Cholecalciferol Supplementation in Critically Ill Patients With Severe Vitamin D Deficiency.
Cholecalciferol Supplementation in Critically Ill Patients With Severe Vitamin D Deficiency.
The purpose of the research study is to determine whether a single high dose of vitamin D is
 helpful in reducing critical illness related complications in intensive care patients who are
 having sever vitamin D deficiency.

 Vitamin D deficiency is quite common in critically ill patients ranging from 81.5% to 99%. A
 number of scientific studies have documented a strong correlation between low levels of vit.D
 and increased rate of adverse outcomes including infection, acute kidney injury and mortality
 in ICU patients. A recent randomized controlled trial (RCT) has demonstrated a 50% reduction
 in hospital mortality in severe vit.D deficient patients following a single high dose of
 cholecalciferol (Vitamin D3). However, the role of Vit.D supplementation to boost up host
 immune system and eventually reduction of mortality has yet to be determined by large
 randomized controlled trials in humans. Hence the study aims to run a randomized controlled
 trial (RCT) in order to study the role of Vitamin D in critically ill patients.
DETAILED DESCRIPTION

 Introduction: Vitamin D is a fat soluble vitamin and it affects multiple systems of our body.
 It not only plays a key role in musculoskeletal system but also works on our immune and
 cardiovascular systems. Because of its wide range of anti-inflammatory and metabolic
 properties, vitamin D, recently, has gained an immense importance among the intensivists.

 Most of the critically ill patients have vitamin D deficiency and are at high risk of
 complications ranging from systemic inflammatory response syndrome (SIRS), sepsis, septic
 shock, multi-organ dysfunction, multi-organ failure and finally death. Immune system
 dysregulation has been thought to play a pivotal role in the development of sepsis. Onset and
 progression of sepsis are dependent upon a fine balance between pro-inflammatory and
 anti-inflammatory mediators of the immune system. Massive and uncontrolled release of
 pro-inflammatory cytokines leads to widespread tissue damage and multi-organ failure. It has
 been found that the cells of the immune system (both innate and acquired) express receptors
 for vitamin D. Low levels of it renders the immune system regulatory cells dysfunctional and
 in turn, increases the risk of infections and other adverse outcomes. It has been estimated
 that even with optimal treatment anywhere from 16% to more than 80% of patients with sepsis
 don't survive.

 To improve the survival of critically ill patients, several research studies have been
 focused on the identification of various biomarkers and their correlation with disease
 severity. Timely supplementation of cholecalciferol has been demonstrated as one of the
 mortality reduction interventions. In recent studies, vitamin D has been identified as an
 important regulator of our immune system and its deficiency is quite common in ICU patients
 ranging from 81.5% to 99%.

 A number of scientific studies have documented a strong correlation between low levels of
 vit.D and increased rate of adverse outcomes including infection with multi drug resistant
 organisms, acute kidney injury, decreased left ventricular ejection fraction and mortality in
 ICU patients. It has been found that the emergence of acinetobacter baumannii infections in
 significantly more common in vit D deficient critically ill patients and vit D deficiency is
 an independent risk factor for the development of Acinetobacter baumannii infections in
 intensive care unit.

 A recent RCT has demonstrated 50% reduction in hospital mortality in patients with severe
 vit.D deficiency following a single high dose of cholecalciferol (Vitamin D3). However, the
 role of Vit.D supplementation to boost up host immune system and eventually reduction of
 mortality has yet to be determined by large randomized controlled trials.

 In patients with severe vitamin D deficiency, gastrointestinal absorption of vit.D, after
 enteral supplementation could be variable depending upon the patient's gastrointestinal
 functions, critical illness and the activity of hepatic cytochrome P 450 system. In order to
 restore optimal vit.D level in critically ill patients (possibly within first 48 hours), a
 single high dose of it has been suggested on admission to ICU. As in critically ill patients,
 it is highly unlikely to restore Vitamin D within a reasonable period of time by
 supplementing 400-4000 international units/day (recommended daily allowance). Moreover, a
 single large dose of vit.D through the enteral route is highly unlikely to cause vit.D
 toxicity. The acutely toxic level of vit.D is considered to be more than 150 ng/ml.
 Furthermore, this high loading dose of cholecalciferol has been justified based on the safety
 findings of previous studies.

 In addition, during a pilot study followed by a large randomized controlled trial conducted
 by Karen A et al, no serious adverse events were noted with a single high dose (540,000 I.U)
 of cholecalciferol. The highest 25-hydroxyvitamin D level measured was 107 ng/ml which is far
 below the currently suggested toxic level of vit.D (that is more than 150 ng/ml). Moreover,
 one patient in vitamin D3 group was found to have a total serum calcium level of 12 mg/dl and
 an ionized serum calcium level of 6 mg/dl but that patient had primary hyperparathyroidism
 (although normocalcemic at study inclusion). However, the incidence of falls and fracture was
 similar in vitamin D3 and placebo groups for a follow-up period of six months. So a single
 high dose of cholecalciferol is less likely to increase the incidence of hypocalcemia,
 hypercalciuria, falls and fractures which have been found to be increased with annual high
 doses of vitamin D3.

 Hence the investigator intends to use a single high dose of cholecalciferol in order to
 restore it deficiency quickly, hopefully within 1 to 2 days in order to give maximum benefits
 to our critically ill patients right from the start of their illness.

 The aim of our RCT is to study the role of Vit.D supplementation in critically ill patients.
 By boosting up the already struggling immune system of critically ill patients, the
 investigator assumes a significant reduction in mortality and other adverse outcomes.

 Hypothesis: A single high dose of cholecalciferol supplementation improves survival in
 critically ill patients with severe vitamin D deficiency.

 Null Hypothesis: A single high dose of Cholecalciferol supplementation in critically ill
 patients will not reduce the mortality and adverse outcomes.

 Recruitment and randomization: Patients or their surrogates will be contacted on admission to
 ICU and study information will be provided to them by the research staff members. Consented
 patients will be randomized. Randomization list will be prepared by King Abdullah Medical
 City (KAMC) research center. The list will be used to prepare sealed envelopes each
 containing the assigned treatment. These envelopes will be stored in the pharmacy and opened
 up by the research pharmacist who will prepare medication/placebo for the randomized
 patients.

 Blinding: Blinding will be done by research pharmacist in KAMC pharmacy. Fresh milk will be
 used as a placebo. The study medication (a white-colored, powdered form of cellulose based
 vit.D) will be dissolved in fresh milk so that both interventional drug and placebo will have
 the same color, odor, consistency, taste, and amount as that of interventional medication.

 For all vit. D deficient patients, supplement 50,000 IU of cholecalciferol per week through
 the enteral route as a part of routine ICU treatment plan. As our recruited patients will be
 having severe vitamin D deficiency (Vit. D level below 12ng/ml) so both interventional and
 placebo group patients will receive our routine treatment for vit.D deficiency which is
 50,000 IU of cholecalciferol through enteral route per week.

 Intervention: Patients randomized to vitamin D group will receive 400,000 IU of
 cholecalciferol dissolved in 45 ml of fresh milk through orogastric tube/nasogastric
 tube/Oral within 1st 24 hours of ICU admission. This high dose is in addition to our routine
 treatment for vitamin D deficiency.

 Post-recruitment retention strategies: the study will follow our patients for 30 days or as
 long as they stay in ICU after supplementation of a single high dose of vitamin D or placebo.
 As the investigators are working with critically ill patients, expecting at least a few weeks
 of hospital stay. However, the patient having early and quick recovery will be discharged
 home and will be followed up by one of the assigned research team members who will be
 contacting them by phone and inquire about any complications related to the research study.

 Method: the investigator will complete a randomized controlled trial by supplementing
 cholecalciferol 400,000 IU versus placebo within 24 hours of ICU admission that would be
 added to our routine treatment for vit.D deficiency. Safety of this high dose of vit D has
 been validated in previous studies. This trial will employ block randomization and intention
 to treat protocol. This single-center study would be completed over a period of 2 complete
 years here in KAMC Intensive care Unit.

 Laboratory Measurements: Blood samples will be obtained at baseline (day 0) and days 1, 3, 7,
 and 28 to assess serum parathyroid hormone, total and bioavailable 25-hydroxyvitamin D
 levels, phosphate, procalcitonin, leukocytic count, hemoglobin, creatinine, bilirubin, beta
 natriuretic peptide (BNP), blood glucose and albumin levels. In addition, the investigator
 will also measure urinary calcium and urinary creatinine levels

 Data Collection: Patients will be followed up (1 month) closely for the development of
 study-drug related complications if any, for example, hypercalcemia, hypercalciuria,
 fractures, etc. Data elements to be collected will include, but not limited to:

 1. - Date and time of admission to hospital

 2. - Mode of admission (Emergency Room or in-patients)

 3. - Date and time of ICU admission

 4. - 25 - hydroxyl vitamin D level on admission to ICU.

 5. - Sequential Organ Failure Assessment (SOFA) score

 6. - Acute Physiology And Chronic Health Index (APACHI) Score 7-Patient's co-morbidities
 (Diabetes, Hypertension, Chronic kidney disease, Chronic obstructive pulmonary disease,
 Ischemic Heart Disease, Coronary Artery Bypass Grafting, Cerebrovascular accident,
 Arrhythmias, Anemias, smoking, obesity, cancer)

 8 - Mode of Oxygen delivery to the patient 9 - Previous positive cultures and antibiotic
 therapy within the last 3 months 10 - Empirical antibiotic therapy on admission to hospital
 and ICU 11 - Baseline clinically relevant investigation, for example, Echo,
 Electrocardiography, Ultrasound Doppler for Deep venous thrombosis, CT brain/chest/abdomen,
 12 - Endo/bronchoscopic findings if any 13 - Vasopressors and ionotropic support duration 14
 - Central venous catheter, arterial line, pigtail, chest tube (site, date and time of
 insertion) 15 - Evidence of acute or acute on chronic kidney injury on admission to ICU. 16 -
 Surgeries - previous and recent surgeries and any post-op complications 17 - Previous
 immunosuppressive therapies for example chemo/radio/glucocorticoid therapy.

 Sample size calculation: A recent RCT demonstrated almost 50% reduction in hospital mortality
 (46.1% in placebo versus 28.6% in Vit D group) by supplementing 540,000 IU of Vit D3 to
 critically ill patients having severe vitamin D deficiency (25-hydroxyvitamin D level ≤ 12
 ng/ml). With an alpha = 5% (two tailed test), power = 95%, baseline mortality control group
 30% and test group mortality 15%, the sample size required would be 195 patients per group.
 To account for losses to follow up of around 10%, the study aims to recruit 215 patients in
 each group. So the total number of patients required for both the groups would be 430 in 2
 full years.

 Statistical Analysis: the investigator will use an intention to treat approach to avoid the
 effects of crossover and dropout. Standard statistical analysis will include normally or near
 normally distributed variables reported as means and non-normally distributed variables as
 medians. Means will be compared by using student's t-test and medians by using Mann-Whitney U
 test. Differences in proportions among categorical data will be assessed using Fisher's exact
 test. A p-value of less than 0.05 will be considered to represent statistical significance
 for all comparisons.
Inclusion Criteria:

 1. 18 years or older.

 2. Both male and female

 3. Within 24 hours from admission.

 4. Having 25 -Hydroxyvitamin D level of 12 ng/ml or lower.

 Exclusion Criteria

 1. Pregnant or lactating females.

 2. Do not resuscitate (DNR) status or comfort measures only

 3. No consent

 4. Severely impaired gastrointestinal functions (e.g, paralytic ileus, continuous
 nasogastric tube drainage, strict nil per oral- no medication, malabsorption syndrome,
 chronic diarrhea etc)

 5. History of renal stones within past year

 6. Past history of hypercalcemia, tuberculosis or sarcoidosis.

 7. Baseline serum total calcium ≥10.6 mg/dl or ionized serum calcium ≥ 5.4 mg/dl.