Designing a Bayesian adaptive clinical trial to evaluate novel mechanical ventilation strategies in acute respiratory failure using integrated nested Laplace approximations.

BACKGROUND: Adaptive trials usually require simulations to determine values for design parameters, demonstrate error rates, and establish the sample size. We designed a Bayesian adaptive trial comparing ventilation strategies for patients with acute hypoxemic respiratory failure using simulations. The complexity of the analysis would usually require computationally expensive Markov Chain Monte Carlo methods but this barrier to simulation was overcome using the Integrated Nested Laplace Approximations (INLA) algorithm to provide fast, approximate Bayesian inference. METHODS: We simulated two-arm Bayesian adaptive trials with equal randomization that stratified participants into two disease severity states. The analysis used a proportional odds model, fit using INLA. Trials were stopped based on pre-specified posterior probability thresholds for superiority or futility, separately for each state. We calculated the type I error and power across 64 scenarios that varied the probability thresholds and the initial minimum sample size before commencing adaptive analyses. Two designs that maintained a type I error below 5%, a power above 80%, and a feasible mean sample size were evaluated further to determine the optimal design. RESULTS: Power generally increased as the initial sample size and the futility threshold increased. The chosen design had an initial recruitment of 500 and a superiority threshold of 0.9925, and futility threshold of 0.95. It maintained high power and was likely to reach a conclusion before exceeding a feasible sample size. CONCLUSIONS: We designed a Bayesian adaptive trial to evaluate novel strategies for ventilation using the INLA algorithm to efficiently evaluate a wide range of designs through simulation.

Association between Patient Race and Ethnicity and Use of Invasive Ventilation in the United States.

Rationale: Outcomes for people with respiratory failure in the United States vary by patient race and ethnicity. Invasive ventilation is an important treatment initiated based on expert opinion. It is unknown whether the use of invasive ventilation varies by patient race and ethnicity. Objectives: To measure 1) the association between patient race and ethnicity and the use of invasive ventilation; and 2) the change in 28-day mortality mediated by any association. Methods: We performed a multicenter cohort study of nonintubated adults receiving oxygen within 24 hours of intensive care admission using the Medical Information Mart for Intensive Care IV (MIMIC-IV, 2008-2019) and Phillips eICU (eICU, 2014-2015) databases from the United States. We modeled the association between patient race and ethnicity (Asian, Black, Hispanic, White) and invasive ventilation rate using a Bayesian multistate model that adjusted for baseline and time-varying covariates, calculated hazard ratios (HRs), and estimated 28-day hospital mortality changes mediated by differential invasive ventilation use. We reported posterior means and 95% credible intervals (CrIs). Results: We studied 38,258 patients, 52% (20,032) from MIMIC-IV and 48% (18,226) from eICU: 2% Asian (892), 11% Black (4,289), 5% Hispanic (1,964), and 81% White (31,113). Invasive ventilation occurred in 9.2% (3,511), and 7.5% (2,869) died. The adjusted rate of invasive ventilation was lower in Asian (HR, 0.82; CrI, 0.70-0.95), Black (HR, 0.78; CrI, 0.71-0.86), and Hispanic (HR, 0.70; CrI, 0.61-0.79) patients compared with White patients. For the average patient, lower rates of invasive ventilation did not mediate differences in 28-day mortality. For a patient on high-flow nasal cannula with inspired oxygen fraction of 1.0, the odds ratios for mortality if invasive ventilation rates were equal to the rate for White patients were 0.97 (CrI, 0.91-1.03) for Asian patients, 0.96 (CrI, 0.91-1.03) for Black patients, and 0.94 (CrI, 0.89-1.01) for Hispanic patients. Conclusions: Asian, Black, and Hispanic patients had lower rates of invasive ventilation than White patients. These decreases did not mediate harm for the average patient, but we could not rule out harm for patients with more severe hypoxemia.

Association of Noninvasive Respiratory Support with Extubation Outcomes in Brain-injured Patients Receiving Mechanical Ventilation: A Secondary Analysis of the ENIO Prospective Observational Study.

Rationale: Noninvasive respiratory support using a high-flow nasal cannula (HFNC) or noninvasive positive pressure ventilation (NIPPV) can decrease the risk of reintubation in patients being liberated from mechanical ventilation, but effects in patients with acute brain injury (ABI) are unknown. Objectives: To evaluate the association between postextubation noninvasive respiratory support and reintubation in patients with ABI being liberated from mechanical ventilation. Methods: This was a secondary analysis of a prospective, observational study of mechanically ventilated patients with ABI (clinicaltrials.gov identifier NCT03400904). The primary endpoint was reintubation during ICU admission. We used mixed-effects logistic regression models with patient-level covariates and random intercepts for hospital and country to evaluate the association between prophylactic (i.e., planned) HFNC or NIPPV and reintubation. Measurements and Main Results: 1,115 patients were included from 62 hospitals and 19 countries, of whom 267 received HFNC or NIPPV following extubation (23.9%). Compared with conventional oxygen therapy, neither prophylactic HFNC nor NIPPV was associated with decreased odds of reintubation (respectively, odds ratios of 0.97 [95% confidence interval, 0.54-1.73] and 0.63 [0.30-1.32]). Findings remained consistent in sensitivity analyses accounting for alternate adjustment procedures, missing data, shorter time frames of the primary endpoint, and competing risks precluding reintubation. In a Bayesian analysis using skeptical and data-driven priors, the probabilities of reduced reintubation ranged from 17% to 34% for HFNC and from 46% to 74% for NIPPV. Conclusions: In a large cohort of brain-injured patients undergoing liberation from mechanical ventilation, prophylactic use of HFNC and NIPPV were not associated with reintubation. Prospective trials are needed to confirm treatment effects in this population. Primary study registered with www.clinicaltrials.gov (NCT03400904).

Methodology and design of platform trials: a meta-epidemiological study.

OBJECTIVES: Adaptive platforms allow for the evaluation of multiple interventions at a lower cost and have been growing in popularity, especially during the COVID-19 pandemic. The objective of this review is to summarize published platform trials, examine specific methodological design features among these studies, and hopefully aid readers in the evaluation and interpretation of platform trial results. METHODS: We performed a systematic review of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov from January 2015 to January 2022 for protocols or results of platform trials. Pairs of reviewers, working independently and in duplicate, collected data on trial characteristics of trial registrations, protocols, and publications of platform trials. We reported our results using total numbers and percentages, as well as medians with interquartile range (IQR) when appropriate. RESULTS: We identified 15,277 unique search records and screened 14,403 titles and abstracts after duplicates were removed. We identified 98 unique randomized platform trials. Sixteen platform trials were sourced from a systematic review completed in 2019, which included platform trials reported prior to 2015. Most platform trials (n = 67, 68.3%) were registered between 2020 and 2022, coinciding with the COVID-19 pandemic. The included platform trials primarily recruited or plan to recruit patients from North America or Europe, with most subjects being recruited from the United States (n = 39, 39.7%) and the United Kingdom (n = 31, 31.6%). Bayesian methods were used in 28.6% (n = 28) of platform RCTs and frequentist methods in 66.3% (n = 65) of trials, including 1 (1%) that used methods from both paradigms. Out of the twenty-five trials with peer-reviewed publication of results, seven trials used Bayesian methods (28%), and of those, two (8%) used a predefined sample size calculation while the remainder used pre-specified probabilities of futility, harm, or benefit calculated at (pre-specified) intervals to inform decisions about stopping interventions or the entire trial. Seventeen (68%) peer-reviewed publications used frequentist methods. Out of the seven published Bayesian trials, seven (100%) reported thresholds for benefit. The threshold for benefit ranged from 80% to >99%. CONCLUSION: We identified and summarized key components of platform trials, including the basics of the methodological and statistical considerations. Ultimately, improving standardization and reporting in platform trials require an understanding of the current landscape. We provide the most updated and rigorous review of platform trials to date.

Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts.

BACKGROUND: The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. METHODS: This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008-2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003-2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF < 110, < 98, and < 88 on 28-day mortality. MIMIC-IV was used for the primary analysis and AmsterdamUMCdb for the secondary analysis. We obtained posterior means and 95% credible intervals (CrI) with nonparametric Bayesian G-computation. RESULTS: We studied 3,357 patients in the primary analysis. For invasive ventilation initiation thresholds SF < 110, SF < 98, and SF < 88, the predicted 28-day probabilities of invasive ventilation were 72%, 47%, and 19%. Predicted 28-day mortality was lowest with threshold SF < 110 (22.2%, CrI 19.2 to 25.0), compared to SF < 98 (absolute risk increase 1.6%, CrI 0.6 to 2.6) or SF < 88 (absolute risk increase 3.5%, CrI 1.4 to 5.4). In the secondary analysis (1,279 patients), the predicted 28-day probability of invasive ventilation was 50% for initiation threshold SF < 110, 28% for SF < 98, and 19% for SF < 88. In contrast with the primary analysis, predicted mortality was highest with threshold SF < 110 (14.6%, CrI 7.7 to 22.3), compared to SF < 98 (absolute risk decrease 0.5%, CrI 0.0 to 0.9) or SF < 88 (absolute risk decrease 1.9%, CrI 0.9 to 2.8). CONCLUSION: Initiating invasive ventilation at lower hypoxemia severity will increase the rate of invasive ventilation, but this can either increase or decrease the expected mortality, with the direction of effect likely depending on baseline mortality risk and clinical context.

Do Thresholds for Invasive Ventilation in Hypoxemic Respiratory Failure Exist? A Cohort Study.

Rationale: Invasive ventilation is a significant event for patients with respiratory failure. Physiologic thresholds standardize the use of invasive ventilation in clinical trials, but it is unknown whether thresholds prompt invasive ventilation in clinical practice. Objectives: To measure, in patients with hypoxemic respiratory failure, the probability of invasive ventilation within 3 hours after meeting physiologic thresholds. Methods: We studied patients admitted to intensive care receiving FiO2 of 0.4 or more via nonrebreather mask, noninvasive positive pressure ventilation, or high-flow nasal cannula, using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019) and the Amsterdam University Medical Centers Database (AmsterdamUMCdb) (2003-2016). We evaluated 17 thresholds, including the ratio of arterial to inspired oxygen, the ratio of saturation to inspired oxygen ratio, composite scores, and criteria from randomized trials. We report the probability of invasive ventilation within 3 hours of meeting each threshold and its association with covariates using odds ratios (ORs) and 95% credible intervals (CrIs). Measurements and Main Results: We studied 4,726 patients (3,365 from MIMIC, 1,361 from AmsterdamUMCdb). Invasive ventilation occurred in 28% (1,320). In MIMIC, the highest probability of invasive ventilation within 3 hours of meeting a threshold was 20%, after meeting prespecified neurologic or respiratory criteria while on vasopressors, and 19%, after a ratio of arterial to inspired oxygen of <80 mm Hg. In AmsterdamUMCdb, the highest probability was 34%, after vasopressor initiation, and 25%, after a ratio of saturation to inspired oxygen of <90. The probability after meeting the threshold from randomized trials was 9% (MIMIC) and 13% (AmsterdamUMCdb). In MIMIC, a race/ethnicity of Black (OR, 0.75; 95% CrI, 0.57-0.96) or Asian (OR, 0.6; 95% CrI, 0.35-0.95) compared with White was associated with decreased probability of invasive ventilation after meeting a threshold. Conclusions: The probability of invasive ventilation within 3 hours of meeting physiologic thresholds was low and associated with patient race/ethnicity.

When Should We Intubate in Hypoxemic Respiratory Failure?

Intubation during Hypoxemic Respiratory FailureThere is little evidence to guide the common and high-stakes decision to initiate invasive ventilation in hypoxemic respiratory failure. In this Tomorrow's Trial, Yarnell and Patel propose a randomized trial of different physiological thresholds for the initiation of invasive ventilation.

Clinical decision analysis of elective delivery vs expectant management for pregnant individuals with COVID-19-related acute respiratory distress syndrome.

BACKGROUND: Pregnant individuals are vulnerable to COVID-19-related acute respiratory distress syndrome. There is a lack of high-quality evidence on whether elective delivery or expectant management leads to better maternal and neonatal outcomes. OBJECTIVE: This study aimed to determine whether elective delivery or expectant management are associated with higher quality-adjusted life expectancy for pregnant individuals with COVID-19-related acute respiratory distress syndrome and their neonates. STUDY DESIGN: We performed a clinical decision analysis using a patient-level model in which we simulatedpregnant individuals and their unborn children. We used a patient-level model with parallel open-cohort structure, daily cycle length, continuous discounting, lifetime horizon, sensitivity analyses for key parameter values, and 1000 iterations for quantification of uncertainty. We simulated pregnant individuals at 32 weeks of gestation, invasively ventilated because of COVID-19-related acute respiratory distress syndrome. In the elective delivery strategy, pregnant individuals received immediate cesarean delivery. In the expectant management strategy, pregnancies continued until spontaneous labor or obstetrical decision to deliver. For both pregnant individuals and neonates, model outputs were hospital or perinatal survival, life expectancy, and quality-adjusted life expectancy denominated in years, summarized by the mean and 95% credible interval. Maternal utilities incorporated neonatal outcomes in accordance with best practices in perinatal decision analysis. RESULTS: Model outputs for pregnant individuals were similar when comparing elective delivery at 32 weeks' gestation with expectant management, including hospital survival (87.1% vs 87.4%), life-years (difference, -0.1; 95% credible interval, -1.4 to 1.1), and quality-adjusted life expectancy denominated in years (difference, -0.1; 95% credible interval, -1.3 to 1.1). For neonates, elective delivery at 32 weeks' gestation was estimated to lead to a higher perinatal survival (98.4% vs 93.2%; difference, 5.2%; 95% credible interval, 3.5-7), similar life-years (difference, 0.9; 95% credible interval, -0.9 to 2.8), and higher quality-adjusted life expectancy denominated in years (difference, 1.3; 95% credible interval, 0.4-2.2). For pregnant individuals, elective delivery was not superior to expectant management across a range of scenarios between 28 and 34 weeks of gestation. Elective delivery in cases where intrauterine death or maternal mortality were more likely resulted in higher neonatal quality-adjusted life expectancy, as did elective delivery at 30 weeks' gestation (difference, 1.1 years; 95% credible interval, 0.1 - 2.1) despite higher long-term complications (4.3% vs 0.5%; difference, 3.7%; 95% credible interval, 2.4-5.1), and in cases where intrauterine death or maternal acute respiratory distress syndrome mortality were more likely. CONCLUSION: The decision to pursue elective delivery vs expectant management in pregnant individuals with COVID-19-related acute respiratory distress syndrome should be guided by gestational age, risk of intrauterine death, and maternal acute respiratory distress syndrome severity. For the pregnant individual, elective delivery is comparable but not superior to expectant management for gestational ages from 28 to 34 weeks. For neonates, elective delivery was superior if gestational age was ≥30 weeks and if the rate of intrauterine death or maternal mortality risk were high. We recommend basing the decision for elective delivery vs expectant management in a pregnant individual with COVID-19-related acute respiratory distress syndrome on gestational age and likelihood of intrauterine or maternal death.

Personal, professional, and psychological impact of the COVID-19 pandemic on hospital workers: A cross-sectional survey.

OBJECTIVES: We aimed to evaluate the personal, professional, and psychological impact of the COVID-19 pandemic on hospital workers and their perceptions about mitigating strategies. DESIGN: Cross-sectional web-based survey consisting of (1) a survey of the personal and professional impact of the COVID-19 pandemic and potential mitigation strategies, and (2) two validated psychological instruments (Kessler Psychological Distress Scale [K10] and Impact of Events Scale Revised [IES-R]). Regression analyses were conducted to identify the predictors of workplace stress, psychological distress, and post-traumatic stress. SETTING AND PARTICIPANTS: Hospital workers employed at 4 teaching and 8 non-teaching hospitals in Ontario, Canada during the COVID-19 pandemic. RESULTS: Among 1875 respondents (84% female, 49% frontline workers), 72% feared falling ill, 64% felt their job placed them at great risk of COVID-19 exposure, and 48% felt little control over the risk of infection. Respondents perceived that others avoided them (61%), reported increased workplace stress (80%), workload (66%) and responsibilities (59%), and 44% considered leaving their job. The psychological questionnaires revealed that 25% had at least some psychological distress on the K10, 50% had IES-R scores suggesting clinical concern for post-traumatic stress, and 38% fulfilled criteria for at least one psychological diagnosis. Female gender and feeling at increased risk due to PPE predicted all adverse psychological outcomes. Respondents favoured clear hospital communication (59%), knowing their voice is heard (55%), expressions of appreciation from leadership (55%), having COVID-19 protocols (52%), and food and beverages provided by the hospital (50%). CONCLUSIONS: Hospital work during the COVID-19 pandemic has had important personal, professional, and psychological impacts. Respondents identified opportunities to better address information, training, and support needs.

Evaluating satisfaction with the quality and provision of end-of-life care for patients from diverse ethnocultural backgrounds.

BACKGROUND: Recently immigrated and ethnic minority patients in Ontario, Canada are more likely to receive aggressive life-prolonging treatment at the end of life in comparison to other patients. To explore this finding further, this survey-based observational study aimed to evaluate satisfaction with the quality of end-of-life care for patients from diverse ethnocultural backgrounds. METHODS: The End-of-Life Satisfaction Survey was used to measure satisfaction with the quality of inpatient end-of-life care from the perspective of next-of-kin of recently deceased patients at Sunnybrook Health Sciences Centre in Toronto, Ontario (between March 2012 to May 2019). The primary outcome was the global rating of satisfaction. Associations with patient ethnicity, patient religion, level of religiosity/spirituality, language/communication barriers, and location of death were assessed using univariable and multivariable modified Poisson regression. Secondary outcomes included differences in satisfaction and rates of dying in intensive care units (ICU) among patient population subgroups, and identification of high priority areas for quality-of-care improvement. RESULTS: There were 1,543 respondents. Patient ethnicities included Caucasian (68.2%), Mediterranean (10.5%), East Asian (7.6%), South Asian (3.5%), Southeast Asian (2.1%) and Middle Eastern (2.0%); religious affiliations included Christianity (66.6%), Judaism (12.3%) and Islam (2.1%), among others. Location of death was most commonly in ICU (38.4%), hospital wards (37.0%) or long-term care (20.0%). The mean(SD) rating of satisfaction score was 8.30(2.09) of 10. After adjusting for other covariates, satisfaction with quality of end-of-life care was higher among patients dying in ICU versus other locations (relative risk [RR] 1.51, 95%CI 1.05-2.19, p=0.028), lower among those who experienced language/communication barriers (RR 0.49 95%CI 0.23-1.06, p=0.069), and lower for Muslim patients versus other religious affiliations (RR 0.46, 95%CI 0.21-1.02, p=0.056). Survey items identified as highest priority areas for quality-of-care improvement included communication and information giving; illness management; and healthcare provider characteristics such as emotional support, doctor availability and time spent with patient/family. CONCLUSION: Satisfaction with quality-of-care at the end of life was higher among patients dying in ICU and lower among Muslim patients or when there were communication barriers between families and healthcare providers. These findings highlight the importance of measuring and improving end-of-life care across the ethnocultural spectrum.

Observational study of agreement between attending and trainee physicians on the surprise question: "Would you be surprised if this patient died in the next 12 months?"

BACKGROUND: Optimal end-of-life care requires identifying patients that are near the end of life. The extent to which attending physicians and trainee physicians agree on the prognoses of their patients is unknown. We investigated agreement between attending and trainee physician on the surprise question: "Would you be surprised if this patient died in the next 12 months?", a question intended to assess mortality risk and unmet palliative care needs. METHODS: This was a multicentre prospective cohort study of general internal medicine patients at 7 tertiary academic hospitals in Ontario, Canada. General internal medicine attending and senior trainee physician dyads were asked the surprise question for each of the patients for whom they were responsible. Surprise question response agreement was quantified by Cohen's kappa using Bayesian multilevel modeling to account for clustering by physician dyad. Mortality was recorded at 12 months. RESULTS: Surprise question responses encompassed 546 patients from 30 attending-trainee physician dyads on academic general internal medicine teams at 7 tertiary academic hospitals in Ontario, Canada. Patients had median age 75 years (IQR 60-85), 260 (48%) were female, and 138 (25%) were dependent for some or all activities of daily living. Trainee and attending physician responses agreed in 406 (75%) patients with adjusted Cohen's kappa of 0.54 (95% credible interval 0.41 to 0.66). Vital status was confirmed for 417 (76%) patients of whom 160 (38% of 417) had died. Using a response of "No" to predict 12-month mortality had positive likelihood ratios of 1.84 (95% CrI 1.55 to 2.22, trainee physicians) and 1.51 (95% CrI 1.30 to 1.72, attending physicians), and negative likelihood ratios of 0.31 (95% CrI 0.17 to 0.48, trainee physicians) and 0.25 (95% CrI 0.10 to 0.46, attending physicians). CONCLUSION: Trainee and attending physician responses to the surprise question agreed in 54% of cases after correcting for chance agreement. Physicians had similar discriminative accuracy; both groups had better accuracy predicting which patients would survive as opposed to which patients would die. Different opinions of a patient's prognosis may contribute to confusion for patients and missed opportunities for engagement with palliative care services.

Effect of Lowering Vt on Mortality in Acute Respiratory Distress Syndrome Varies with Respiratory System Elastance.

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation with lower Vt on mortality would be predicted to vary according to respiratory system elastance (Ers). Objectives: To determine whether the mortality benefit of ventilation with lower Vt varies according to Ers. Methods: In a secondary analysis of patients from five randomized trials of lower- versus higher-Vt ventilation strategies in ARDS and acute hypoxemic respiratory failure, the posterior probability of an interaction between the randomized Vt strategy and Ers on 60-day mortality was computed using Bayesian multivariable logistic regression. Measurements and Main Results: Of 1,096 patients available for analysis, 416 (38%) died by Day 60. The posterior probability that the mortality benefit from lower-Vt ventilation strategies varied with Ers was 93% (posterior median interaction odds ratio, 0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63-1.02). Ers was classified as low (<2 cm H2O/[ml/kg], n = 321, 32%), intermediate (2-3 cm H2O/[ml/kg], n = 475, 46%), and high (>3 cm H2O/[ml/kg], n = 224, 22%). In these groups, the posterior probabilities of an absolute risk reduction in mortality ≥ 1% were 55%, 82%, and 92%, respectively. The posterior probabilities of an absolute risk reduction ≥ 5% were 29%, 58%, and 82%, respectively. Conclusions: The mortality benefit of ventilation with lower Vt in ARDS varies according to elastance, suggesting that lung-protective ventilation strategies should primarily target driving pressure rather than Vt.