Rapid Normalization of Vitamin D Deficiency in PICU

Summary

Participation Requirements

Description

Rationale: Documented roles for vitamin D in calcium homeostasis, cardiovascular and respiratory health, innate immunity, and neuromuscular function have led to the hypothesis that vitamin D deficiency (VDD) represents a modifiable risk factor for outcomes in critical illness. Recently, dozens of ad...

Rationale: Documented roles for vitamin D in calcium homeostasis, cardiovascular and respiratory health, innate immunity, and neuromuscular function have led to the hypothesis that vitamin D deficiency (VDD) represents a modifiable risk factor for outcomes in critical illness. Recently, dozens of adult and pediatric intensive care unit (ICU) studies have reported high deficiency rates (50% globally) and associations between VDD, organ dysfunction and mortality. Given the cumulative body of basic science and clinical literature, it has been hypothesized that high-dose vitamin D supplementation could improve ICU outcomes. Recent meta-analyses of multiple small to moderate sized adult clinical trials have suggested improvements in clinical outcome following high-dose supplementation, including survival. Two large multicentre trials have been initiated in the United States and Europe to confirm these findings. In contrast, the benefits and risks of rapid normalization of vitamin D status in the pediatric intensive care unit (PICU) have not been evaluated as part of a large multicentre clinical trial. Study Design: VITdALIZE-KIDS is a Phase III double blind randomized clinical trial (RCT) to determine whether rapid normalization of VDD in critically ill children improves clinical outcome. In total, 766 critically ill children with VDD will be enrolled from PICUs in Canada. Objectives: Primary: We will determine if rapid normalization of vitamin D status reduces the decline in health-related quality of life (HRQL), including mortality, that follows pediatric critical illness. Secondary: We will evaluate the impact of rapid normalization of vitamin D status on new or progressive multi-organ dysfunction. Eligibility Criteria: 1) Anticipated ICU stay of >48 hours; 2) age 37 weeks corrected gestational age to <18 years; 3) expected to require in-hospital clinically indicated blood work >48 hours post-enrollment (range 2-7 days); 4) does not meet any exclusion criteria; and 5) blood 25 hydroxyvitamin D (25OHD) under 50 nmol/l. Patients meeting who meet all eligibility criteria and provide consent will be enrolled and randomized. Interventions: Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) or placebo equivalent in volume to the appropriate dose of cholecalciferol. This dose was evaluated in our pilot dose evaluation trial and shown to be effective (raised group 25OHD levels >75 nmol/L in >75% of participants) and safe (no cases of hypercalcemia or nephrocalcinosis, no difference in the rate of hypercalciuria between study arms). Participants may also receive standard vitamin D dosing at the discretion of the care team (e.g. 400-1000 IU/day). Data Collection: Baseline HRQL (prior to admission) will be obtained within 72 hours of PICU admission. Follow-up measurements will be obtained in person (for patients who are still in hospital) or by telephone (for patients who have been discharged from hospital) at 28 and 90 days. Data on organ dysfunction, demographics, hospital course, adverse events, and health resource utilization will be collected throughout PICU and hospital stay. A blood sample collected at enrollment on Day 5 (range: Day 3-7) to determine 25OHD response and evaluate vitamin D axis functioning. An additional blood sample will be collected following specific interventions known to significantly reduce 25OHD concentrations, including: cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), plasma exchange. A urine sample will be collected an enrollment and on Day 5 (range: Day 3-7) for analysis of calcium:creatinine ratio. Significance: High VDD rates in PICUs and the recognized interaction between vitamin D status and the health of multiple organ systems suggests vitamin D could represent an inexpensive and safe means of improving outcome. However, the true benefits or risks have not been evaluated in PICU in a clinical trial. The proposed trial seeks to address this question. Study findings will be used to inform guidelines for vitamin D supplementation in PICU, which will be easily generalizable to critically ill children worldwide.

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