Hypovitaminosis D in Neurocritical Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomized Clinical Trial of Hypovitaminosis D Treatment in the Neurocritical Care Unit

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

Intervention / Treatment
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* Drug: Cholecalciferol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Placebo control (simple oral syrup) | Other: Placebo<br>* Oral syrup placebo<br>|
| Experimental: Vitamin D3<br>Cholecalciferol/Vitamin D3 (540,000 IU orally or by feeding tube once) | Drug: Cholecalciferol<br> <br> * Other names: vitamin D3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intent-to-treat Hospital Length-of-stay | Intent-to-treat hospital length-of-stay | Until discharge | 
| As-treated Hospital Length of Stay | 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. | Until discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intent-to-treat ICU Length of Stay | 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. | Until discharge | 
| As-treated ICU Length of Stay | 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. | Until discharge | 
| In-hospital Mortality | In-hospital mortality | Until discharge | 
| Number of Participants With Study Drug Related Adverse Events | 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. | Until discharge | 
| Number of Participants With Sepsis | Diagnosis of sepsis | Until discharge | 
| Number of Participants With Pneumonia | Pneumonia diagnosis | Until discharge | 
| Number of Participants With Urinary Tract Infection | Urinary tract infection diagnosis | Until discharge | 
| Number of Participants With Deep Vein Thrombosis | Deep vein thrombosis diagnosis | Until discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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seizures, critical illness, craniocerebral trauma, intracranial aneurysm, spinal cord injuries, meningitis, stroke, vitamin d deficiency, cholecalciferol, intracranial hemorrhages