Abstract
BackgroundThe vast majority of children undergoing cardiac surgery have low vitamin D levels post-operative, which may contribute to greater illness severity and worse clinical outcomes. Prior to the initiation of a large phase III clinical trial focused on clinical outcomes, studies are required to evaluate the feasibility of the study protocol, including whether the proposed dosing regimen can safely prevent post-operative vitamin D deficiency in this high-risk population.MethodsWe conducted a two-arm, double-blind dose evaluation randomized controlled trial in children requiring cardiopulmonary bypass for congenital heart disease. Pre-operatively, participants were randomized to receive cholecalciferol representing usual care (< 1 year = 400 IU/day, > 1 year = 600 IU/day) or a higher dose approximating the Institute of Medicine tolerable upper intake level (< 1 year = 1600 IU/day, > 1 year = 2400 IU/day). The feasibility outcomes were post-operative vitamin D status (primary), vitamin D-related adverse events, accrual rate, study withdrawal rate, blinding, and protocol non-adherence.ResultsForty-six children were randomized, and five withdrew prior to surgery, leaving 41 children (21 high dose, 20 usual care) in the final analysis. The high dose group had higher 25-hydroxyvitamin D concentrations both intraoperatively (mean difference + 25.9 nmol/L; 95% CI 8.3–43.5) and post-operatively (mean difference + 17.2 nmol/L; 95% CI 5.5–29.0). Fewer participants receiving high-dose supplementation had post-operative serum 25-hydroxyvitamin D concentrations under 50 nmol/L, compared with usual care (RR 0.31, 95% CI 0.11–0.87). Post-operative vitamin D status was associated with the treatment arm and the number of doses received. There were no cases of hypercalcemia, and no significant adverse events related to vitamin D. While only 75% of the target sample size was recruited (limited funding), the consent rate (83%), accrual rate (1.5 per site month), number of withdrawals (11%), and ability to maintain blinding support feasibility of a larger trial.ConclusionsPre-operative daily high-dose supplementation improved vitamin D status pre-operatively and at time of pediatric ICU admission. The protocol for a more definitive trial should limit enrollment of children with at least 30 days between randomization and surgery to allow adequate duration of supplementation or consider a loading dose.Trial registrationClinicalTrials.gov, NCT01838447. Registered on April 24, 2013
Highlights
The vast majority of children undergoing cardiac surgery have low vitamin D levels post-operative, which may contribute to greater illness severity and worse clinical outcomes
Fewer participants receiving high-dose supplementation had post-operative serum 25-hydroxyvitamin D concentrations under 50 nmol/L, compared with usual care (RR 0.31, 95% confidence intervals (CI) 0.11– 0.87)
A systematic review of 17 observational studies reporting on 25-hydroxyvitamin D (25OHD) concentrations in the general pediatric intensive care unit (ICU) setting concluded that 55% of critically ill children worldwide have admission 25-Hydroxyvitamin D (25OHD) concentrations below the accepted target threshold of 50 nmol/L required for optimal axis functioning [9]
Summary
The vast majority of children undergoing cardiac surgery have low vitamin D levels post-operative, which may contribute to greater illness severity and worse clinical outcomes. Congenital heart disease (CHD) is a common condition occurring in 1 per 100 births Many of these lesions are pathological, necessitating cardiac surgery to prevent death and improve short- and long-term quality of life [1]. Supplementing this work, four studies focused on children with CHD report that between 50 and 90% have post-operative serum 25OHD concentrations below 50 nmol/L [14,15,16,17]. Observational work by multiple groups describes an abrupt 40% decline in 25OHD concentrations during pediatric CHD surgery, which coincided with the initiation of cardiopulmonary bypass [15, 17]. The available literature suggests that usual low-dose daily supplementation based on the recommended daily allowance issued by the Insititute of Medicine is inadequate to maintain post-operative 25OHD concentrations above 50 nmol/L in the CHD population [19]
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