PROJECT SUMMARY Three out of four patients who survive acute respiratory distress syndrome (ARDS) will develop long-term cognitive impairment (LTCI), which is defined as a new deficit or a worsening of a pre-existing deficit in cognition that remains persistent. This growing public health problem extends beyond ARDS, and affects all intensive care unit (ICU) survivors. A substantial proportion of these patients will also have impairments in executive function, which is a cognitive domain fundamental to living a productive life. LTCI and executive dysfunction has devastating consequences for the patient as they become debilitated, have poor health-related quality of life, and have a reduction in employment. Unfortunately, interventions that preserve long-term cognition and executive function after critical illness are lacking. Early, high-dose oral Vitamin D treatment may preserve long-term cognition and executive function in ICU survivors by attenuating systemic and central nervous system inflammation, as well as subsequent endothelial dysfunction, blood brain barrier (BBB) injury, and neuronal cell death. Therefore, we propose this randomized control trial to evaluate the effects of Vitamin D treatment on cognitive outcomes among critically ill patients at risk for ARDS and have Vitamin D deficiency (plasma 25-hydroxyvitamin D < 20 ng/ml). Our trial, entitled Vitamin D to Improve Outcomes by Leveraging Early Treatment: Long-term Brain Outcomes in Vitamin D Deficient Patients (VIOLET-BUD), has the following specific aims: (1) Determine if early administration of a single, high dose (>540,000 IU), enteral vitamin D3 (cholecalciferol) treatment improves 6-month global cognition and executive function as determined by comprehensive neuropsychological testing compared with placebo; and (2) Determine if serum biomarkers of systemic inflammation (IL-6, TNF-α, IL-1β, C-reactive protein [CRP]), endothelial dysfunction (E-selectin), and BBB injury (S100B) are associated with poorer 6-month global cognition and executive function and determine if they are mediators for any relationships observed between Vitamin D treatment and these cognitive outcomes. VIOLET-BUD is an ancillary study to the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) randomized controlled trial which is actively enrolling and is supported by the Prevention and Early Treatment of Acute Lung Injury (PETAL) network. VIOLET (parent study) will provide the infrastructure needed to screen, randomize, and administer the treatment within 12 hours. VIOLET-BUD will provide the funding and resources necessary to collect additional baseline cognition, functional status, and employment data, additional blood specimens during hospitalization, serum biomarker measurements, and 6- month cognitive and secondary outcome measurements. By leveraging VIOLET and the PETAL network’s massive resources, VIOLET-BUD is a unique opportunity to efficiently evaluate the effects of Vitamin D treatment on cognition that is currently unaddressed the parent VIOLET trial.

Narrative Three out of four survivors of acute respiratory distress syndrome (ARDS) will develop long- term cognitive impairment and executive dysfunction. There is an abundance of data that suggest Vitamin D deficiency is associated with poorer long-term cognition. As a result, we propose this randomized control trial to determine if a single, high dose, enteral Vitamin D3 treatment (540,000 IU) given within 12 hours of admission improves 6-month global cognition and executive function compared with placebo in critically ill patients with ARDS risk factors.