Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Retroclavicular approach vs infraclavicular approach for plexic bloc anesthesia of the upper limb: study protocol randomized controlled trial.

BACKGROUND: The coracoid approach is recognized as the simplest approach to perform brachial plexus anaesthesia, but needle visualization needs to be improved. With a different needle entry point, the retroclavicular approach confers a perpendicular angle between the ultrasound and the needle, which theoretically enhances needle visualization. This trial compares these two techniques. The leading hypothesis is that the retroclavicular approach is comparable to the infraclavicular coracoid approach in general aspects, but needle visualization is better with this novel approach. METHODS: We designed a multicentre, randomized, non-inferiority trial. Patients eligible for the study are older than 18 years, able to consent, will undergo urgent or elective upper limb surgery distal to the elbow and are classified with American Society of Anaesthesiologists risk score (ASA) I-III. They will be excluded if they meet contraindicated criteria to regional anaesthesia, have affected anatomy of the clavicle or are pregnant. Randomization will be done by a computer-generated randomization schedule stratified for each site and in 1:1 ratio, and concealment will be maintained with opaque, sealed envelopes in a locked office. The primary outcome, the performance time, will be analyzed using non-inferiority analysis while secondary outcomes will be analyzed with superiority analysis. Needle visualization will be ranked on a Likert scale of 1-5 that is subjective and represents a pitfall. Two separate persons will rank needle visualization to compensate this pitfall. According to previous studies, 49 patients per group are required for statistical power of 0.90 and one-sided type I error of 0.05. DISCUSSION: The conduct of this study will bring clear answers to our questions and, if our hypothesis is confirmed, will confer an anatomic alternative to difficult coracoid infraclavicular brachial blocks or could even become a standard for brachial plexus anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02913625 . Registered on 12 September 2016.