvasive positive pressure ventilation success (live discharge without endotracheal intubation). Fine-Gray subdistribution hazard models were used to identify patient characteristics associated with high-flow oxygen delivered through nasal cannula and/or noninvasive positive pressure ventilation failure (endotracheal intubation and/or in-hospital mortality). SETTING: One large academic health system, including five hospitals (one quaternary referral center, a tertiary hospital, and three community hospitals), in New York City. PATIENTS: All hospitalized adults 18-100 years old with coronavirus disease 2019 admitted between March 1, 2020, and April 28, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 331 and 747 patients received high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation as the highest level of noninvasive respiratory support, respectively; 154 (46.5%) in the high-flow oxygen delivered through nasal cannula cohort and 167 (22.4%) in the noninvasive positive pressure ventilation cohort were successfully discharged without requiring endotracheal intubation. In adjusted models, significantly increased risk of high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation failure was seen among patients with cardiovascular disease (subdistribution hazard ratio, 1.82; 95% CI, 1.17-2.83 and subdistribution hazard ratio, 1.40; 95% CI, 1.06-1.84, respectively). Conversely, a higher peripheral blood oxygen saturation to Fio2 ratio at high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation initiation was associated with reduced risk of failure (subdistribution hazard ratio, 0.32; 95% CI, 0.19-0.54, and subdistribution hazard ratio 0.34; 95% CI, 0.21-0.55, respectively). CONCLUSIONS: A significant proportion of patients receiving noninvasive respiratory modalities for coronavirus disease 2019 acute hypoxemic respiratory failure achieved successful hospital discharge without requiring endotracheal intubation, with lower success rates among those with comorbid cardiovascular disease or more severe hypoxemia. The role of high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation in coronavirus disease 2019-related acute hypoxemic respiratory failure warrants further consideration.

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19.

OBJECTIVE: To explore the relationship between hyperglycemia in the presence and absence of diabetes mellitus (DM) and adverse outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: The study included 133 patients with COVID-19 admitted to an intensive care unit (ICU) at an urban academic quaternary-care center between March 10 and April 8, 2020. Patients were categorized based on the presence or absence of DM and early-onset hyperglycemia (EHG), defined as a blood glucose >180 mg/dL during the first 2 days after ICU admission. The primary outcome was 14-day all-cause in-hospital mortality; also examined were 60-day all-cause in-hospital mortality and the levels of C-reactive protein, interleukin 6, procalcitonin, and lactate. RESULTS: Compared to non-DM patients without EHG, non-DM patients with EHG exhibited higher adjusted hazard ratios (HRs) for mortality at 14 days (HR 7.51, CI 1.70-33.24) and 60 days (HR 6.97, CI 1.86-26.13). Non-DM patients with EHG also featured higher levels of median C-reactive protein (306.3 mg/L, P = .036), procalcitonin (1.26 ng/mL, P = .028), and lactate (2.2 mmol/L, P = .023). CONCLUSION: Among critically ill COVID-19 patients, those without DM with EHG were at greatest risk of 14-day and 60-day in-hospital mortality. Our study was limited by its retrospective design and relatively small cohort. However, our results suggest the combination of elevated glucose and lactate may identify a specific cohort of individuals at high risk for mortality from COVID-19. Glucose testing and control are important in individuals with COVID-19, even those without preexisting diabetes.

Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure.

OBJECTIVES: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure. DESIGN: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of Pao2 over the corresponding Fio2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. SETTING: ICUs at 68 U.S. sites. PATIENTS: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of Pao2 over the corresponding Fio2 less than or equal to 200 mm Hg. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97). CONCLUSIONS: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.

PURPOSE: Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). METHODS: We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO2/FiO2 < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model. RESULTS: Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO2/FiO2 prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO2/FiO2 < 80 (HR 0.55; 95% CI 0.40-0.77). CONCLUSION: In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality.