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Table 2 VITdAL-PICU pilot study inclusion and exclusion criteria

From: Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study)

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).