A double blind randomised clinical trial of supplementary intravenous (IV) thiamine versus placebo in the treatment and prevention of delirium in the intensive care unit (ICU)

Research question: In patients in ICU receiving multiorgan support does supplemental IV thiamine, compared to placebo, reduce delirium? Background: Critically ill patients often develop acute confusion, delirium, which is associated with worse outcomes including long-term cognitive impairment. There are no effective drug treatments for delirium. Previous research supports abnormalities in brain glucose utilisation in delirium. Thiamine is essential for cell glucose metabolism. It is cheap, widely used and safe. Proof of concept work shows that it is likely to reduce delirium. Clinical objectives: To determine the clinical efficacy of supplementary IV thiamine on: (1) days alive and free of delirium and coma up to 14 days (primary outcome); and (2) a range of clinically important, patient centred secondary outcomes, including cognitive function and independence at 90 days. Mechanistic objectives: Targeted metabolomic analysis of blood and urine on days 1, 3 and 14 for metabolites relevant to glucose utilisation to determine if IV thiamine reduces delirium through facilitating energy producing cell enzyme activity and glucose utilisation (all patients). Study design: Multicentre, double-blind, placebo controlled randomised controlled trial with one embedded mechanistic sub-studies. Setting: 20 representative UK ICUs that participate in the ICNARC Case Mix Programme (the national clinical audit of adult ICU). Population: Adult ICU patients receiving mechanical ventilation and/or multiorgan support within 72 hours of admission and with an expected further 48 hours requirement for organ support. Intervention: IV thiamine 300 mg IV 12-hourly for five days followed by 300mg IV daily for a total of 14 days or until critical care discharge. Comparator: Matched placebo (0.9% sodium chloride). Primary outcome: Days alive and free of delirium (assessed by CAM-ICU) and coma up to 14 days. Secondary outcomes: Days alive and free of mechanical ventilation up to 14 days; mortality at ICU and hospital discharge, 14, 30 and 90 days; ICU and hospital length of stay; adverse and safety events; health-related quality of life and cognitive function at 90 days; and hospital discharge destination. Sample Size: 520 patients . Timelines for delivery: Months 1-9 study set up, months 10-31 recruitment and follow up, months 32-39 analysis and dissemination. Anticipated impact and dissemination: Delirium is consistently reported the most difficult problem faced by ICU clinicians which prolongs ICU stay and mechanical ventilation long beyond the resolution of the presenting problem. There is no effective pharmacotherapy to treat delirium. Clear evidence of benefit from thiamine, which is cheap, safe, and widely available, would have a rapid worldwide impact. The wider potential impact of this work stems from the mechanistic aspects which have the potential to drive research into novel therapies that improve glucose utilisation in the brain or to investigate thiamine in other related populations. Dissemination plans will be co-produced with key stakeholders, including our PPIE partners and EDI panel, and will use multiple approaches and media to reach all relevant audiences.