Discussion
renal failure, critically ill, nephrocalcinosis
CRITICALLY ILL, RENAL FAILURE, RECRUITMENT, HYPERCALCEMIA, REGRESSION, NEPHROCALCINOSIS
This pilot phase II RCT confirms that a single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children identified as vitamin D deficient (< 50 nmol/L) during admission to the PICU, and that proceeding with a Phase III trial is feasible.We recruited vitamin D deficient (median ~ 35 nmol/L) children from 4 PICUs and 1 NICU at 4 academic centers in Canada, Austria and Chile. The evaluation of baseline characteristics demonstrates the study cohort was severely ill, with 80% requiring mechanical ventilation and 50% receiving vasoactive agents. The loading dose regimen rapidly increased blood levels within 1 day, peaked on days 2 and 3, with 80% of participants exceeding the target blood threshold of 75 nmol/L. These findings are similar to studies with comparable doses administered to critically ill adults with admission 25(OH)D levels < 50 nmol/L. For example, the VITdAL study reported an increase of 50 nmol/L following a 540,000 IU cholecalciferol dose, with 52% exceeding 75 nmol/L [In addition, this study also assessed the feasibility of the weight-based loading dose regimen through an evaluation of vitamin D toxicity data. Loading dose cholecalciferol, when using excessive or repeated doses or in particular in infants and young children, has been linked to hypercalcemia, nephrocalcinosis and renal failure [An important study observation relates to significant variability in post loading dose 25(OH)D concentrations. Eight of 10 of participants in the treatment arm exceed the 75 nmol/L threshold following the single loading dose. However, while the group average 25(OH)D concentration achieved was successful, individual patient responses were variable with some patients exhibiting minimal change and not reaching concentrations > 75 nmol/L (n = 7). In addition, a few patients achieved concentrations > 200 nmol/L (n = 4) or > 250 nmol/L (n = 2). Significant variability in post-study drug concentrations has been previously recognized, with regression analysis of data from pediatric interventional trial literature calculating the SD to average 42% of the mean 25(OH)D [The results of this phase II trial support the feasibility of large-scale, multicentre phase III trial powered for clinical outcome. We met our a priori established feasibility criteria for protocol adherence, blinding, study withdrawal and patient accrual. The patient accrual rate was 3.4 patients per month (~ 1.9 patients/month/site). However, with the exception of the lead site, the other sites were only recruiting for ≤ 5 months, while peak recruitment in critical care RCTs is generally not achieved until at least 7 months after a site initiates recruitment [Recognizing the importance of patient-centred outcomes in clinical trials, we engaged with participating families to seek input on the primary outcome for the Phase III trial. Feedback from families participating in this trial and a concurrent survey by Merrit et al. [