Anti-gm-csf monoclonal antibody gimsilumab improved ventilator-free survival, decreased hospitalization length, and prevented nt-probnp rise in invasively ventilated patients with hyperinflammatory covid19 pneumonia: A subgroup analysis from the breathe trial suggests neurohormonal role for gm-csf inhibition

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myeloid cell growth factor and pro-inflammatory cytokine, may drive the overactive host immune response in COVID-19. We conducted a clinical trial assessing the anti-GM-CSF monoclonal antibody gimsilumab for hyperinflammatory COVID-19 pneumonia (BREATHE). Here, we report a pre-specified subgroup analysis demonstrating a signal of benefit in patients invasively ventilated at baseline. Methods: BREATHE (NCT04351243) was a double-blind, randomized, placebo-controlled trial at 21 US locations. Patients were randomized 1:1 to receive two doses of IV gimsilumab or placebo one week apart. The study included hospitalized COVID-19 patients with hyperinflammation (CRP ≥50 mg/L or ferritin ≥1,000 ng/mL) and pre-ARDS lung injury or ARDS. The primary endpoint was all cause mortality at day 43, and key secondary outcomes assessed ventilator use and hospitalization length. Results: 225 patients were randomized and dosed. 41 patients were invasively ventilated at baseline. Steroid use and baseline characteristics were generally balanced across study arms in this subgroup. Ventilated patients treated with gimsilumab demonstrated improvements over placebo on the primary and key secondary endpoints (Table 1). Contrasting the placebo group, gimsilumabtreated patients did not experience a sharp rise in NT-proBNP, a marker of heart failure, through day 43 (Figure 1). Conclusions: GM-CSF inhibition may be therapeutic in ventilated COVID-19 patients through a neurohormonal mechanism. More studies are needed to assess the role of GM-CSF in COVID-19-associated cardiomyopathy, volume status, and ARDS.

Emergency Department Management and Outcomes of COVID-19 Acute Hypoxemic Respiratory Failure During the New York City Surge

Study Objectives: Delays in intensive care unit (ICU) admission for critically ill patients are associated with worse outcomes, but the effect of “boarding” during the COVID-19 pandemic has not been well characterized. This study describes the emergency department (ED)-based care for patients presenting with COVID-19-related acute hypoxemic respiratory failure (AHRF) to five hospitals in a large, academic health system during the initial surge in New York City, examining both respiratory modality choice and settings. For those managed with noninvasive respiratory support, we also aimed to explore the association between ED boarding time and patient morbidity and mortality. Methods: We conducted a retrospective cohort study of ED patients presenting from 3/1/2020 to 7/10/2020 with COVID-19-related AHRF and requiring ICU admission at any time during their hospitalization. Patient demographics, comorbidities, severity of illness (Mortality Probability Model III on admission), clinical course, including the use, settings (initial and changes), and duration of respiratory support modalities (ie, noninvasive ventilation [NIV], high flow nasal cannula [HFNC], invasive mechanical ventilation [IMV]), as well as hospital site, were collected through validated electronic query and standardized manual chart abstraction. AHRF severity was defined using a PaO2/FiO2 ratio (PF): 200-300 (mild), 100-199 (moderate), and <100 (severe). For patients without a PaO2, the PF was imputed using SpO2/FiO2 ratio using previously validated non-linear conversion. Boarding was defined as the time interval from ED request for admission to ED departure. The primary outcome was a composite outcome of ICU admission, intubation, or mortality within 48 hours of ED arrival. Descriptive analyses stratified by boarding duration and AHRF were completed. Multivariable logistic regression modelling was used to determine the association between ED boarding and the primary outcome. Results: A total of 679 ED patients with COVID-19 AHRF required ICU admission during the study period. They were managed with low flow oxygen only (261, 38.4%), or with NIV (120, 17.7%), HF (51, 7.5%), and/or IMV (99, 14.6%), with setting ranges detailed in Table 1. Of the patients with a known PF ratio (N=418), 110 (26.35%) had mild, 34 (5.0%) had moderate, and 274 (40.4%) had severe AHRF. Of these patients, 279 (41.1%) had a change documented to their settings, with increased likelihood of adjustments with longer boarding time (p<0.001) and higher AHRF severity (p<0.001). Median boarding duration across all site was 9.5 hours (IQR 5.3-16.9 hours) with site variation. AHRF severity and support modality were not associated with differences of boarding time (p = 0.77 and p=0.54). Controlling for age, sex, race, and severity of illness, boarding time was not associated with worse patient outcomes in 48 hours (OR 0.85, 95% CI 0.67-1.08, p=0.17) Conclusion: During the COVID-19 pandemic, critically ill patients presented to the ED and boarded for long periods of time, requiring prolonged ventilatory management. Despite the surge state and resource limitations, boarding times did not worsen post-ED outcomes for patients managed with non-invasive modalities. [Formula presented]

Cardiovascular disease and severe hypoxemia are associated with higher rates of non-invasive respiratory support failure in COVID-19 pneumonia

RATIONALE Acute hypoxemic respiratory failure (AHRF) is the major complication of coronavirus disease 2019 (COVID-19), yet optimal respiratory support strategies are uncertain. We aimed to describe outcomes with highflow oxygen delivered through nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV) in COVID-19 AHRF and identify individual factors associated with non-invasive respiratory support failure. METHODS We conducted a retrospective cohort study of hospitalized adults with COVID-19 within a large academic health system in New York City early in the pandemic to describe outcomes with HFNC and NIPPV. Patients were categorized into the HFNC cohort if they received HFNC but not NIPPV, whereas the NIPPV cohort included patients who received NIPPV with or without HFNC. We described rates of HFNC and NIPPV success, defined as live discharge without endotracheal intubation (ETI). Further, using Fine-Gray sub-distribution hazard models, we identified demographic and patient characteristics associated with HFNC and NIPPV failure, defined as the need for ETI and/or in-hospital mortality. RESULTS Of the 331 patients in the HFNC cohort, 154 (46.5%) patients were successfully discharged without requiring ETI. Of the 177 (53.5%) who experienced HFNC failure, 100 (56.5%) required ETI and 135 (76.3%) patients ultimately died. Among the 747 patients in the NIPPV cohort, 167 (22.4%) patients were successfully discharged without requiring ETI, and 8 (1.1%) were censored. Of the 572 (76.6%) patients who failed NIPPV, 338 (59.1%) required ETI and 497 (86.9%) ultimately died. In adjusted models, significantly increased risk of HFNC and NIPPV failure was observed among patients with co-morbid cardiovascular disease (sub-distribution hazard ratio (sHR) 1.82;95% confidence interval (CI), 1.17-2.83 and sHR 1.40;95% CI 1.06-1.84, respectively). Conversely, a higher oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) at HFNC and NIPPV initiation was associated with reduced risk of failure (sHR, 0.32;95% CI 0.19-0.54, and sHR 0.34;95% CI 0.21-0.55, respectively). CONCLUSIONS A subset of patients with COVID-19 AHRF was effectively managed with non-invasive respiratory modalities and achieved successful hospital discharge without requiring ETI. Notably, patients with co-morbid cardiovascular disease and more severe hypoxemia experienced lower success rates with both HFNC and NIPPV. Identification of specific patient factors may help inform more selective use of non-invasive respiratory strategies, and allow for a more personalized approach to the management of COVID-19 AHRF in pandemic settings.

Predictors of pre-icu duration and its association with mortality in COVID-19 infection: A secondary analysis of the stop-covid registry

Rationale: High patient volume and limited ICU resources associated with the COVID-19 pandemic have exacerbated ICU capacity strain, leading to longer pre-ICU lengths-of-stay (LOS). We examined the patient- and hospital-level predictors of pre-ICU LOS, and the association of pre-ICU LOS on in-hospital mortality for patients with COVID-19. Methods: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID), a multicenter cohort study of critically ill adults with COVID-19 admitted to 68 US hospitals. All patients had a minimum of 28-day follow-up;those discharged from hospital were presumed alive. The primary outcome was pre-ICU LOS, dichotomized into brief (≤1 day) vs. prolonged (>1 day). We constructed a multivariate mixed effects model, adjusting for patient factors (e.g., demographics, comorbidities, and pre-hospital symptom duration) and hospital factors (pre-COVID ICU beds number, countylevel case rates of COVID-19 (number of cases per 100,000 residents), and the hospital site itself) to determine predictors of pre-ICU LOS. Using 1:3 propensity score matching for pre-ICU period, we used multivariate mixed effect modelling to examine the association between pre-ICU LOS and in-hospital mortality. Results: A total of 4738 patients with complete data were admitted to the ICU, 36.6% were female, with median age 62 years (IQR 52-71). The majority (85.5%) were admitted from the ED or wards, with 62.5% classified as having a brief pre- ICU LOS. While demographics and co-morbidities (cancer, diabetes, and end-stage renal disease) were not associated with pre-ICU LOS, pre-existing lung disease (OR 1.33, 95% CI 1.02-1.74) was a patient-level predictor of a brief pre-ICU LOS as compared to a prolonged LOS. Having more available ICU beds (>100 vs. 0-48 ICU beds, OR 1.41, 95% CI 1.03-1.92) was a hospital-level predictor of a brief pre-ICU LOS. More patients were intubated at the time of ICU arrival in the prolonged pre-ICU LOS group, compared to the brief LOS group (64.6% vs. 59.2%, p≤0.001). In the mixed model, propensity matched for pre-ICU LOS, and adjusted for patient/hospital characteristics, differential pre-ICU LOS was not predictive of in-hospital mortality (OR 1.22, 95%CI 0.81-1.87), though oxygen support modality was associated with mortality. Conclusion: Patient- and hospital-level factors, such as ICU capacity, had an impact on pre-ICU duration, with more patients requiring a higher level of oxygen support at ICU arrival if admitted later in their course. However, once adjusting for clinical and hospital factors, pre-ICU LOS was not associated with in-hospital mortality.