Hypovitaminosis D in Neurocritical Patients

Vitamin D has been shown to impact prognosis in a variety of retrospective and randomized clinical trials within an intensive care unit (ICU) environment. Despite these findings, there have been no studies examining the impact of hypovitaminosis D in specialized neurocritical care units (NCCU). Given the often significant differences in the management of patients in NCCU and more generalized intensive care units there is a need for further inquiries into the impact of low vitamin D levels in this specific environment. This study proposes a randomized, double-blinded, placebo-controlled, single center evaluation of vitamin D supplementation in the emergent NCCU patient population. The primary outcome will involve length-of-stay for emergent neurocritical care patients. Various secondary outcomes, including in-hospital mortality, ICU length-of-stay, Glasgow Outcome Score on discharge, complications and quality-of-life metrics. Patients will be followed for 6 months post-discharge.

Vitamin D has been shown as an important marker of prognosis in a variety of clinical settings, including overall mortality, acute respiratory distress syndrome (ARDS), infection/sepsis, asthma, cardiovascular disease, diabetes, and pediatric/medical/surgical intensive care unit outcomes. Vitamin D not only plays a role in bone maintenance, but also a variety of extra-axial functions including immune-dysregulation and systemic inflammation. In addition, a number of randomized clinical trials support the supplementation of vitamin D as improving outcome in critical care patients. While the evaluation of vitamin D levels remains a standard-of-care at our institution, the widespread use of vitamin D monitoring and impact on neurocritical care patients remains limited. The investigators' recent prospective observational study of vitamin D levels in neurocritical patients showed that deficiency (<20ng/dL) was highly associated with prolonged hospital stay and increased in-hospital mortality for emergent patients. Moreover, a number of limitations arise from this study due to its observational nature. This study proposes a randomized, double-blinded, placebo-controlled, single center evaluation of vitamin D supplementation in the neurocritical care patient population. Patients admitted to the neurocritical care unit for emergent cases and with vitamin D deficiency (<20ng/dL) will undergo vitamin D serum draw on admission and be randomized to receive cholecalciferol/vitamin D3 supplementation (540,000 IU once orally) or placebo. The primary outcome measured will be hospital length-of-stay. Secondary outcomes will include length of ICU course, complications, medication adverse events, discharge Glasgow Outcome Score, in-hospital and 30-day mortality, as well as quality-of-life. Power analysis estimates 198 patients will be needed for each subgroup to determine a 2 day difference in length-of-stay, and the study plans to recruit 218 patients per treatment arm to account for dropout, which will take approximately 6-9 months to recruit. Interim analysis and safety monitoring will be performed. The investigators hypothesize that vitamin D supplementation may make a significant impact on reducing morbidity and mortality in the neurocritical care population. The possibility of reducing hospital length of stay and mortality from a simple, safe, and cost-effective intervention such as vitamin D supplementation may be a useful adjuvant treatment in the neurocritical care population.

Craniocerebral Trauma, Intracranial Aneurysm, Brain Neoplasms, Spinal Cord Injuries, Seizures, Meningitis, Stroke, Intracranial Hemorrhages, Critical Illness, Vitamin d Deficiency

critical illness, craniocerebral trauma, intracranial aneurysm, spinal cord injuries, seizures, meningitis, stroke, vitamin d deficiency, cholecalciferol, intracranial hemorrhages

Two-sided t-test evaluated comparing length of stay in vitamin D3 vs. placebo treated patients utilizing patients after randomization, factoring excluded patients (e.g., as-treated) using a p<0.05 as significant.

Two-sided t-test evaluated comparing length of stay within the ICU specifically in vitamin D3 vs. placebo treated patients utilizing patients after randomization (e.g., intent-to-treat) using a p<0.05 as significant.

Two-sided t-test evaluated comparing length of stay within the ICU specifically in vitamin D3 vs. placebo treated patients utilizing patients after randomization but excluding patients who did not receive treatment (e.g., as-treated) using a p<0.05 as significant.

The occurrence of patients who suffered mortality, adverse events or severe adverse events, related specifically to the study drug was monitored. Severe adverse events are defined using common terminology criteria for adverse events (CTCAE) grade 3 or higher specific to vitamin D from time of study drug administration to discharge.

Inclusion Criteria: Patients >18 years of age Patients admitted to the neurosurgery or neurology services Patients admitted to a critical care unit Informed consent Expected to stay in the ICU for 48 hours or more Vitamin D deficiency (<20ng/mL) Exclusion Criteria: Patients where a vitamin D level was not drawn within 48 hours of admission Patients not randomized within 48 hours of admission Readmitted patients to the critical care unit Lack of informed consent Prior supplementation with vitamin D Severely impaired gastrointestinal function Other trial participation Pregnant or lactating women Hypercalcemia (total calcium of >10.6 mg/dL or ionized serum calcium of >5.4 mg/dL Tuberculosis history or clinical exam Sarcoidosis history or clinical exam Nephrolithiasis within the prior year Patients not deemed suitable for study participation (ie, psychiatric disease, living remotely from the clinic, or prisoner status) Pregnant or nursing women

Guan J, Karsy M, Brock AA, Eli IM, Ledyard HK, Hawryluk GWJ, Park MS. A prospective analysis of hypovitaminosis D and mortality in 400 patients in the neurocritical care setting. J Neurosurg. 2017 Jul;127(1):1-7. doi: 10.3171/2016.4.JNS16169. Epub 2016 Jul 1.

Carter BS, Barker FG. Editorial. Choices in clinical trial design. J Neurosurg. 2019 Sep 13:1-3. doi: 10.3171/2019.7.JNS183276. Online ahead of print. No abstract available.

Karsy M, Guan J, Eli I, Brock AA, Menacho ST, Park MS. The effect of supplementation of vitamin D in neurocritical care patients: RandomizEd Clinical TrIal oF hYpovitaminosis D (RECTIFY). J Neurosurg. 2019 Sep 13:1-10. doi: 10.3171/2018.11.JNS182713. Online ahead of print.