Designing a Bayesian adaptive clinical trial to evaluate novel mechanical ventilation strategies in acute respiratory failure using Integrated Nested Laplace Approximations

Background: We aimed to design a Bayesian adaption trial through extensive simulations to determine values for key design parameters, demonstrate error rates, and establish the expected sample size. The complexity of the proposed outcome and analysis meant that Markov Chain Monte Carlo methods were required, resulting in an infeasible computational burden. Thus, we leveraged the Integrated Nested Laplace Approximations (INLA) algorithm, a fast approximation method, to ensure the feasibility of these simulations. Methods: We simulated Bayesian adaptive two-arm superiority trials that stratified participants into two disease severity states. The outcome was analyzed with proportional odds logistic regression. Trials were stopped for superiority or futility, separately for each state. We calculated the type I error and power across 64 scenarios that varied the stopping thresholds and the minimum sample size before commencing adaptive analyses. We incorporated dynamic borrowing and used INLA to compute the posterior distributions at each adaptive analysis. Designs that maintained a type I error below 5%, a power above 80%, and a feasible mean sample size were then evaluated across 22 scenarios that varied the odds ratios for the two severity states. Results: Power generally increased as the initial sample size and the threshold for declaring futility increased. Two designs were selected for further analysis. In the comprehensive simulations, the one design had a higher chance of reaching a trial conclusion before the maximum sample size and higher probability of declaring superiority when appropriate without a substantial increase in sample size for the more realistic scenarios and was selected as the trial design. Conclusions: We designed a Bayesian adaptive trial to evaluate novel strategies for ventilation using the INLA algorithm to and optimize the trial design through simulation

Cost effectiveness of stapled haemorrhoidopexy and traditional excisional surgery for the treatment of haemorrhoidal disease

Objective Our objective was to compare the cost effectiveness of stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH) in the treatment of grade II–IV haemorrhoidal disease from the perspective of the UK national health service. Methods An economic evaluation was conducted alongside an open, two-arm, parallel-group, pragmatic, multicentre, randomised controlled trial conducted in several hospitals in the UK. Patients were randomised into either SH or TH surgery between January 2011 and August 2014 and were followed up for 24 months. Intervention and subsequent resource use data were collected using case review forms and questionnaires. Benefits were collected using the EQ-5D-3L (EuroQoL—five dimensions—three levels) instrument. The primary economic outcome was incremental cost measured in pounds (£), year 2016 values, relative to the incremental benefit, which was estimated using quality-adjusted life-years (QALYs). Cost and benefits accrued in the second year were discounted at 3.5%. The base-case analysis was based on imputed data. Uncertainty was explored using univariate sensitivity analyses. Results Participants (n = 777) were randomised to SH (n = 389) or TH (n = 388). The mean cost of SH was £337 (95% confidence interval [CI] 251–423) higher than that of TH and the mean QALYs were −0.070 (95% CI −0.127 to −0.011) lower than for TH. The base-case cost-utility analysis indicated that SH has zero probability of being cost effective at both the £20,000 and the £30,000 threshold. Results from the sensitivity analyses were similar to those from the base-case analysis. Conclusions The evidence suggests that, on average, the total mean costs over the 24-month follow-up period were significantly higher for the SH arm than for the TH arm. The QALYs were also, on average, significantly lower for the SH arm. These results were supported by the sensitivity analyses. Therefore, in terms of cost effectiveness, TH is a superior surgical treatment for the management of grade II–IV haemorrhoids when compared with SH

Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial

Background Two commonly performed surgical interventions are available for severe (grade II–IV) haemorrhoids; traditional excisional surgery and stapled haemorrhoidopexy. Uncertainty exists as to which is most eff ective. The eTHoS trial was designed to establish the clinical effectiveness and cost-eff ectiveness of stapled haemorrhoidopexy compared with traditional excisional surgery. Methods The eTHoS trial was a large, open-label, multicentre, parallel-group, pragmatic randomised controlled trial done in adult participants (aged 18 years or older) referred to hospital for surgical treatment for grade II–IV haemorrhoids. Participants were randomly assigned (1:1) to receive either traditional excisional surgery or stapled haemorrhoidopexy. Randomisation was minimised according to baseline EuroQol 5 dimensions 3 level score (EQ-5D-3L), haemorrhoid grade, sex, and centre with an automated system to stapled haemorrhoidopexy or traditional excisional surgery. The primary outcome was area under the quality of life curve (AUC) measured with the EQ-5D-3L descriptive system over 24 months, assessed according to the randomised groups. The primary outcome measure was analysed using linear regression with adjustment for the minimisation variables. This trial is registered with the ISRCTN registry, number ISRCTN80061723. Findings Between Jan 13, 2011, and Aug 1, 2014, 777 patients were randomised (389 to receive stapled haemorrhoidopexy and 388 to receive traditional excisional surgery). Stapled haemorrhoidopexy was less painful than traditional excisional surgery in the short term and surgical complication rates were similar between groups. The EQ-5D-3L AUC score was higher in the traditional excisional surgery group than the stapled haemorrhoidopexy group over 24 months; mean diff erence –0·073 (95% CI –0·140 to –0·006; p=0·0342). EQ-5D-3L was higher for stapled haemorrhoidopexy in the fi rst 6 weeks after surgery, the traditional excisional surgery group had signifi cantly better quality of life scores than the stapled haemorrhoidopexy group. 24 (7%) of 338 participants who received stapled haemorrhoidopexy and 33 (9%) of 352 participants who received traditional excisional surgery had serious adverse events. Interpretation As part of a tailored management plan for haemorrhoids, traditional excisional surgery should be considered over stapled haemorrhoidopexy as the surgical treatment of choice

Lung Recruitment Assessed by Electrical Impedance Tomography (RECRUIT):A Multicenter Study of COVID-19 Acute Respiratory Distress Syndrome

Rationale: Defining lung recruitability is needed for safe positive end-expiratory pressure (PEEP) selection in mechanically ventilated patients. However, there is no simple bedside method including both assessment of recruitability and risks of overdistension as well as personalized PEEP titration. Objectives: To describe the range of recruitability using electrical impedance tomography (EIT), effects of PEEP on recruitability, respiratory mechanics and gas exchange, and a method to select optimal EIT-based PEEP. Methods: This is the analysis of patients with coronavirus disease (COVID-19) from an ongoing multicenter prospective physiological study including patients with moderate-severe acute respiratory distress syndrome of different causes. EIT, ventilator data, hemodynamics, and arterial blood gases were obtained during PEEP titration maneuvers. EIT-based optimal PEEP was defined as the crossing point of the overdistension and collapse curves during a decremental PEEP trial. Recruitability was defined as the amount of modifiable collapse when increasing PEEP from 6 to 24 cm H2O (DCollapse24–6). Patients were classified as low, medium, or high recruiters on the basis of tertiles of DCollapse24–6. Measurements and Main Results: In 108 patients with COVID-19, recruitability varied from 0.3% to 66.9% and was unrelated to acute respiratory distress syndrome severity. Median EIT-based PEEP differed between groups: 10 versus 13.5 versus 15.5 cm H2O for low versus medium versus high recruitability (P, 0.05). This approach assigned a different PEEP level from the highest compliance approach in 81% of patients. The protocol was well tolerated; in four patients, the PEEP level did not reach 24 cm H2O because of hemodynamic instability. Conclusions: Recruitability varies widely among patients with COVID-19. EIT allows personalizing PEEP setting as a compromise between recruitability and overdistension.</p

The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline

Purpose: High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings. Methods: We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions. Results: The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty). Conclusions: This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians

The Rise of Adaptive Platform Trials in Critical Care

As durable learning research systems, adaptive platform trials represent a transformative new approach to accelerating clinical evaluation and discovery in critical care. This Perspective provides a brief introduction to the concept of adaptive platform trials, describes several established and emerging platforms in critical care, and surveys some opportunities and challenges for their implementation and impact.<br/