J. Dayre McNally

The Association of Vitamin D Status With Pediatric Critical Illness

OBJECTIVES: Vitamin D is a pleiotropic hormone important for the proper functioning of multiple organ systems. It has been hypothesized that vitamin D deficiency could contribute to or worsen outcomes in critical illness. The study objective was to determine the prevalence of vitamin D deficiency, risk factors for its presence, and potential association with clinically relevant outcomes in critically ill children. METHODS: A prospective cohort study, conducted from 2005 to 2008 in 6 tertiary-care PICUs in Canada. Data and biological samples from 326 critically ill children up to 17 years of age were available for analysis. Total serum 25 hydroxyvitamin D or 25(OH)D was measured by using liquid chromatography-mass spectrometry. RESULTS: The prevalence of 25(OH)D <50 nmol/L was 69% (95% confidence interval, 64–74), and 23% (95% confidence interval, 19–28) for 25(OH)D between 50 to 75 nmol/L. Lower levels were associated with hypocalcemia, catecholamine utilization, and significant fluid bolus administration. Vitamin D deficiency was independently associated with a longer PICU length of stay (+1.92 days, P = .03) and increasing severity of illness as determined by the Pediatric Risk of Mortality score with every additional point increasing the likelihood of being vitamin D deficient by 8% (P = .005). CONCLUSIONS: This study provides evidence that vitamin D deficiency is both common among critically ill children and associated with greater severity of critical illness. Further research will determine whether targeted vitamin D supplementation or rapid restoration will improve outcome.

Impact of anesthesia and surgery for congenital heart disease on the vitamin d status of infants and children: a prospective longitudinal study.

Background:Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levels and clinical course. Methods:A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquid chromatography–mass spectrometry. Results:The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P = 0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associated with increased fluid requirements and intubation duration. Conclusions:Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperative vitamin D deficiency improves outcome.

Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis.

A number of small studies have suggested a relationship between vitamin D status and severe acute lower respiratory tract infection (ALRI), including RSV—bronchiolitis. The objective of this study was to evaluate the relationship between vitamin D receptor (VDR) polymorphism and severe RSV‐bronchiolitis through a systemic literature review and meta‐analysis.

Understanding vitamin D deficiency in intensive care patients

)Division of Endocrinology and Metabolism,Department of Internal Medicine, MedicalUniversity of Graz, Graz, Austriae-mail: karin.amrein@yahoo.deK. B. ChristopherRenal Division, Brigham and Women’sHospital, Harvard Medical School, Boston,MA, USAJ. D. McNallyChildren’s Hospital of Eastern Ontario,Ottawa, ON, Canada

Vitamin D intake in young children with acute lower respiratory infection

OBJECTIVE To determine if vitamin D intake is associated with acute lower respiratory infections (ALRI) in children. METHODS The vitamin D intakes of children younger than 5 years of age admitted to hospital with either bronchiolitis or pneumonia were compared to an unmatched control group of the same age without respiratory infection. Caregivers of 197 children completed a questionnaire collecting information on demographic variables, ALRI risk factors and diet. Associations of ALRI with vitamin D intake and other ALRI risk factors were determined. RESULTS The mean vitamin D intake of children with ALRI was 48 IU/kg/d compared to 60 IU/kg/d in the control group. When controlling for age, ethnicity, socio-economic status, northern residence, breastfeeding, immunizations and smoking contact, children with a vitamin D intake of less than 80 IU/kg/d were greater than 4 times more likely to have ALRI compared to children with a vitamin D intake exceeding 80 IU/kg/day (OR 4.9, 95% CI: 1.5, 16.4). CONCLUSIONS A higher vitamin D intake than currently recommended might be needed to offer protection against diseases such as ALRI. Increased vitamin D supplementation could have important public health consequences, as bronchiolitis and pneumonia are the most common reasons for hospitalization in young children.

Epidemiologic Considerations in Unexplained Pediatric Arthralgia: The Role of Season, School, and Stress

Objective. To determine demographic and epidemiologic characteristics in children with unexplained joint pain. Methods. The study population included 730 children (< 18 yrs of age) referred between 1981 and 2007 to the Saskatchewan Pediatric Rheumatology Program, University of Saskatchewan, because of arthralgia. Parents and patients completed a questionnaire at the time of initial presentation, and a diagnosis of unexplained arthralgia was assigned based on clinical assessment. Serum vitamin D levels were measured in 73 patients diagnosed with arthralgia. Results. Subjects with arthralgia were more likely to report psychosocial stresses including family discord and illness in the family, and to be cared for by a single parent as a consequence of parental separation or death. Significantly more patients reported fall and winter (30%) as the season of symptom onset compared to spring or summer (20%; p = 0.01). Significantly more survey respondents in the arthralgia group reported missing school compared to the control group (62% vs 31%; p = 0.001). Referrals from northern Saskatchewan were significantly more numerous than from southern Saskatchewan (107 vs 45 per 100,000; p < 0.001). Serum vitamin D concentrations measured in a subgroup of patients (n = 73) showed that 62 (82%) were abnormally low, 42% between 50 and 75 nmol/l (insufficient), and 40% < 50 nmol/l (deficient). Conclusion. Our results suggest an association between psychosocial stress, school absenteeism, vitamin D insufficiency, and unexplained arthralgia in children.

1,25-Dihydroxyvitamin D Levels in Pediatric Intensive Care Units: Risk Factors and Association With Clinical Course

CONTEXT Multiple adult and some pediatric critical care studies have suggested that poor vitamin D status is associated with illness severity and outcome. The majority have evaluated vitamin D status through serum 25-hydroxyvitamin D [25(OH)D]. Critical illness-related organ dysfunction may result in impaired conversion of 25(OH)D to the active hormone 1,25-dihydroxyvitamin D [1,25(OH)2D]. Consequently 1,25(OH)2D levels could be an independent additive prognostic marker in the intensive care unit. OBJECTIVES The distribution of 1,25(OH)2D levels, prevalence of low levels, investigation of risk factors, and tests for associations with markers of illness severity and outcome are reported. DESIGN, SETTING, AND PATIENTS This was a secondary analysis of data and samples collected as part of a prospective cohort study in six Canadian pediatric intensive care units (PICUs). MAIN OUTCOME MEASURE Admission blood 1,25(OH)2D concentrations were measured. RESULTS The median cohort 1,25(OH)2D level was 93.3 pmol/L (interquartile range, 53.0-121.9) with 13% (95% confidence interval, 9-17) and 21% (95% confidence interval, 17-27) of patients having levels of <40 and <50 pmol/L, respectively. Low 1,25(OH)2D levels occurred more often in patients with low 25(OH)D and hepatic, renal, and parathyroid organ dysfunction. After adjustment for 25(OH)D, low 1,25(OH)2D levels were not associated with catecholamine or fluid administration, ventilation, PICU length of stay, or mortality. CONCLUSION Critically ill children are at risk for low 1,25(OH)2D levels, particularly in the presence of established risk factors. However, the lack of association between the 1,25(OH)2D level and selected outcome measures, after controlling for 25(OH)D, does not suggest value in measuring this metabolite at the time of PICU admission.

Clarification needed for the systematic review of vitamin D trials in the ICU

Dear Editor, We read with interest the analysis by Weng et al. heralding the era of meta-analyses evaluating the role of vitamin D supplementation in critical illness [1]. In their study, Weng and colleagues reference the large body of observational literature demonstrating the relationship between vitamin D deficiency (VDD) and outcome following critical illness [2]. They correctly note that observational studies do not prove causality, and seek to evaluate the evidence from randomized controlled trials (RCTs). Ultimately, they conclude that the available literature does not prove benefit and suggest further study in this area. Although we agree with their conclusion, we would like to highlight some concerns about how the study was approached and reported. The authors report that following a systematically review of literature there were four eligible RCTs (Table 1). Unfortunately, the methodology used to find and select these four trials is unclear, as the full eligibility criteria are not provided. Further, there is no online supplement or reference to a registered protocol (e.g., PROSPERO). Given the absence of this information, readers are left to draw conclusions using the details of known RCTs. First, with respect to study design, given the absence of the Nair RCT [3], one must conclude that only placebocontrolled trials were considered. Second, with respect to population, it appears that trials enrolling cohorts with VDD or undifferentiated vitamin D status were eligible. Third, when considering interventions, it appears that the protocol allowed for trials investigating different metabolites, based on the presence of the Leaf trial that studied calcitriol. Although these conclusions seem logical, we cannot then easily explain the absence of the Van den Berghe RCT [4] or VITDAL-ICU pilot [5]. Although exclusion of the Van den Berghe RCT could potentially be explained by some unknown definition of high dose, we cannot explain exclusion of the VITDAL-ICU pilot. Further, without details on the search strategy we cannot determine whether the absence of these articles was intentional or if they were inadvertently missed. We recognize that the authors were under a strict word count while attempting to report their study in letter format. Nonetheless, as details on search strategy and eligibility criteria are considered standard in systematic review reporting, we would request the authors be allowed to provide these protocol components. As part of their response, we would also encourage Weng and colleagues to explain a number of important protocol decisions. Primary among these is the decision to include data from trials with different ICU populations (i.e., vitamin D status) and different vitamin D metabolites. Failure to recognize significant clinical heterogeneity can undermine a meta-analysis. It will be important for future reviews in this area to evaluate for and consider relevant heterogeneity through restriction, subgroup analyses, or meta-regression techniques. Further, we would encourage the authors to rationalize both their decision to perform a meta-analysis when 80% of patients originate from one study and the use of fixed effects despite the presence of significant clinical heterogeneity. Finally, we encourage the authors to address the discordant number of trials in their Fig. 1.