Background
Severe vitamin D deficiency (VDD) is a well-established cause of disease, including hypocalcemia and skeletal abnormalities (e.g., rickets) [
1‐
3]. Although severe deficiency causing classic bone manifestations is now rare, many adults and children endure a subclinical VDD state that may predispose them to neurologic, cardiovascular, respiratory, and immune pathology [
4‐
6]. Because these organ systems are essential to the development of and recovery from critical illness, VDD has been hypothesized to be a risk factor for morbidity and mortality in the intensive care unit (ICU) [
7].
Basic vitamin D physiology, specifically how the endocrine axis regulates calcium balance, is well described. Circulating 25-hydroxyvitamin D [25(OH)D], the inert precursor to the active hormone, is the accepted marker of body vitamin D status [
8,
9]. Although thresholds and terminology vary, VDD is generally accepted as a 25(OH)D concentration below 50 nmol/L, with severe deficiency developing at 25–30 nmol/L [
10‐
14]. These thresholds are based on both biochemical indicators of axis stress and values below which symptoms and disease predisposition rise. Briefly, when 25(OH)D falls into the 50 nmol/L range, maintenance of active hormone levels requires elevation of serum parathyroid hormone and increased renal enzyme activity [
15,
16]. As 25(OH)D falls into the 30 nmol/L range, production of active hormone begins to fall, and healthy individuals can develop electrolyte disturbances and clinically evident disease related to inadequate blood and body calcium (rickets, seizures, myocardial disease) [
16‐
18]. Although overt clinical disease is not evident in otherwise healthy individuals until 25(OH)D values drop below 30 nmol/L, population-based research has established improved bone health with 25(OH)D values over 50 nmol/L [
10]. In addition to impaired calcium regulation within the gastrointestinal, renal, and skeletal systems, there are other mechanisms through which VDD could contribute to organ dysfunction in the ICU patient. For example, vitamin D is known to be essential for proper cardiovascular health, both indirectly through calcium and by controlling cell function directly via vitamin D receptors (VDRs) present on myocytes and endothelial cells. As a second example, there are functional VDRs present on all major immune cell types, and VDD has been implicated in proinflammatory states [
19‐
21] and with impaired innate immunity [
22‐
24]. As a consequence of these mechanisms and others including potential roles in skeletal myopathy and kidney disease [
25‐
28], critical care physicians and researchers have hypothesized that VDD could lead to poorer outcome in the ICU setting.
Over the past 10 years, there have been dozens of observational studies evaluating vitamin D status in adult critical care settings, with recent meta-analyses calculating VDD to be associated with an almost twofold increased risk of death [
29‐
31]. Because vitamin D status is rapidly modifiable, researchers have followed up these findings with multiple pilot clinical trials [
32‐
38] and a single phase III randomized controlled trial (RCT) suggesting benefit derived from rapid normalization through enteral loading therapy [
39]. Three meta-analyses of interventional vitamin D trials in critically ill adults have been published since 2016, further emphasizing the current relevance of this topic [
40‐
42]. Unfortunately, owing to the small number of total evaluable patients and heterogeneity in study populations, these meta-analyses could only suggest potential benefit to supplementation, and they have set the stage for large phase III clinical trials in the adult ICU setting [
43].
In recent years, multiple research groups have evaluated vitamin D status in critically ill children. However, owing to small sample sizes, the majority of these studies have lacked the power to sufficiently evaluate the relationship between vitamin D status, illness severity, and clinical course. Our objective here was to conduct a systematic review and meta-analysis to overcome these limitations. Our primary objective was to estimate the prevalence of VDD in the pediatric intensive care unit (PICU), and compare vitamin D status with that in healthy control populations. Secondarily, we sought to evaluate whether VDD is associated with mortality, increased illness severity, ICU interventions, and clinical course. This study will help inform the field regarding the need for further observational work and whether interventional trials should be entertained.
Discussion
To our knowledge, this is the first systematic review evaluating vitamin D status in critically ill children. We identified 17 studies from 8 countries and 5 continents. The worldwide prevalence of VDD was calculated as 54% at the time of PICU admission, with deficiency associated with greater illness severity, use of ICU interventions, and mortality.
Evaluation of vitamin D status was the primary objective in most studies. VDD was most commonly defined as 25(OH)D under 50 nmol/L. By combining data from 2555 children, we were able to generate a robust estimate of the VDD event rate (54%) in critically ill children. Although a small difference was observed between developed (47%) and developing (64%) countries, the risk of VDD remained high regardless of geography. Importantly, multiple studies also provided vitamin D levels for a control population, with meta-analyses concluding that critically ill children have lower 25(OH)D, by an average of 17 nmol/L. In addition, indirect comparison with large national population-based studies also suggests vitamin D levels to be lower. For example, the Canadian Health Measures Survey estimated the mean concentration of 25(OH)D to be 75 nmol/L among children aged 6–11 years, and a separate study of preschoolers estimated that 88% had 25(OH)D levels above 50 nmol/L [
74,
75]. Similarly, estimates from national surveys done in the United States and European countries also suggest average 25(OH)D concentration to be near 70 nmol/L, with only 20% having levels under 50 nmol/L [
76,
77]. In contrast, adult ICU studies show comparable vitamin D levels, with reported mean 25(OH)D levels ranging from 13 to 62 nmol/L and with 80% of studies since 2009 identifying average group levels below 50 nmol/L [
78]. Despite the established rate of VDD in the ICU and associations with poorer outcome, there is still insufficient evidence on which to base supplementation guidelines specific to the critically ill population [
79,
80]. Accordingly, the prevalence of VDD in the ICU remains high.
This review also sought to investigate the relationship of VDD with illness severity, ICU interventions, and clinical outcomes. We focused on mortality as the primary clinical outcome because it is a commonly reported objective measure amenable to meta-analysis that is accepted as meaningful [
81,
82]. Mortality data were available for 15 studies and 2710 patients, representing 97% of the total cohort. Individual studies lacked adequate power to evaluate the relationship between VDD and mortality, owing to small sample size. For example, although four studies reported all deaths in the VDD group [
58,
62,
63,
71], the findings achieved statistical significance only in the Chilean study [
71]. The association with mortality was stronger and achieved greater statistical significance (OR 2.6,
p = 0.003) when developing countries were removed. Our findings are consistent with the results from systematic reviews by de Haan et al. [
29] (RR 1.7, 95% CI 1.49–2.16) and Zhang et al. [
30] (OR 1.76, 95% CI 1.38–2.24) evaluating the same question in the adult ICU setting. There are multiple biologically plausible mechanisms through which VDD could influence the development and recovery from critical illness, including calcium homeostasis and the stress response of nonclassical organs, including the immune, cardiac, and respiratory systems [
83‐
85]. Our study findings further support the pleiotropic nature of the hormone, with significant associations between VDD and mechanical ventilation, vasopressor use, and confirmed bacterial or nosocomial infection.
A common question in this area of research relates to the mechanisms leading to low blood concentrations of vitamin D in critical illness. In the ambulatory setting, the risk factors are well defined and include impaired skin synthesis, restricted dietary intake, and genetics [
14,
85‐
87]. Some PICU studies incorporated these variables and were able to confirm that factors such as such as season of presentation [
57,
60], absent vitamin D supplementation [
60,
63], non-Caucasian race [
55,
57,
60], and obesity [
66,
67] were associated with greater risk of VDD among critically ill children. Unfortunately, the available studies were not designed to fully explain why critically ill children as a whole have considerably lower vitamin D levels. It has been suggested that altered metabolism and acute care interventions may rapidly lower blood vitamin D concentration. This has been confirmed in some targeted studies evaluating levels before and after surgeries, extracorporeal interventions, and conditions associated with severe inflammation [
88‐
90]. Consequently, many researchers have cautioned against overinterpreting observational study findings, suggesting that confounding factors may be driving the relationship between vitamin D status and outcome [
91].
Regardless of how critically ill children arrive at their vitamin D-deficient state, VDD may contribute to secondary pathophysiology. Furthermore, restoring blood concentrations has the potential to facilitate clinical recovery in the PICU and presents a target question for interventional trials. The present systematic review helps to pave the way for future RCTs of vitamin D supplementation in critically ill children by guiding outcome measure selection. Our results suggest that mortality may not be the best choice for a primary outcome, owing to the low event rate (less than 5%) in developed countries and lack of significant association in developing countries. Because our systematic review findings also suggested pleiotropic actions of vitamin D, it would be reasonable to consider a composite outcome of mortality and faster resolution of organ dysfunction (e.g., PICU stay) or postillness health-related quality of life.
Although based on an exhaustive literature search and comprehensive synthesis effort, this review has limitations. First, the findings are based on data derived from observational data, so one should be careful not to draw conclusions on causation, because the relationship may be driven by confounding factors. Second, although total serum 25(OH)D is well accepted as the best marker of vitamin D status in stable outpatient populations, some uncertainty remains regarding whether an alternative assay [e.g., free 25(OH)D or active hormone] might better define VDD in the ICU [
59,
68]. Third, although 50 nmol/L is well accepted as a legitimate threshold for defining VDD, some evidence shows that the benefit of supplementation, or type of benefit, may be limited to lower thresholds (e.g., below 30 nmol/L) [
39,
61]. Because few studies reported 25(OH)D levels using alternate thresholds for severe deficiency, it was not possible to evaluate whether the relationship of VDD to PICU outcomes was more significant in this subgroup. Finally, only a minority of studies controlled for relevant patient characteristics in their investigation of the relationship between VDD and clinical outcome. To contribute significantly, any further observational studies should be adequately designed and powered to consider covariates in their analyses.