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 RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary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.

Pediatric Chiari I malformation: novel and traditional measurements associated with syrinx and surgery.

PURPOSE: Multiple imaging parameters have been examined to estimate the presence of syrinx and the need for surgery in Chiari I patients (CM1); however, no consistent or definitive criteria have been proposed. The objective of this study was to review existing and identify novel radiological and clinical characteristics of CM1 patients that associate syrinx development and surgical intervention. METHODS: Patients with Chiari I malformation diagnosed on imaging between 0 and 18 years were retrospectively reviewed from January 1, 2007 to February 12, 2020. Participants were included if they had a baseline MRI of the head and spine prior to surgical intervention if required. Forty age-matched controls with cranial imaging were identified for comparison. Imaging parameters and clinical symptoms were recorded. RESULTS: A total of 122 CM1 patients were included in this study. Of the 122 patients, 28 (23%) had syrinx, and 27 (22%) had surgery. The following imaging parameters associated with syrinx and surgical intervention were identified: midbrain length (P < 0.001; P = 0.032), the obex position (P = 0.002; P < 0.001) and medullary kinking (P = 0.041; P < 0.001). Among the clinical features, the presence of overall pain (P = 0.017; P = 0.042), neck pain (P = 0.005; P = 0.027), and sensory dysfunction (P < 0.001) were found to be strongly associated with syrinx and surgery. CONCLUSION: While further investigation is needed, these specific radiological and clinical parameters should be considered when evaluating CM1 patients and may be used to guide further management.

Use of Complementary Health Approaches for Acute Complaints Presenting to the Emergency Department.

OBJECTIVE: This study aimed to determine the prevalence of complementary health approaches (CHAs) specifically for acute complaints in patients assessed in a pediatric emergency department (ED) and factors associated with use. METHODS: A cross-sectional survey was offered to patients between the age of 28 days and 18 years assessed at a tertiary pediatric ED between December 2014 and July 2015. Univariate and multivariate logistic regressions were used to identify variables associated with CHA use. RESULTS: Of 475 potential participants, 412 (86.7%) participated, of which 369 (89.5%) completed the survey. Overall, 28.7% (95% confidence interval [CI], 24.3-33.5) reported using any CHA for their child to treat the presenting complaint in the prior 72 hours to the ED visit. Gastrointestinal complaints had the highest use of CHA (46.3% of presentations endorsed use). The most common complementary health products used were vitamins and minerals (40.9%; 95% CI, 31.2-51.4); the most common complementary health practice used was massage (37.2%; 95% CI, 24.4-52.1). Multivariate analysis showed lower odds of using CHA for rash/skin complaint (odds ratio, 0.23; 95% CI, 0.09-0.59; P < 0.01) or musculoskeletal/extremity complaints (odds ratio, 0.23; 95% CI, 0.07-0.75; P = 0.01) compared with use for fever. No statistically significant association was found between CHAs use and child's sex, child's age, private insurance, or caregiver education. CONCLUSIONS: Caregivers commonly use CHA for acute pediatric complaints requiring an ED visit, with greatest use for gastrointestinal complaints. Clinicians should consider the use and safety of CHA when evaluating children presenting to the ED with acute conditions.

Use and perceived effectiveness of complementary health approaches in children.

BACKGROUND AND OBJECTIVES: Up to one-half of children may use complementary health approaches (CHA). However, current prevalence in North America, variables associated with CHA use and caregiver perceptions of effectiveness are unclear. We aimed to determine the self-reported use of CHA during the previous 12 months in paediatric patients, demographic variables associated with CHA use and perceptions around effectiveness of CHA. METHODS: A cross-sectional survey study of patients aged between 28 days and 18 years who presented to a large paediatric emergency department was conducted between December 2014 and July 2015. Univariate analysis and multivariate logistic regression were used to examine variables associated with CHA use. RESULTS: Of 475 potential participants, 412 (86.7%) responded to the questionnaire, of whom 369 (89.5%) had completed the entire survey. Of these, 61.7% (95% confidence interval [CI] 56.7% to 66.6%) reported using CHA for their child. The most used CHA products were vitamins and minerals (59.2%, 95% CI 52.4% to 65.7%). Among CHA practices, massage (50.0%, 95% CI 15.5% to 30.1%) was most common. Most CHA users perceived effectiveness of the therapy used. Parental education remained statistically significant (P=0.03) in multivariate logistic regression; the odds of CHA use among caregivers with university-level education were 1.65 times higher when compared with those without (95% CI 1.04% to 2.61%). CONCLUSIONS: CHA use is higher than previously reported in children. Given the high self-reported perceived effectiveness, paediatricians and family physicians should review CHA use with their patients in an open, non-judgmental manner, exploring both perceptions of safety and efficacy.

A nurse-initiated jaundice management protocol improves quality of care in the paediatric emergency department.

BACKGROUND: Hyperbilirubinemia is a common neonatal condition requiring timely management to prevent acute bilirubin encephalopathy. Management protocols allow nonphysicians to initiate designated actions prior to physician assessment. OBJECTIVE: To assess the effectiveness of a nurse-initiated neonatal jaundice management protocol for serum bilirubin sampling and phototherapy for neonates presenting with hyperbilirubinemia to the Paediatric Emergency Department (PED). METHODS: A health records review was performed for jaundiced neonates 12 months prior to the introduction of the management protocol (control period) and 12 months after (intervention period). Randomly selected charts were evaluated for time to serum bilirubin sampling, phototherapy initiation, ED length of stay, admission rate, completion of direct antiglobulin test and nursing documentation. RESULTS: Two hundred and sixty-six neonates (131 control and 135 intervention) were included. Median time to serum bilirubin sampling was reduced by 22% (36 min versus 28 min; P<0.001) with 34 min difference at the 90th percentile (94 min [95% confidence interval (CI) 63.7 to 116.9] versus 60 min [95% CI 49.0 to 78.2]). Statistically significant improvements were found in time to phototherapy initiation (127 min [95% CI 72.0 to 160.7] versus 65 min [95% CI 50.0 to 72.4] at 90th percentile), ED length of stay (267 min [95% CI 180.9 to 292.9] versus 216 min [95% CI 171.1 to 247.4] at 90th percentile) and hospital admissions (36% versus 17%; P<0.001). Improvements were also observed in direct antiglobulin test measurement (P<0.001) and nursing documentation (P=0.017). CONCLUSIONS: Implementation of a PED neonatal jaundice management protocol was associated with improved timeliness and standardization of care for this common and important condition.

Nutrient Insufficiencies/Deficiencies in Children With Sickle Cell Disease and Its Association With Increased Disease Severity.

BACKGROUND: Sickle cell disease (SCD) is characteristically described as a disease of hemolytic anemia and vaso-occlusive crises (VOCs). However, patients suffer from a multitude of other problems including impaired development, chronic pain, and increased susceptibility to infection. Nutritional deficiency has been implicated as a contributor to these issues. PROCEDURE: We reported the nutrition status with respect to vitamin D, zinc, B6, B12, folate, and homocysteine serum levels in Canadian children with SCD (n = 91). We also tested for associations between nutrients and markers of disease severity and growth. RESULTS: Almost half the sample (42%) had multiple nutrient insufficiencies/deficiencies, and a further 27% had a single insufficiency/deficiency. The most common insufficiency/deficiency was zinc in 57% followed by calcidiol (25 dihydroxyvitamin D (25(OH)D)) (52%). Sixteen percent of patients had low vitamin B6 levels, while folate, calcitriol (1,25(OH)D), and homocysteine levels were normal. Increased number of vitamin insufficiencies/deficiencies was associated with increasing disease severity (P = 0.018). Zinc insufficiency/deficiency was significantly associated with an increased number of home pain crises (P = 0.001) and an increased incidence of hospitalizations for VOCs (P = 0.01). CONCLUSIONS: Our findings show that patients with SCD commonly have multiple nutrient insufficiencies/deficiencies and support the growing evidence for the link between low zinc and increased VOC. It also indicates that increased nutrient insufficiencies/deficiencies are associated with increased disease severity in SCD. Prospective studies with larger samples are needed to further elucidate the relationship between nutrient deficiencies and SCD, and to determine whether nutrient supplementation can improve the disease course.

Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review.

BACKGROUND: Many residents of the United States and Canada depend on dietary sources of vitamin D to help maintain vitamin D status. Because few natural food sources contain vitamin D, fortified foods may be required. OBJECTIVE: We aimed to determine the effects of vitamin D-fortified foods on serum 25-hydroxyvitamin D [25(OH)D] concentrations. DESIGN: We searched MEDLINE (1966 to June Week 3 2006), Embase, CINAHL, AMED, Biological Abstracts, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) comparing vitamin D-fortified foods with a control and reporting serum 25(OH)D concentrations. Two reviewers independently determined study eligibility, assessed trial quality, and extracted relevant data. Disagreements were resolved by consensus. Meta-analyses of absolute mean change in 25(OH)D were conducted by using a random-effects model, with evaluation of heterogeneity. RESULTS: Nine RCTs (n = 889 subjects) were included, of which 8 consistently showed a significant beneficial effect of food fortification on 25(OH)D concentrations. Although 7 RCTs (n = 585 subjects) potentially were meta-analyzable, we were unable to combine the overall results because of significant heterogeneity. The individual treatment effects ranged from 14.5 (95% CIs: 10.6, 18.4) nmol/L to 34.5 (17.64, 51.36) nmol/L (3.4-25 microg vitamin D/d). Subgroup analyses showed a reduction in heterogeneity and significant treatment effect when 4 trials that used milk as the fortified food source were combined. CONCLUSION: Most trials were small in size and inadequately reported allocation concealment, but results showed that vitamin D-fortified foods improved vitamin D status in adults.

Effectiveness and safety of vitamin D in relation to bone health.

OBJECTIVES: To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. DATA SOURCES: MEDLINE(R) (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). REVIEW METHODS: Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. RESULTS: 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of <400 IU to doses >/= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. CONCLUSIONS: The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms.

Effect of calcium and vitamin D supplementation on bone mineral density in children with inflammatory bowel disease.

OBJECTIVES: The purpose of this study was to evaluate the effect of calcium and vitamin D2 supplementation on bone mineral density (BMD) in children with inflammatory bowel disease (IBD). PATIENTS AND METHODS: This was an open-label, prospective study conducted over a 12-month period. Seventy-two patients were divided into 2 groups based on lumbar spine areal BMD (L2-4 aBMD). Patients with an L2-4 aBMD z score of -1 or higher were assigned to the control group (n = 33; mean age, 11.0 +/- 3.5 years; 20 boys). Patients with an L2-4 aBMD of less than -1 (n = 39; mean age 11.8 +/- 2.5 years; 25 boys) were allocated to the intervention group and received 1000 mg of supplemental elemental calcium daily for 12 months (n = 19) or supplemental calcium for 12 months and 50,000 IU of vitamin D2 monthly for 6 months (n = 20). RESULTS: The 2 groups differed in L2-4 aBMD z scores (intervention, -1.9 +/- 0.6; control, -0.2 +/- 0.6; P < 0.001) and volumetric L2-4 BMD (vBMD; intervention, 0.29 +/- 0.04; control, 0.33 +/- 0.06; P < 0.001). After 1 year of therapy, the control and intervention groups had similar changes in height z scores, L2-4 aBMD, L2-4 vBMD (z score change, L2-4 aBMD: control 0.2 +/- 0.6 [n = 21], intervention 0.4 +/- 0.6; P = 0.4 [n = 26]; z score change, L2-4 vBMD: control 0.1 +/- 0.4, intervention 0.2 +/- 0.6; P = 0.74). The changes in these parameters were similar between patients who had received calcium only or calcium plus vitamin D. CONCLUSIONS: These results suggest that, in children with IBD, supplementation of calcium and vitamin D does not accelerate accrual in L2-4 BMD.