Clinical research remains a vital contributor to medical knowledge, and is an established and integral part of the practice of medicine worldwide. Respect for patient autonomy and ethical principles dictate that informed consent must be obtained from subjects before they can be enrolled into clinical research, yet these conditions may be difficult to apply in real practice in the intensive care unit (ICU). A number of factors serve to complexify the consent process in critically ill patients, notably decisional incapacity of the patient due to illness or sedation. Obtaining consent for research from a designated proxy or family member, commonly termed a “surrogate decision maker” (SDM) may be difficult, since SDMs dealing with the emotional, psychological and logistic impact of a sudden hospitalisation of their loved-one are not always receptive to the idea of research or emotionally equipped to reflect rationally on the opportunities being proposed to them. In addition, time constraints and workload pressures on the attending physician may render consent opportunities unfeasible, and the resulting loss of eligible patients could represent a bias in clinical trials, or limit the generalizability of their results. Alternative procedures such as deferred or waived consent have been used in the past and may be suitable alternatives in certain conditions, provided appropriate approval from institutional review boards (IRBs) can be obtained, in accordance with existing legislation. Some of the main questions inherent to the conduct of clinical research in critically ill patients are discussed in this review.

/pdf/ethical-challenges-involved-in-obtaining-consent-for-1sb46g6aie.pdf

Ethical challenges involved in obtaining consent for research from patients hospitalized in the intensive care unit.

Bacteremia is a leading cause of mortality and morbidity in critically ill adults. No previous randomized controlled trials have directly compared shorter versus longer durations of antimicrobial treatment in these patients. This is a multicenter pilot randomized controlled trial in critically ill patients with bacteremia. Eligible patients will be adults with a positive blood culture with pathogenic bacteria identified while in the intensive care unit. Eligible, consented patients will be randomized to either 7 days or 14 days of adequate antimicrobial treatment for the causative pathogen(s) detected on blood cultures. The diversity of pathogens and treatment regimens precludes blinding of patient and clinicians, but allocation concealment will be extended to day 7 and outcome adjudicators will be blinded. The primary outcome for the main trial will be 90-day mortality. The primary outcome for the pilot trial is feasibility defined by (i) rate of recruitment exceeding 1 patient per site per month and (ii) adherence to treatment duration protocol ≥ 90%. Secondary outcomes include intensive care unit, hospital and 90-day mortality rates, relapse rates of bacteremia, antibiotic-related side effects and adverse events, rates of Clostridium difficile infection, rates of secondary infection or colonization with antimicrobial resistant organisms, ICU and hospital lengths of stay, mechanical ventilation and vasopressor duration in intensive care unit, and procalcitonin levels on the day of randomization, and day 7, 10 and 14 after the index blood culture. The BALANCE pilot trial will inform the design and execution of the subsequent BALANCE main trial, which will evaluate shorter versus longer duration treatment for bacteremia in critically ill patients, and thereby provide an evidence basis for treatment duration decisions for these infections. The Pilot Trial was registered on 26 September 2014. Trial registration number: NCT02261506
 .

/pdf/bacteremia-antibiotic-length-actually-needed-for-clinical-4rlpjwf9og.pdf

Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE): study protocol for a pilot randomized controlled trial

Clonidine in the sedation of mechanically ventilated children: a pilot randomized trial.

Involving adults lacking capacity (ALC) in research on end of life care (EoLC) or serious illness is important, but often omitted. We aimed to develop evidence-based guidance on how best to include individuals with impaired capacity nearing the end of life in research, by identifying the challenges and solutions for processes of consent across the capacity spectrum. Methods Of Researching End of Life Care_Capacity (MORECare_C) furthers the MORECare statement on research evaluating EoLC. We used simultaneous methods of systematic review and transparent expert consultation (TEC). The systematic review involved four electronic databases searches. The eligibility criteria identified studies involving adults with serious illness and impaired capacity, and methods for recruitment in research, implementing the research methods, and exploring public attitudes. The TEC involved stakeholder consultation to discuss and generate recommendations, and a Delphi survey and an expert ‘think-tank’ to explore consensus. We narratively synthesised the literature mapping processes of consent with recruitment outcomes, solutions, and challenges. We explored recommendation consensus using descriptive statistics. Synthesis of all the findings informed the guidance statement. Of the 5539 articles identified, 91 met eligibility. The studies encompassed people with dementia (27%) and in palliative care (18%). Seventy-five percent used observational designs. Studies on research methods (37 studies) focused on processes of proxy decision-making, advance consent, and deferred consent. Studies implementing research methods (30 studies) demonstrated the role of family members as both proxy decision-makers and supporting decision-making for the person with impaired capacity. The TEC involved 43 participants who generated 29 recommendations, with consensus that indicated. Key areas were the timeliness of the consent process and maximising an individual’s decisional capacity. The think-tank (n = 19) refined equivocal recommendations including supporting proxy decision-makers, training practitioners, and incorporating legislative frameworks. The MORECare_C statement details 20 solutions to recruit ALC nearing the EoL in research. The statement provides much needed guidance to enrol individuals with serious illness in research. Key is involving family members early and designing study procedures to accommodate variable and changeable levels of capacity. The statement demonstrates the ethical imperative and processes of recruiting adults across the capacity spectrum in varying populations and settings.

/pdf/processes-of-consent-in-research-for-adults-with-impaired-fwoid9vpkm.pdf

Processes of consent in research for adults with impaired mental capacity nearing the end of life: systematic review and transparent expert consultation (MORECare_Capacity statement).

Introduction Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probiotic Lactobacillus rhamnosus GG on VAP and other clinically important outcomes in critically ill adults. Methods PROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×1010 colony forming units of L. rhamnosus GG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. Secondary outcomes are other ICU-acquired infections including Clostridioides difficile infection, diarrhoea (including antibiotic-associated diarrhoea), antimicrobial use, ICU and hospital length of stay and mortality. The planned sample size of 2650 patients is based on an estimated 15% VAP rate and will provide 80% power to detect a 25% relative risk reduction. Ethics and dissemination This protocol and statistical analysis plan outlines the methodology, primary and secondary analyses, sensitivity analyses and subgroup analyses. PROSPECT is approved by Health Canada (#9427-M1133-45C), the research ethics boards of all participating hospitals and Public Health Ontario. Results will be disseminated via academic channels (peer reviewed journal publications, professional healthcare fora including international conferences) and conventional and social media. The results of PROSPECT will inform practice guidelines worldwide. Trialregistration number NCT02462590; Pre-results.

https://bmjopen.bmj.com/content/bmjopen/9/6/e025228.full.pdf

Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

Tracey McArdle

Papers

Enhancing the informed consent process for critical care research: Strategies from a thromboprophylaxis trial