A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

Prevention of post-cardiac surgery vitamin D deficiency in children with congenital heart disease: a pilot feasibility dose evaluation randomized controlled trial.

BACKGROUND: 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. 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. METHODS: We 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. RESULTS: Forty-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. CONCLUSIONS: Pre-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 REGISTRATION: ClinicalTrials.gov, NCT01838447. Registered on April 24, 2013.

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

BACKGROUND: Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. METHODS/DESIGN: The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). DISCUSSION: Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. TRIAL REGISTRATION: Clinicaltrials.gov NCT02452762.

Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients with sepsis, this intervention would be easy to implement. However, the cumulative evidence from several randomized clinical trials (RCTs) remains unclear. METHODS: We searched the Cochrane Library, MEDLINE, and EMBASE through December 2016 for RCTs on parenteral or enteral omega-3 supplementation in adult critically ill patients diagnosed with sepsis or septic shock. We analysed the included studies for mortality, intensive care unit (ICU) length of stay, and duration of mechanical ventilation, and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of the evidence for each outcome. RESULTS: A total of 17 RCTs enrolling 1239 patients met our inclusion criteria. Omega-3 supplementation compared to no supplementation or placebo had no significant effect on mortality [relative risk (RR) 0.85; 95% confidence interval (CI) 0.71, 1.03; P = 0.10; I 2 = 0%; moderate quality], but significantly reduced ICU length of stay [mean difference (MD) -3.79 days; 95% CI -5.49, -2.09; P < 0.0001, I 2 = 82%; very low quality] and duration of mechanical ventilation (MD -2.27 days; 95% CI -4.27, -0.27; P = 0.03, I 2 = 60%; very low quality). However, sensitivity analyses challenged the robustness of these results. CONCLUSION: Omega-3 nutritional supplementation may reduce ICU length of stay and duration of mechanical ventilation without significantly affecting mortality, but the very low quality of overall evidence is insufficient to justify the routine use of omega-3 fatty acids in the management of sepsis.

A systematic review of pediatric clinical trials of high dose vitamin D.

Background. Due to inadequate UV exposure, intake of small quantities of vitamin D is recommended to prevent musculoskeletal disease. Both basic science and observational literature strongly suggest that higher doses may benefit specific populations and have non-musculoskeletal roles. Evaluating the evidence surrounding high dose supplementation can be challenging given a relatively large and growing body of clinical trial evidence spanning time, geography, populations and dosing regimens. Study objectives were to identify and summarize the clinical trial literature, recognize areas with high quality evidence, and develop a resource database that makes the literature more immediately accessible to end users. Methods. Medline (1946 to January 2015), Embase (1974 to January 2015), and Cochrane databases (January 2015), were searched for trials. All pediatric (0-18 years) trials administering doses higher than 400 IU (<1 year) or 600 IU (≥1 year) were included. Data was extracted independently by two of the authors. An online searchable database of trials was developed containing relevant extracted information (http://www.cheori.org/en/pedvitaminddatabaseOverview). Sensitivity and utility were assessed by comparing the trials in the database with those from systematic reviews of vitamin D supplementation including children. Results. A total of 2,579 candidate papers were identified, yielding 169 trials having one or more arms meeting eligibility criteria. The publication rate has increased significantly from 1 per year (1970-1979) to 14 per year (2010-2015). Although 84% of the total trials focused on healthy children or known high risk populations (e.g., renal, prematurity), this proportion has declined in recent years due to the rise in trials evaluating populations and outcomes not directly related to the musculoskeletal actions of vitamin D (27% in 2010s). Beyond healthy children, the only pediatric populations with more than 50 participants from low risk of bias trials evaluating a clinically relevant outcome were prematurity and respiratory illness. Finally, we created and validated the online searchable database using 13 recent systematic reviews. Of the 38 high dose trials identified by the systematic review, 36 (94.7%) could be found within the database. When compared with the search strategy reported in each systematic review, use of the database reduced the number of full papers to assess for eligibility by 85.2% (±13.4%). Conclusion. The pediatric vitamin D field is highly active, with a significant increase in trials evaluating non-classical diseases and outcomes. Despite the large overall number there are few high quality trials of sufficient size to provide answers on clinical efficacy of high-dose vitamin D. An open access online searchable data should assist end users in the rapid and comprehensive identification and evaluation of trials relevant to their population or question of interest.

Prevention of vitamin D deficiency in children following cardiac surgery: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin D is a pleiotropic hormone important for the recovery of organ systems after critical illness. Recent observational studies have suggested that three out of every four children are vitamin D deficient following cardiac surgery, with inadequate preoperative intake and surgical losses playing important contributory roles. Observed associations between postoperative levels, cardiovascular dysfunction and clinical course suggest that perioperative optimization of vitamin D status could improve outcome. With this two-arm, parallel, double blind, randomized controlled trial (RCT), we aim to compare immediate postoperative vitamin D status in children requiring cardiopulmonary bypass for congenital heart disease who receive preoperative daily high dose vitamin D supplementation (high-dose arm) with those who receive usual intake (low-dose arm). METHODS/DESIGN: Eligibility requirements include age (>36 weeks, <18 years) and a congenital heart defect requiring cardiopulmonary bypass surgical correction. Enrollment of 62 participants will take place at a single Canadian tertiary care center over a period of 2 years. Children randomized to the high-dose group will receive age-based dosing that was informed by the Institute of Medicine (IOM) daily tolerable upper intake level (<1 year old = 1,600 IU/day, >1 year old = 2,400 IU/day). Children in the low-dose arm will receive usual care based on IOM recommendations (<1 year old = 400 IU, >1 year old = 600 IU). The primary outcome measure is immediate postoperative vitamin D status, using blood 25(OH)D. DISCUSSION: Maintaining adequate postoperative vitamin D levels following surgery could represent an effective therapy to speed recovery following CHD surgery. The proposed research project will determine whether preoperative supplementation with a dosing regimen based on the IOM recommended daily upper tolerable intake will prevent postoperative vitamin-D deficiency in the majority of children. The results will then be used to inform the design of a large international RCT exploring whether preoperative optimization of vitamin D status might improve short and long-term outcomes in this vulnerable population. TRIAL REGISTRATION: Clinicaltrials.gov Identifier--NCT01838447 Date of registration: 11 April 2013.

Rapid normalization of vitamin D levels: a meta-analysis.

BACKGROUND: Vitamin D deficiency may represent a modifiable risk factor to improve outcome in severe illness. The efficacy of high-dose regimens in rapid normalization of vitamin D levels is uncertain. METHODS: We conducted a systematic review of pediatric clinical trials administering high-dose vitamin D to evaluate 25-hydroxyvitamin D (25[OH]D) response and characteristics associated with final 25(OH)D levels by using Medline, Embase, and the Cochrane Central Register of Controlled Trials, including reference lists of systematic reviews and eligible publications. Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (≥1000 IU) ergocalciferol or cholecalciferol were selected. Two reviewers independently extracted and verified predefined data fields. RESULTS: We identified 88 eligible full-text articles. Two of 6 studies that administered daily doses approximating the Institute of Medicine's Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >75 nmol/L within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >75 nmol/L. In meta-regression, baseline 25(OH)D, regimen type, dose, age, and time factors were associated with final 25(OH)D levels. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses <400 000 IU (or 10 000 IU/kg). Few studies in adolescents evaluated loading dose regimens >300 000 IU. CONCLUSIONS: Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight). Loading doses >300 000 IU should be avoided until trials are conducted to better evaluate risk and benefit.