Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Monitoring the venous circulation: novel techniques and applications.

PURPOSE OF REVIEW: Venous pressure is an often-unrecognized cause of patient morbidity. However, bedside assessment of PV is challenging. We review the clinical significance of venous pressure measurement, existing techniques, and introduce the Venous Excess Ultrasound (VExUS) Score as a novel approach using doppler ultrasound to assess venous pressure. RECENT FINDINGS: Studies show clear associations between elevated venous pressure and adverse outcomes in critically ill patients. Current venous pressure measurement techniques include physical examination, right heart catheterization (RHC), two-dimensional ultrasound, and a variety of labor-intensive research-focused physiological maneuvers. Each of these techniques have specific shortcomings, limiting their clinical utility. To address these gaps, Beaubien-Souligny et al. introduced the VExUS Score, a novel doppler ultrasound-based method that integrates IVC diameter with doppler measurements of the hepatic, portal, and renal veins to generate a venous congestion assesment. Studies show strong correlations between VExUS score and RHC measurements, and well as an association between VExUS score and improvement in cardiorenal acute kidney injury, diuretic response, and fluid status shifts. However, studies in noncardiac populations have been small, heterogenous, and inconclusive. SUMMARY: Early studies evaluating the use of doppler ultrasound to assess venous congestion show promise, but further research is needed in diverse patient populations and clinical settings.

Dynamic monitoring tools for patients admitted to the emergency department with circulatory failure: narrative review with panel-based recommendations.

Intravenous fluid therapy is commonly administered in the emergency department (ED). Despite the deleterious potential of over- and under-resuscitation, professional society guidelines continue to recommend administering a fixed volume of fluid in initial resuscitation. Predicting whether a specific patient will respond to fluid therapy remains one of the most important, but challenging questions that ED clinicians face in clinical practice. Surrogate parameters (i.e. blood pressure and heart rate), are widely used in usual care to estimate changes in stroke volume (SV). Due to their inadequacy in estimating SV, noninvasive techniques (e.g. bioreactance, echocardiography, noninvasive finger cuff technology), have been proposed as a more accurate and readily deployable method for assessing flow and preload responsiveness. Dynamic monitoring systems based on cardiac preload challenge and assessment of SV, by using noninvasive and continuous methods, provide more accurate, feasible, efficient, and reasonably accurate strategy for prediction of fluid responsiveness than static measurements. In this article, we aimed to analyze the different methods currently available for dynamic monitoring of preload responsiveness.

Drivers of Decision-Making for Adult Tracheostomy for Prolonged Mechanical Ventilation: A Qualitative Study.

Background: Decision-making about tracheostomy and prolonged mechanical ventilation (PMV) is emotionally complex. Expectations of surrogate decision-makers and physicians rarely align. Little is known about what surrogates need to make goal-concordant decisions. We sought to identify drivers of tracheostomy and PMV decision-making. Methods: Using Grounded Theory, we performed a qualitative study with semi-structured interviews with surrogates of patients receiving mechanical ventilation (MV) being considered for tracheostomy and physicians routinely caring for patients receiving MV. Recruitment was stopped when thematic saturation was reached. Separate codebooks were created for surrogate and physician interviews. Themes and factors affecting decision-making were identified and a theoretical model tracheostomy decision-making was developed. Results: 43 participants (23 surrogates and 20 physicians) completed interviews. A theoretical model of themes and factors driving decision-making emerged for the data. Hope, Lack of Knowledge & Data, and Uncertainty emerged as the three main themes all which were interconnected with one another and, at times, opposed each other. Patient Wishes, Past Activity/Medical History, Short and Long-Term Outcomes, and Meaningful Recovery were key factors upon which surrogates and physicians based decision-making. The themes were the lens through which the factors were viewed and decision-making existed as a balance between surrogate emotions and understanding and physician recommendations. Conclusions: Tracheostomy and prolonged MV decision-making is complex. Hope and Uncertainty were conceptual themes that often battled with one another. Lack of Knowledge & Data plagued both surrogates and physicians. Multiple tangible factors were identified that affected surrogate decision-making and physician recommendations. Implications: Understanding this complex decision-making process has the potential to improve the information provided to surrogates and, potentially, increase the goal concordant care and alignment of surrogate and physician expectations. Highlights: Decision-making for tracheostomy and prolonged mechanical ventilation is a complex interactive process between surrogate decision-makers and providers.Using a Grounded Theory framework, a theoretical model emerged from the data with core themes of Hope, Uncertainty, and Lack of Knowledge & Data that was shared by both providers and surrogates.The core themes were the lenses through which the key decision-making factors of Patient Wishes, Past Activity/Medical History, Short and Long-Term Outcomes, and Meaningful Recovery were viewed.The theoretical model provides a roadmap to design a shared decision-making intervention to improve tracheostomy and prolonged mechanical ventilation decision-making.

Utilization of Hospital Do-Not-Resuscitate Orders in Older Adults During COVID-19 Surges in 2020.

Background: Reports of poor outcomes among older adults with COVID-19 may have changed patient perceptions of Do-Not-Resuscitate (DNR) orders or caused providers to pressure older adults into accepting DNR orders to conserve resources. Objective: We determined early-DNR utilization during COVID-19 surges compared with nonsurge periods among nonsurgical adults ≥75 and its connection to hospital mortality. Methods: We conducted a retrospective cohort study among adults ≥75 years using the California Patient Discharge Database 2020. The primary outcome was early-DNR utilization. Control cohorts included nonsurgical adults <75 years in 2020 and nonsurgical adults ≥75 in 2019. Multiple causal inference methods were used to address measured and unmeasured confounding. Results: A total of 487,955 adults ≥75 years were identified, with 233,678 admitted during COVID-19 surges. Older adults admitted during surges had higher rates of early-DNR orders (30.1% vs. 29.4%, absolute risk differences = 0.7, 95% confidence interval [CI]: 0.5-1.0) even after adjusting for patient case-mix (adjusted odds ratio [aOR] = 1.02, 95% CI: 1.01-1.04). Patients with early-DNR orders experienced higher hospital mortality (15.5% vs. 4.8%, aOR = 3.96, 95% CI: 3.85-4.06). Difference-in-difference analyses demonstrated that adults <75 years in 2020 and adults ≥75 years in 2019 did not experience variation in early-DNR utilization. Conclusions: Older adults had slightly higher rates of early-DNR orders during COVID-19 surges compared with nonsurge periods. While the difference in early-DNR utilization was small, it was linked to higher odds of death. The increase in early-DNR use only during COVID-19 surges and only among older adults may reflect changes in patient preferences or increased pressure on older adults stemming from provider fears of rationing during COVID-19 surges.

The Relationship Between Metabolic Syndrome and Mortality Among Patients With Acute Respiratory Distress Syndrome in Acute Respiratory Distress Syndrome Network and Prevention and Early Treatment of Acute Lung Injury Network Trials.

OBJECTIVES: Metabolic syndrome is known to predict outcomes in COVID-19 acute respiratory distress syndrome (ARDS) but has never been studied in non-COVID-19 ARDS. We therefore aimed to determine the association of metabolic syndrome with mortality among ARDS trial subjects. DESIGN: Retrospective cohort study of ARDS trials' data. SETTING: An ancillary analysis was conducted using data from seven ARDS Network and Prevention and Early Treatment of Acute Lung Injury Network randomized trials within the Biologic Specimen and Data Repository Information Coordinating Center database. PATIENTS: Hospitalized patients with ARDS and metabolic syndrome (defined by obesity, diabetes, and hypertension) were compared with similar patients without metabolic syndrome (those with less than three criteria). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day mortality. Among 4288 ARDS trial participants, 454 (10.6%) with metabolic syndrome were compared with 3834 controls (89.4%). In adjusted analyses, the metabolic syndrome group was associated with lower 28-day and 90-day mortality when compared with control (adjusted odds ratio [aOR], 0.70 [95% CI, 0.55-0.89] and 0.75 [95% CI, 0.60-0.95], respectively). With each additional metabolic criterion from 0 to 3, adjusted 28-day mortality was reduced by 18%, 22%, and 40%, respectively. In subgroup analyses stratifying by ARDS etiology, mortality was lower for metabolic syndrome vs. control in ARDS caused by sepsis or pneumonia (at 28 d, aOR 0.64 [95% CI, 0.48-0.84] and 90 d, aOR 0.69 [95% CI, 0.53-0.89]), but not in ARDS from noninfectious causes (at 28 d, aOR 1.18 [95% CI, 0.70-1.99] and 90 d, aOR 1.26 [95% CI, 0.77-2.06]). Interaction p = 0.04 and p = 0.02 for 28- and 90-day comparisons, respectively. CONCLUSIONS: Metabolic syndrome in ARDS was associated with a lower risk of mortality in non-COVID-19 ARDS. The relationship between metabolic inflammation and ARDS may provide a novel biological pathway to be explored in precision medicine-based trials.

Prospective Evaluation of Venous Excess Ultrasound for Estimation of Venous Congestion.

BACKGROUND: Venous excess ultrasound (VExUS) is a novel ultrasound technique previously reported as a noninvasive measure of venous congestion and predictor of cardiorenal acute kidney injury. RESEARCH QUESTION: Are there associations between VExUS grade and cardiac pressures measured by right heart catheterization (RHC) and cardiac biomarkers and clinical outcomes in patients undergoing RHC? STUDY DESIGN AND METHODS: We conducted a prospective cohort study at the Denver Health Medical Center from December 20, 2022, to March 25, 2023. All patients undergoing RHC underwent a blinded VExUS assessment prior to their procedure. Multivariable regressions were conducted to assess relationships between VExUS grade and cardiac pressures, biomarkers, and changes in weight among patients with heart failure, a proxy for diuretic success. Receiver operating characteristic curve and area under the curve (AUC) were derived for VExUS, inferior vena cava (IVC) diameter, and IVC collapsibility index (ICI) to predict right atrial pressure (RAP) > 10 and < 7 mm Hg. RESULTS: Among 81 patients, 45 of whom were inpatients, after adjusting for age, sex, and Charlson Comorbidity Index, there were significant relationships between VexUS grade of 2 (ß = 4.8; 95% CI, 2.6-7.1; P < .01) and 3 (ß = 11; 95% CI, 8.9-14; P < .01) and RAP, VExUS grade of 2 (ß = 6.8; 95% CI, 0.16-13; P = .045) and 3 (ß = 15; 95% CI, 7.3-22; P < .01) and mean pulmonary artery pressure, and VExUS grade of 2 (ß = 7.0; 95% CI, 3.9-10; P < .01) and 3 (ß = 13; 95% CI, 9.5-17; P < .01) and pulmonary capillary wedge pressure. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP > 10 mm Hg were 0.9 (95% CI, 0.83-0.97), 0.77 (95% CI, 0.68-0.88), and 0.65 (95% CI, 0.52-0.78), respectively. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP < 7 mm Hg were 0.79 (95% CI, 0.70-0.87), 0.74 (95% CI, 0.64-0.84), and 0.62 (95% CI, 0.49-0.76), respectively. In a subset of 23 patients with heart failure undergoing diuresis, there was a significant association between VExUS grade 3 and change in weight between time of RHC and discharge (P = .025). INTERPRETATION: Although more research is required, VExUS has the potential to increase diagnostic and therapeutic capabilities of physicians at the bedside and increase our understanding of the underappreciated problem of venous congestion.

Real-world Accuracy of CGM in Inpatient Critical and Noncritical Care Settings at a Safety-Net Hospital.

OBJECTIVE: We sought to determine real-world accuracy of inpatient continuous glucose monitoring (CGM) at multiple levels of acuity in a large safety-net hospital. RESEARCH DESIGN AND METHODS: We analyzed records from hospitalized patients on Dexcom G6 CGM, including clinical, point of care (POC), and laboratory (Lab) glucose, and CGM data. POC/Lab values were matched to the closest timed CGM value. Encounters were divided into not critically ill (NCI) versus critically ill (CI). CGM accuracy was evaluated. RESULTS: Paired readings (2,744 POC-CGM; 3,705 Lab-CGM) were analyzed for 233 patients with 239 encounters (83 NCI, 156 CI). POC-CGM aggregated and average mean absolute relative differences (MARD) were 15.1% and 17.1%. Lab-CGM aggregated and average MARDs were 11.4% and 12.2%. Accuracy for POC-CGM and Lab-CGM was 96.5% and 99.1% in Clarke Error Grid zones A/B. CONCLUSIONS: Real-world accuracy of inpatient CGM is acceptable for NCI and CI patients. Further exploration of conditions associated with lower CGM accuracy in real-world settings is warranted.

Healthcare Trajectories and Outcomes in the First Year After Tracheostomy Based on Patient Characteristics.

OBJECTIVES: To define healthcare trajectories after tracheostomy to inform shared decision-making efforts for critically ill patients. DESIGN: Retrospective epidemiologic cohort study. SETTING: California Patient Discharge Database 2018-2019. PATIENTS: Patients who received a tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tracked 1-year outcomes after tracheostomy, including survival and time alive in and out of a healthcare facility (HCF. Patients were stratified based on surgical status (did the patient require a major operating room procedure or not), age (65 yr old or older and less than 65 yr), pre-ICU comorbid states (frailty, chronic organ dysfunction, cancer, and robustness), and the need for dialysis during the tracheostomy admission. We identified 4,274 nonsurgical adults who received a tracheostomy during the study period with 50.9% being 65 years old or older. Among adults 65 years old or older, median survival after tracheostomy was less than 3 months for individuals with frailty, chronic organ dysfunction, cancer, or dialysis. Median survival was 3 months for adults younger than 65 years with cancer or dialysis. Most patients spent the majority of days alive after a tracheostomy in an HCF in the first 3 months. Older adults had very few days alive and out of an HCF in the first 3 months after tracheostomy. Most patients who ultimately died in the first year after tracheostomy spent almost all days alive in an HCF. CONCLUSIONS: Cumulative mortality and median survival after a tracheostomy were very poor across most ages and groups. Older adults and several subgroups of younger adults experienced high rates of prolonged hospitalization with few days alive and out of an HCF. This information may aid some patients, surrogates, and providers in decision-making.

Video versus Direct Laryngoscopy for Tracheal Intubation of Critically Ill Adults.

BACKGROUND: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain. METHODS: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death. RESULTS: The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; P<0.001). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups. CONCLUSIONS: Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195.).

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.

Association of Hospital Mortality With Initiation of Mechanical Ventilation on a Weekend: A Retrospective Cohort Study.

RATIONALE: Increased mortality in patients admitted to hospitals on weekends is a well-described phenomenon labeled the "weekend effect." Studies evaluating the weekend effect in intensive care units (ICUs) have arrived at conflicting results. Identifying a weekend effect for critically-ill patients may inform clinical care pathways and resource allocation. OBJECTIVES: Determine the association of initiation of mechanical ventilation (MV) upon admission on a weekend versus weekday with hospital mortality. METHODS: We conducted a retrospective cohort study of non-surgical adult patients using the California Patient Discharge Database from 2018 to 2019. We identified MV initiated on the day of admission and diagnoses using discharge billing codes. The primary exposure was admission and initiation of MV on a weekend versus weekday and the primary outcome was hospital mortality. Hierarchical logistic regression was used to determine the association between hospital mortality and MV initiation timing, adjusting for case-mix. RESULTS: Among 90 288 admissions in 2018 and 2019 meeting inclusion criteria, 24 771 (27.5%) had MV initiated on weekends, while 65 517 (72.6%) had MV initiated on weekdays. Patient demographics and comorbidities were similar between groups. Chronic alcohol and substance use disorders, and acute intoxications and traumas were more prevalent among patients with MV initiated on weekends. No difference in hospital mortality was observed with initiation of MV on weekends versus weekdays (23.1% vs 22.8%, ARD = 0.3%, aOR = 1.02, 95% CI 0.98, 1.07). CONCLUSIONS: Contrary to prior studies, no increased mortality was observed among newly admitted patients initiated on MV on weekends compared to weekdays. While weekend effects may exist in other settings, newly admitted patients likely have MV initiated in the emergency department or ICU, which tend to have more consistent staffing levels. Further research is needed to determine if care patterns in these units could be used as a model for units where weekend effects continue to impact outcomes.

Correlation between the VExUS score and right atrial pressure: a pilot prospective observational study.

Venous congestion is an under-recognized contributor to mortality in critically ill patients. Unfortunately, venous congestion is difficult to measure, and right heart catheterization (RHC) has been considered the most readily available means for measuring venous filling pressure. Recently, a novel "Venous Excess Ultrasound (VExUS)" score was developed to noninvasively quantify venous congestion using inferior vena cava (IVC) diameter and Doppler flow through the hepatic, portal, and renal veins. A preliminary retrospective study of post-cardiac surgery patients showed promising results, including a high positive-likelihood ratio of high VExUS grade for acute kidney injury. However, studies have not been reported in broader patient populations, and the relationship between VExUS and conventional measures of venous congestion is unknown. To address these gaps, we prospectively assessed the correlation of VExUS with right atrial pressure (RAP), with comparison to inferior vena cava (IVC) diameter. Patients undergoing RHC at Denver Health Medical Center underwent VExUS examination before their procedure. VExUS grades were assigned before RHC, blinding ultrasonographers to RHC outcomes. After controlling for age, sex, and common comorbidities, we observed a significant positive association between RAP and VExUS grade (P < 0.001, R2 = .68). VExUS had a favorable AUC for prediction of a RAP ≥ 12 mmHg (0.99, 95% CI 0.96-1) compared to IVC diameter (0.79, 95% CI 0.65-0.92). These results suggest a strong correlation between VExUS and RAP in a diverse patient population, and support future studies of VExUS as a tool to assess venous congestion and guide management in a spectrum of critical illnesses.

Disparities in Adult Patient Selection for Extracorporeal Membrane Oxygenation in the United States: A Population-Level Study.

Rationale: Disparities in patient selection for advanced therapeutics in health care have been identified in multiple studies, but it is unclear if disparities exist in patient selection for extracorporeal membrane oxygenation (ECMO), a rapidly expanding critical care resource. Objectives: To determine if disparities exist in patient selection for ECMO based on sex, primary insurance, and median income of the patient's neighborhood. Methods: In a retrospective cohort study using the Nationwide Readmissions Database 2016-2019, we identified patients treated with mechanical ventilation (MV) and/or ECMO with billing codes. Patient sex, insurance, and income level for patients receiving ECMO were compared with the patients treated with MV only, and hierarchical logistic regression with the hospital as a random intercept was used to determine odds of receiving ECMO based on patient demographics. Results: We identified 2,170,752 MV hospitalizations with 18,725 cases of ECMO. Among patients treated with ECMO, 36.1% were female compared with 44.5% of patients treated with> MV only (adjusted odds ratio [aOR] for ECMO, 0.73; 95% confidence interval [CI], 0.70-0.75). Of patients treated with ECMO, 38.1% had private insurance compared with 17.4% of patients treated with MV only. Patients with Medicaid were less likely to receive ECMO than patients with private insurance (aOR, 0.55; 95% CI, 0.52-0.57). Patients treated with ECMO were more likely to live in the highest-income neighborhoods compared with patients treated with MV only (25.1% vs. 17.3%). Patients living in the lowest-income neighborhoods were less likely to receive ECMO than those living in the highest-income neighborhoods (aOR, 0.63; 95% CI, 0.60-0.67). Conclusions: Significant disparities exist in patient selection for ECMO. Female patients, patients with Medicaid, and patients living in the lowest-income neighborhoods are less likely to be treated with ECMO. Despite possible unmeasured confounding, these findings were robust to multiple sensitivity analyses. On the basis of previous work describing disparities in other areas of health care, we speculate that limited access in some neighborhoods, restrictive/biased interhospital transfer practices, differences in patient preferences, and implicit provider bias may contribute to the observed differences. Future studies with more granular data are needed to identify and modify drivers of observed disparities.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

DirEct versus VIdeo LaryngosCopE (DEVICE): protocol and statistical analysis plan for a randomised clinical trial in critically ill adults undergoing emergency tracheal intubation.

INTRODUCTION: Among critically ill patients undergoing orotracheal intubation in the emergency department (ED) or intensive care unit (ICU), failure to visualise the vocal cords and intubate the trachea on the first attempt is associated with an increased risk of complications. Two types of laryngoscopes are commonly available: direct laryngoscopes and video laryngoscopes. For critically ill adults undergoing emergency tracheal intubation, it remains uncertain whether the use of a video laryngoscope increases the incidence of successful intubation on the first attempt compared with the use of a direct laryngoscope. METHODS AND ANALYSIS: The DirEct versus VIdeo LaryngosCopE (DEVICE) trial is a prospective, multicentre, non-blinded, randomised trial being conducted in 7 EDs and 10 ICUs in the USA. The trial plans to enrol up to 2000 critically ill adults undergoing orotracheal intubation with a laryngoscope. Eligible patients are randomised 1:1 to the use of a video laryngoscope or a direct laryngoscope for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of severe complications between induction and 2 min after intubation, defined as the occurrence of one or more of the following: severe hypoxaemia (lowest oxygen saturation <80%); severe hypotension (systolic blood pressure <65 mm Hg or new or increased vasopressor administration); cardiac arrest or death. Enrolment began on 19 March 2022 and is expected to be completed in 2023. ETHICS AND DISSEMINATION: The trial protocol was approved with waiver of informed consent by the single institutional review board at Vanderbilt University Medical Center and the Human Research Protection Office of the Department of Defense. The results will be presented at scientific conferences and submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05239195).

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

The Impact of Choice Architecture on Sepsis Fluid Resuscitation Decisions: An Exploratory Survey-Based Study.

Background: Discordance with well-known sepsis resuscitation guidelines is often attributed to rational assessments of patients at the point of care. Conversely, we sought to explore the impact of choice architecture (i.e., the environment, manner, and behavioral psychology within which options are presented and decisions are made) on decisions to prescribe guideline-discordant fluid volumes. Design: We conducted an electronic, survey-based study using a septic shock clinical vignette. Physicians from multiple specialties and training levels at an academic tertiary-care hospital and academic safety-net hospital were randomized to distinct answer sets: control (6 fluid options), time constraint (6 fluid options with a 10-s limit to answer), or choice overload (25 fluid options). The primary outcome was discordance with Surviving Sepsis Campaign fluid resuscitation guidelines. We also measured response times and examined the relationship between each choice architecture intervention group, response time, and guideline discordance. Results: A total of 189 of 624 (30.3%) physicians completed the survey. Time spent answering the vignette was reduced in time constraint (9.5 s, interquartile range [IQR] 7.3 s to 10.0 s, P < 0.001) and increased in choice overload (56.8 s, IQR 35.9 s to 86.7 s, P < 0.001) groups compared with control (28.3 s, IQR 20.0 s to 44.6 s). In contrast, the relative risk of guideline discordance was higher in time constraint (2.07, 1.33 to 3.23, P = 0.001) and lower in choice overload (0.75, 0.60, to 0.95, P =0.02) groups. After controlling for time spent reading the vignette, the overall odds of choosing guideline-discordant fluid volumes were reduced for every additional second spent answering the vignette (OR 0.98, 0.97, to 0.99, P < 0.001). Conclusions: Choice architecture may affect fluid resuscitation decisions in sepsis regardless of patient conditions, warranting further investigation in real-world contexts. These effects should be considered when implementing practice guidelines. Highlights: Time constrained clinical decision making was associated with increased proportion of guideline-discordant responses and relative risk of failure to prescribe guideline-recommended intravenous fluids using a sepsis clinical vignette.Choice overload increased response times and was associated with decreased proportion of guideline-discordant responses and relative risk of guideline discordance.Physician odds of choosing to prescribe guideline-discordant fluid volumes were reduced with increased deliberation as measured by response times.Clinicians, researchers, policy makers, and administrators should consider the effect of choice architecture on clinical decision making and guideline discordance when implementing guidelines for sepsis and other acute care conditions.