Embedded point of care randomisation for evaluating comparative effectiveness questions: PROSPECTOR-critical care feasibility study protocol.

INTRODUCTION: Many routinely administered treatments lack evidence as to their effectiveness. When treatments lack evidence, patients receive varying care based on the preferences of clinicians. Standard randomised controlled trials are unsuited to comparisons of different routine treatment strategies, and there remains little economic incentive for change.Integrating clinical trial infrastructure into electronic health record systems offers the potential for routine treatment comparisons at scale, through reduced trial costs. To date, embedded trials have automated data collection, participant identification and eligibility screening, but randomisation and consent remain manual and therefore costly tasks.This study will investigate the feasibility of using computer prompts to allow flexible randomisation at the point of clinical decision making. It will compare the effectiveness of two prompt designs through the lens of a candidate research question-comparing liberal or restrictive magnesium supplementation practices for critical care patients. It will also explore the acceptability of two consent models for conducting comparative effectiveness research. METHODS AND ANALYSIS: We will conduct a single centre, mixed-methods feasibility study, aiming to recruit 50 patients undergoing elective surgery requiring postoperative critical care admission. Participants will be randomised to either 'Nudge' or 'Preference' designs of electronic point-of-care randomisation prompt, and liberal or restrictive magnesium supplementation.We will judge feasibility through a combination of study outcomes. The primary outcome will be the proportion of prompts displayed resulting in successful randomisation events (compliance with the allocated magnesium strategy). Secondary outcomes will evaluate the acceptability of both prompt designs to clinicians and ascertain the acceptability of pre-emptive and opt-out consent models to patients. ETHICS AND DISSEMINATION: This study was approved by Riverside Research Ethics Committee (Ref: 21/LO/0785) and will be published on completion. TRIAL REGISTRATION NUMBER: NCT05149820.

Assessment of a rapid diagnostic test to exclude bacteraemia and effect on clinical decision-making for antimicrobial therapy.

Unnecessary antimicrobial treatment promotes the emergence of resistance. Early confirmation that a blood culture is negative could shorten antibiotic courses. The Cognitor Minus test, performed on blood culture samples after 12 hours incubation has a negative predictive value (NPV) of 99.5%. The aim of this study was to determine if earlier confirmation of negative blood culture result would shorten antibiotic treatment. Paired blood cultures were taken in the Critical Care Unit at a teaching hospital. The Cognitor Minus test was performed on one set >12 hours incubation but results kept blind. Clinicians were asked after 24 and 48 hours whether a result excluding bacteraemia or fungaemia would affect decisions to continue or stop antimicrobial treatment. Over 6 months, 125 patients were enrolled. The median time from start of incubation to Cognitor Minus test was 27.1 hours. When compared to 5 day blood culture results from both the control and test samples, Cognitor Minus gave NPVs of 99% and 100% respectively. Test results would have reduced antibiotic treatment in 14% (17/119) of patients at 24 and 48 hours (24% at either time) compared with routine blood culture. The availability of rapid tests to exclude bacteraemia may be of benefit in antimicrobial stewardship.

Simvastatin pre-treatment improves survival and mitochondrial function in a 3-day fluid-resuscitated rat model of sepsis.

Statins may offer protective effects in sepsis through anti-inflammatory, mitochondrial protection and other actions. We thus evaluated the effects of simvastatin on survival, organ and mitochondrial function, tissue and plasma ubiquinone levels and liver transcriptomics in a 3-day rat model of sepsis. Comparisons of rat plasma simvastatin and ubiquinone levels were made against levels sampled in blood from patients with acute lung injury (ALI) enrolled into a trial of statin therapy. Animals received simvastatin by gavage either pre- or post-induction of faecal peritonitis. Control septic animals received vehicle alone. Seventy-two-hour survival was significantly greater in statin pre-treated animals (43.7%) compared with their statin post-treated (12.5%) and control septic (25%) counterparts (P<0.05). Sepsis-induced biochemical derangements in liver and kidney improved with statin therapy, particularly when given pre-insult. Both simvastatin pre- and post-treatment prevented the fall in mitochondrial oxygen consumption in muscle fibres taken from septic animals at 24 h. This beneficial effect was paralleled by recovery of genes related to fatty acid metabolism. Simvastatin pre-treatment resulted in a significant decrease in myocardial ubiquinone. Patients with ALI had a marked variation in plasma simvastatin acid levels; however, their ubiquinone/low-density lipoprotein (LDL) cholesterol ratio did not differ regardless of whether they were receiving statin or placebo. In summary, despite protective effects seen with statin treatment given both pre- and post-insult, survival benefit was only seen with pre-treatment, reflecting experiences in patient studies.