Inclusion criteria | Justification |
Admitted to ICU | Admitted to the pediatric or neonatal ICU. The neonatal ICU was included to improve recruitment and to increase the number of participants aged < 30 days. At randomization, patients are stratified by recruitment site (PICU vs NICU) to account for site-specific practice variation. |
Corrected gestational age > 37 weeks to age < 18 years | Pediatric study (< 18 years). Very premature infants are at significantly increased risk for nephrocalcinosis [40, 41]; children < 37 weeks corrected gestational age are excluded to reduce the risk of enrolling patients with an increased chance of adverse outcome. |
Expected ICU admission in excess of 48 h and likely to have access for bloodwork at 7 days of hospital stay (determined by medical team) | This inclusion criterion was selected to (i) include an ICU population with a higher illness severity and (ii) to increase the likelihood of obtaining a blood sample at day 7 for measurement of the primary outcome. |
25(OH)D level < 50 nmol/L | Although thresholds and terminology can vary, vitamin D deficiency is generally accepted as < 50 nmol/L (severe deficiency as < 30 nmol/L) [42,43,44,45]. Multiple observational ICU studies have shown an association with poorer outcome once vitamin D levels fall below 50 nmol/L [19, 20]. Some evidence exists that shows the benefit of supplementation (as defined by mortality) may be limited to ICU patients with severe deficiency (< 30 nmol/L) [2, 27]. In those with more moderate deficiency (30–50 nmol/L) benefits were observed in repeated infections and quality of life [2, 27]. To evaluate this in PICU, we will compare changes in biochemistry and clinical measures separately for the groups with starting 25(OH)D above and below 30 nmol/L. |
Exclusion criteria | Justification |
Significant gastrointestinal disorder preventing enteral drug administration | At present, there is no intravenous form of cholecalciferol, preventing the inclusion of ICU patients who cannot receive enteral drugs. |
Hypercalcemia, excluding transient abnormalities and those related to parenteral calcium administration for hypocalcemia | Patients presenting with hypercalcemia may be at increased risk for toxicity or adverse outcome with a significant abrupt increase in vitamin D level. |
Confirmed or suspected William’s syndrome | Patient with William’s syndrome have a genetic susceptibility to hypercalcemia, and current guidelines recommend against any vitamin D supplementation [46, 47]. |
Patient know to have nephrolithiasis or nephrocalcinosis | Patients presenting with nephrolithiasis or nephrocalcinosis would be at increased risk for an adverse outcome. |
Imminent plan for withdrawal of care or transfer to another ICU | If a patient will be transferred or have care withdrawn imminently, we would be unlikely to obtain either day 3 or day 7 blood and urine sample (25OHD, hypercalcemia, hypercalciuria). |
Physician refusal | If the treating physician has concerns about study participation (e.g., patient presents with clinical symptoms of severe vitamin D deficiency and treating physician plans to administer a large dose of vitamin D), the patient would not be randomized |
Previous enrolment in the VITdAL-PICU pilot study | Patients who previously participated in the VITdAL-PICU study will be excluded to avoid confounding. |
Patient known to have granulomatous disease (tuberculosis or sarcoidosis) | Excess active vitamin D hormone has been observed in patients with granulomatous diseases (tuberculosis/sarcoidosis) and can potentially lead to hypercalcemia or hypercalciuria through increased intestinal absorption of calcium [48]. |
Severe liver dysfunction/failure | The liver plays an essential role in vitamin D metabolism. Patients with severe liver dysfunction/failure have a minimized capacity to convert vitamin D to its active form. To allow for a study population with a more homogenous ability to metabolize and benefit from vitamin D supplementation, patients with severe liver dysfunction/failure will be excluded. |
Patient known to have hypersensitivity or allergy to vitamin D or any of the non-medicinal ingredients of the formulation | Listed as a contraindication in the product monograph |
Patient on thiazide diuretics who is also receiving regular ongoing calcium supplementation above the daily recommended intake for reasons other than hypocalcemia | There is an increased risk of hypercalcemia if vitamin D is co-administered with both thiazide diuretics and calcium (as per product monograph). |
Adolescent female of child-bearing age with a positive pregnancy serum test | Maternal hypercalcemia, possibly caused by excessive vitamin D intake during pregnancy, has been associated with hypercalcemia in neonates, which may lead to adverse effects (as per product monograph). |
Patient on digoxin therapy | Vitamin D should be used with caution in patients on digoxin. Hypercalcemia (which may result with vitamin D use) may precipitate cardiac arrhythmias (as per product monograph). |