Pharmacokinetic and pharmacodynamic study of intravenous thiamine in intensive care: a prospective, observational cohort study

Background Delirium is common during admission to the intensive care unit (ICU). It is associated with an increase in mortality, morbidity, longer ICU and hospital stay and with long-term cognitive impairment. Currently, there are no definitive pharmacotherapy interventions for ICU delirium. Intravenous (IV) thiamine has been reported to benefit specific ICU patients with delirium in a recent meta-analysis. The dose of IV thiamine in the included trials were variable. There is no consensus for optimal dose of IV thiamine in delirium and limited data on how critical illness impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of IV thiamine. Research Question What is the impact of critical illness (specifically sepsis and septic shock) on PK of IV thiamine and explore the relationship between IV thiamine PK and PD (defined as delirium incidence). Aims To determine the pharmacokinetics and pharmacodynamics (PK/PD) of IV thiamine in an ICU population with and without sepsis or septic shock. Objectives To determine baseline thiamine levels in whole blood in ICU patients (PK) To explore the relationship between standard doses of IV thiamine and its concentration in whole blood (PK) To determine association between thiamine dosing and delirium incidence (PD) To determine the impact of sepsis and septic shock on IV thiamine PK/PD, alongside other confounding factors. Methods A prospective, observational cohort study in ICUs in two hospitals in England, United Kingdom. Twenty participants who will be receiving IV thiamine (Pabrinex®) as part of standard of care will be recruited. Pharmacokinetic study (PK) Whole blood thiamine (WBT) samples will be taken at baseline and at predefined intervals after the dose at: 0.5, 1, 1.5, 2, 4 and 6 hours. This will allow determination of a PK model. Pharmacodynamic study (PD) Confusion Assessment Method (CAM)- ICU scores will be assessed by nurses twice daily, as part of standard practice in ICUs in the UK. Plasma levels of biomarkers (IL-1RA, IL-6, Nfl, AChE), reported as raised in delirium, will be determined at baseline (before dose) and daily over 72 hours. A population PK/PD model will be established using the NONMEM software and further statistical analysis performed using the R software. Timelines Following Health Research Authority (HRA) and local research approval, the PK/PD study is expected to last for 10 months. Data completion, data cleaning and complex analysis is predicted to take 6-7 months. This will allow sufficient time for manuscript preparation and dissemination of research findings. Anticipated impact and dissemination This study will increase our understanding of IV thiamine PK/PD in an ICU population with and without sepsis and septic shock. This will add new knowledge for a commonly prescribed medication (Pabrinex®). This has the potential to reduce treatment costs and optimise treatment, but ensure the ICU patients get the right dose of IV thiamine, with focus on ICU delirium. Key findings will be disseminated to patients and the public and stakeholders at local, regional and national level, presented in national and international conferences, and published in high impact peer-reviewed journals.