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.

Recent advances in the use of high flow nasal oxygen therapies.

High flow nasal oxygen is a relatively new option for treating patients with respiratory failure, which decreases work of breathing, improves tidal volume, and modestly increases positive end expiratory pressure. Despite well-described physiologic benefits, the clinical impact of high flow nasal oxygen is still under investigation. In this article, we review the most recent findings on the clinical efficacy of high flow nasal oxygen in Type I, II, III, and IV respiratory failure within adult and pediatric patients. Additionally, we discuss studies across clinical settings, including emergency departments, intensive care units, outpatient, and procedural settings.

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.

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.

A Cross-sectional Study of Hospital Performance on ICU Utilization Practices for Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: Intensive care unit (ICU) resources are a costly but effective commodity used in the management of critically ill patients with chronic obstructive pulmonary disease (COPD). ICU admission decisions are determined by patient diagnosis and severity of illness, but also may be affected by hospital differences in quality and performance. We investigate the variability in ICU utilization for patients with COPD and its association with hospital characteristics. METHODS: Using a 3M administrative dataset spanning 2008-2013, we conducted a retrospective cohort study of adult patients discharged with COPD at hospitals in three state to determine variability in ICU utilization. Quality metrics were calculated for each hospital using observed-to-expected (O/E) ratios for overall mortality and length of stay. Logistic and multilevel multivariate regression models were constructed, estimating the association between hospital quality metrics on ICU utilization, after adjustment for available clinical factors and hospital characteristics. RESULTS: In 434 hospitals with 570,517 COPD patient visits, overall ICU admission rate was 33.1% [range 0-89%; median (IQR) 24% (8, 54)]. The addition of patient, hospital, and quality characteristics decreased the overall variability attributable to individual hospital differences seen within our cohort from 40.9 to 33%. Odds of ICU utilization were increased for larger hospitals and those seeing lower pulmonary case volume. Hospitals with better overall O/E ratios for length of stay or mortality had lower ICU utilization. CONCLUSIONS: Hospital characteristics, including quality metrics, are associated with variability in ICU utilization for COPD patients, with higher ICU utilization seen for lower performing hospitals.

Noninvasive Ventilation for Critically Ill Subjects With Acute Respiratory Failure in the Emergency Department.

BACKGROUND: We aimed to investigate the association between noninvasive ventilation (NIV) initiated in the emergency department and patient outcomes for those requiring invasive mechanical ventilation so that we could understand the effect of extended NIV use (ie, > 4 h) prior to invasive mechanical ventilation on patient outcomes. METHODS: We conducted a retrospective single-center cohort study at an academic tertiary care hospital center. All emergency department patients with acute respiratory failure requiring invasive mechanical ventilation and admission to the ICU within 48 h of initial presentation over a 24-month period were included. RESULTS: Subject characteristics, ventilator parameters, and clinical course were captured via electronic query, respiratory billing data, and standardized chart abstraction. A total of 431 subjects with acute respiratory failure requiring invasive mechanical ventilation within 48 h of arrival were identified, of whom 115 (26.7%) were exposed to NIV prior to invasive mechanical ventilation, with a median duration of 4 h (interquartile range 1.9-9.3). Based on a multivariable model controlling for covariates, any NIV exposure prior to invasive mechanical ventilation was not associated with an increased odds of persistent organ dysfunction or death. However, in the subset of subjects exposed to NIV, extended NIV use (ie, > 4 h) prior to invasive mechanical ventilation was associated with increased odds of persistent organ dysfunction or death (odds ratio 4.11, 95% CI 1.51-11.19). Extended NIV use was also associated with increased odds of in-hospital mortality (odds ratio 4.02, 95% CI 1.51-10.74). CONCLUSIONS: Although any exposure to NIV prior to invasive mechanical ventilation did not appear to affect morbidity and mortality, extended NIV use prior to invasive mechanical ventilation was associated with worse patient outcomes, suggesting a need for additional study to better understand the ramifications of duration of NIV use prior to failure on outcomes. Given this early timeframe for intervention, future studies should be collaborations between the emergency department and ICU.