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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 3  |  Page : 645-652

Role of vitamin D and its deficiency in pediatric critical illness


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Kafr El-Sheikh Health Sector, Kafr El-Sheikh Governorate, Egypt

Date of Submission21-Aug-2016
Date of Acceptance23-Oct-2016
Date of Web Publication15-Nov-2017

Correspondence Address:
Mohamed A El Monem Gohar
Gharb-Tera, El-Hamoul, Kafr El-Sheikh Governorate, 33729
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.218279

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  Abstract 

Objectives
The aim of this study was to assess the role of vitamin D and its deficiency in pediatric critical illness.
Methods
Medline databases (PubMed, Medscape, ScienceDirect) and all materials available in the Internet from 2003 to 2016. The initial search presented 98 articles, of which 32 fulfilled the inclusion criteria. The articles studied the role of vitamin D and its deficiency in pediatric critical illness. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was obtained, eligibility criteria were specified, there were appropriate controls, there was adequate information, and defined assessment measure. Comparisons were made by structured review with the results tabulated.
Results
In total, 32 potentially relevant publications were included. The studies have identified that vitamin D insufficiency and deficiency are associated with poor clinical outcomes in all pediatric age groups. These disorders are especially prevalent in critically ill patients. The data related to vitamin D deficiency and morbidity and mortality are varied, but in larger studies, it has been associated with major adverse effects on clinical outcome and mortality.
Conclusion
We found that vitamin D plays a major role during the course of several critical diseases in the body such as critical diseases of the cardiovascular, respiratory, nervous, endocrine, renal systems, etc. Vitamin D deficiency is associated with poor clinical outcomes in all populations. These disorders are especially prevalent in critically ill patients.

Keywords: critical illness, deficiency, pediatric, vitamin D


How to cite this article:
Khattab AA, Saleh NY, El Monem Gohar MA. Role of vitamin D and its deficiency in pediatric critical illness. Menoufia Med J 2017;30:645-52

How to cite this URL:
Khattab AA, Saleh NY, El Monem Gohar MA. Role of vitamin D and its deficiency in pediatric critical illness. Menoufia Med J [serial online] 2017 [cited 2017 Dec 18];30:645-52. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/645/218279


  Introduction Top


Vitamin D is a key regulator in calcium and phosphorus metabolism and likely serves physiologically very important functions that include cardioprotective and immunomodulatory effects as well as improvement of antimicrobial action [1]. Endogenous synthesis in the presence of ultraviolet (UV-B) radiation is the main source of vitamin D. Therefore, immobilized and elderly individuals are prone to developing vitamin D deficiency (VDD). Low vitamin D levels are highly prevalent in critically ill adults and children [2].

Today, most guidelines agree that a 'low' vitamin D status is present when serum 25-hydroxyvitamin D [25(OH)D] levels are below 20 ng/ml [3].

Recently, many studies have shown that the prevalence of VDD among critically ill children is 25–84% at admission to the pediatric ICU [4].

Vitamin D levels decrease further during ICU stay, which can be explained by insufficient replacement of vitamin D by enteral or parenteral nutrition in the absence of UV-B exposure. There is an association between vitamin D levels in critically ill patients and severity of disease including length of ICU stay and mortality [5].

Severe VDD in humans causes rickets in children, together with vitamin D myopathy, whereas low vitamin D levels may be associated with an increased prevalence of a multitude of other diseases including an increase in mortality [6].

In critically ill patients, hypocalcemia is frequently present and has been related to increased morbidity and mortality. The reasons for the development of hypocalcemia are not well understood, but besides elevated levels of interleukin (IL)-6, VDD may play a decisive role. Without correction of VDD, normalization of calcium levels may be impossible [7].

Severe hypocalcemia may cause life-threatening, reversible heart failure. Vitamin D seems to inhibit activation of the renin–angiotensin system as well as the expression of genes involved in the development of myocardial hypertrophy. There is accumulating evidence that VDD may be an important factor in the development of congestive heart failure and sudden cardiac death [8].

Vitamin D acts on both adaptive and innate immunity systems. Most cells of immune system express the vitamin D receptors (VDRs). It enables macrophages to respond to and kill bacterial and viral organisms [6].

Vitamin D also exerts an influence on epidermal keratinocytes to serve their barrier function. Monocytes cultured in severely VDD plasma express less cathelicidines that are important antimicrobial peptides of great interest in critically ill patients because they constitute part of the initial defense line against pathogens [9].

Cathelicidines are expressed in the epithelia of airways, the bladder, and the gastrointestinal tract, which are all considered important entry sites of nosocomial infections. Treatment of normal human bronchial epithelial cells with 1,25(OH)2D results in a 10-fold upregulation of cathelicidin mRNA levels after 12 h [10].

In septic ICU patients, a positive correlation has been reported between circulating 25(OH)D and IL-37 levels, the active fragment of cathelicidin. In a large retrospective study, the risk for blood culture positivity was significantly higher in VDD critically ill patients [11].

Of interest in this context is also the finding that the incidence and case-fatality rates of sepsis are significantly higher in winter despite similarities in disease severity during the summer [12].

Severe VDD is associated with myopathy, decreased muscle strength, and an increased risk for falls. In intensive care, this may translate into the necessity of prolonged mechanical ventilation and difficulties during weaning from ventilatory support in patients with low vitamin D status [13].


  Methods Top


Search strategy

We reviewed papers on the role of vitamin D and its deficiency in pediatric critical illness from Medline databases (PubMed, Medscape, ScienceDirect) and also materials available on the Internet. We used vitamin D, deficiency, pediatric, critical illness, heart failure, respiratory distress, brain tumors, and renal failure as search terms. The search was performed in the electronic databases from 2003 to 2016.

Study selection

All the studies were assessed independently for inclusion. They were included if they fulfilled the following criteria.

  1. Published in the English language
  2. Published in peer-reviewed journals
  3. Focused on vitamin D and pediatric critical illness
  4. Discussed the role of vitamin D and its deficiency in pediatric critical illness
  5. If a study had several publications in certain aspects, we used the latest publication with the most relevant data.


Data extraction

If the studies did not fulfill the above criteria, they were excluded such as studies on vitamin D overdose, VDD in adults, and VDD in pediatric patients without critical illness.

Quality assessment

The quality of all the studies was assessed. Important factors included, study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis carried out in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.


  Results Top


Study selection and characteristics

In total, 130 potentially relevant publications were identified; 98 articles were excluded as they did not fulfill our inclusion criteria. A total of 32 studies were included in the review as they were deemed eligible by fulfillment of the inclusion criteria. The majority of these studies examined the role of vitamin D during the course and severity of critical illness in pediatrics [14]. A summary of these studies is shown in [Table 1]. These studies considered that normal vitamin D=≥30 ng/ml, insufficient=<15–30 ng/ml, deficient=<15 ng/ml.
Table 1: Summary of studies evaluating the effect of vitamin D status in the critically ill population

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The recommended dietary allowance for vitamin D is 400 IU for infants younger than 1 year of age and 600 IU for children older than 1 year of age [15]. The recommended dietary allowances for vitamin D is shown in [Table 2].
Table 2: Recommended dietary allowances for vitamin D

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VDD is common and has been estimated to affect about one billion individuals worldwide. Although the primary role of this pleiotropic hormone is regulation of calcium metabolism, it also plays a key role in several pathways of the innate immune response system, controlling cell growth, differentiation, and apoptosis [16].

Relation between vitamin D and the severity of the disease and length of ICU stay in critically ill patients

Over the last few years, several groups have reported an inverse association between vitamin D levels in critically ill patients and severity of disease including length of ICU stay and mortality [17]. Moreover, vitamin D levels decrease further during ICU stay, which can be explained by insufficient replacement of vitamin D by enteral or parenteral nutrition in the absence of UV-B exposure [5].

Vitamin D and cardiac critical illness

Calcitriol, through VDR, has a significant impact on the morphology, proliferation, and growth of cardiac cells. Calcitriol is known to be one of the negative endocrine regulators of the renin–angiotensin–aldosterone system (RAAS). Calcitriol supplementation was shown to reduce plasma renin activity, angiotensin II levels, blood pressure, and myocardial hypertrophy. VDD is linked to various mechanisms that play a significant role in the pathogenesis of congestive heart failure. These mechanisms include the activation of RAAS, the presence of oxidative stress in different tissues including the skin, skeletal muscles, heart, and peripheral blood mononuclear cells, and activation of proinflammatory cytokines such as IL-8 and tumor necrosis factor-α [Figure 1] [18].
Figure 1: The role of vitamin D deficiency in the pathogenesis of congestive heart failure (CHF). IL, interleukin; TNF, tumor necrosis factor.

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Vitamin D and immunity

Cells of the innate and adaptive immune system were shown to express the VDR [19]. Vitamin D enables macrophages to respond to and kill bacterial and viral organisms [20] and exerts an influence on epidermal keratinocytes to serve their barrier function [21]. Monocytes cultured in severely VDD plasma express fewer cathelicidines and improve their function with 25(OH)D as well as 1,25(OH)2D. Cathelicidines are important antimicrobial peptides that are of great interest in critically ill patients because they constitute part of the initial defense line against pathogens. They are expressed in the epithelia of airways, the bladder, and the gastrointestinal tract, which are all considered important entry sites of nosocomial infections. In septic ICU patients, a positive correlation has been reported between circulating 25(OH)D and IL-37 levels, the active fragment of cathelicidin [20].

Vitamin D and respiratory diseases

VDD has been shown to increase the risk of viral respiratory tract infections and respiratory syncytial virus-associated bronchiolitis. Also, serum vitamin D levels decrease in children with bronchiolitis, suggesting that vitamin D may play a role in the pathogenesis of bronchiolitis [22]. VDR is present in bronchial smooth muscle cells that are associated with active protein synthesis. It has been shown that vitamin D inhibits bronchial smooth muscle proliferation induced by platelet-derived growth factor and it also influences the microarray gene expression signature in bronchial smooth muscle cells. This finding suggests a role of vitamin D in cell growth and survival and morphogenesis and airway remodeling, which may be important in asthma pathophysiology and treatment [23]. Low serum vitamin D levels are a risk factor for pneumonia. The risk of contracting pneumonia was more than 2.5 times greater in patients with the lowest vitamin D levels than in patients with high vitamin D levels [24]. Prehospital vitamin D inadequacy [25(OH)D<20 ng/ml] is associated with incident acute respiratory failure during critical illness and death in patients with acute respiratory failure [25].

Vitamin D and renal diseases

VDD is common in critically ill patients and associated with increased mortality, as well as an increased risk of acute kidney injury. Potential mechanisms of how a deficiency in vitamin D could predisposes individuals to an increased risk of acute renal failure include dysregulation of the immune system, predisposing patients to sepsis, endothelial dysfunction, and prevention of healing of renal ischemia–reperfusion injury. Toll-like receptors, NF-κβ and RAAS, are mediators of the effects of vitamin D [26]. The nonclassical effects of vitamin D may play a relevant role in the mortality and morbidity of patients with chronic kidney diseases, specifically affecting the possible progression of their renal disease and coexisting cardiovascular disease, which is the major cause of death in this population [27],[28] [Figure 2].
Figure 2: Conceptual model of major pathways through which vitamin D deficiency in patients with chronic kidney disease (CKD) may lead to CKD progression and complications such as premature cardiovascular disease (CVD). VSM, vascular smooth muscle.

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Vitamin D and neurological diseases

Hypocalcemia is one of the electrolyte disturbances that can cause seizures. Having a stable extracellular ionized calcium concentration is critical for normal brain cell function, and vitamin D and parathyroid hormone play a central role in maintaining a stable extracellular ionized calcium concentration [29]. A diet of a standard amount of vitamin D3 (1500 IU/kg) is sufficient to decrease the susceptibility of the brain against central nervous system (CNS) infection. A diet containing a high amount of vitamin D3 (75 000 IU/kg) supported pathogen elimination and can inhibit inflammation in the CNS. High-dose vitamin D may be able to modulate the inflammatory response to CNS infections [30]. Epidemiologic evidence suggests a possible link between brain cancer and VDD [31].

Vitamin D and endocrinal critical diseases

Several studies have linked low levels of vitamin D with a higher risk for type 1 (T1DM) and type 2 diabetes. Some studies are also looking at possible links between vitamin D and diabetes complications such as kidney and eye diseases [32]. The mean 25(OH)D level in T1DM in different countries is shown in [Table 3].
Table 3: Mean 25-hydroxyvitamin D level in type 1 diabetes mellitus in different countries

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1,25(OH)2D3 plays an immunomodulatory role in the prevention of T1DM, through the VDR expressed in antigen presenting cells, activated T cells, and pancreatic islet β-cells. 1,25(OH)2D3, administered early on protects against or reduces the severity of pancreatic inflammation by a dual action on the pancreatic β-cells and the immune cells. Administration of 1,25(OH)2D3 in combination with cyclosporine A, after the onset of the autoimmune attack, which is known as a prediabetic state, can prevent clinical diabetes [Figure 3] [33]. VDD has been associated with insulin deficiency and insulin resistance [34]. Patients with hypothyroidism had hypovitaminosis D with hypocalcemia [35].
Figure 3: Immunomodulatory effect of vitamin D in the prevention of diabetes.

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Vitamin D and hepatic disorders

In patients with liver failure, the levels of 25(OH)D can be low because of impaired synthesis. Low vitamin D levels and bone disease are well-recognized complications of 'cholestatic' liver disease, which decreases the production or flow of bile [36].

Effect of vitamin D on muscles in ICU patients

Severe VDD is associated with myopathy, decreased muscle strength [37]. Therefore, in intensive care, this may translate into the necessity for prolonged mechanical ventilation and difficulties during remobilization and weaning from ventilatory support in patients with low Vitamin D status [19].


  Discussion Top


Vitamin D is now considered to play additional beneficial roles besides the traditional concept of its bone health benefit. With the discovery of receptors for vitamin D in various tissues including immune-regulating cells, the heart, and the brain, its role in the extraskeletal 'pleiotropic effects' has been studied extensively in the last few years [38]. The present essay aimed to discuss the role of vitamin D and the effect of its deficiency on outcome among critically ill children admitted to the pediatric ICU including the severity of the disease, duration of stay at pediatric ICU, and the effect of supplementation on these patients.

Several studies have evaluated the effect of 25(OH)D sufficiency, insufficiency, and deficiency on morbidity and mortality in critically ill patients. All the studies cited here included either medical, surgical, or trauma ICU patients.

Two early prospective observational studies evaluated the effect of 25(OH)D concentrations on outcomes and mortality in critically ill patients [39],[40]. The studies reported that there was no significant association between 25(OH)D concentrations with mortality and length of ICU stay.

Nosocomial infections or hospital-acquired infections were not significantly different among those patients with vitamin D sufficiency or deficiency. The limitations of this study include the short time frame for observation, the limited sample size, and the lack of sequential vitamin D blood sampling [39].

Cecchi et al. [40] found no significant difference in outcomes, including ICU length of stay and hospital length of stay, between patients with vitamin D sufficiency or deficiency. The lack of significance found in these initial studies may be because of the limited number of patients.

Two large multiyear, multicenter observational studies assessed the relationship between 25(OH)D status in critically patients and 30-day mortality after ICU admission [16],[41]. The major difference between the two studies is that the first study included patients who had 25(OH)D concentrations drawn 1 week to 1 year before ICU admission. This enabled inference of a potential relationship between vitamin D and the onset of critical illness. The second study included patients who had 25(OH)D concentrations drawn 7 days before or after admission.

A prospective study analyzed medical and surgical ICU patients in a tertiary care hospital to observe the trend of vitamin D status throughout a patient's ICU stay and the relationship between 25(OH)D concentrations and adverse clinical outcomes, particularly length of ICU stay, risk of infection, and mortality. Serum 25(OH)D concentrations were determined at the time of admission and then assessed again after 3 and 10 days of ICU stay. This is the first study to observe a statistically significant post-admission decrease in 25(OH)D concentrations during ICU stay. Patients who had sufficient 25(OH)D levels had a significantly shorter time-to-alive ICU discharge of 5.9 ± 5.4 days compared with 10.6 ± 8.4 days observed in deficient patients (P = 0.01). The study reported a trend toward higher rates of infection in patients with insufficient and deficient 25(OH)D levels. Vitamin D status was not significantly associated with all-cause 28-day mortality [42].

All except two of these studies found a correlation between VDD and adverse clinical outcomes [16],[41],[43]. Both the negative studies were limited by the small sample size [39],[44].

Lucidarme O et al. [39], who included a large number of patients, found a significant association between low 25(OH)D concentrations and mortality. The literature indicates that there is a link between clinical outcomes and vitamin D status in the critically ill.

Although a literature has highlighted the prevalence of VDD and linked it to adverse clinical outcomes, there is uncertainty on how to correct VDD in the critically ill setting. A small number of studies have evaluated the effect of vitamin D supplementation on serum 25(OH)D concentrations in this patient population [5].

For hospitalized patients, the current recommendation by the American Society for Parenteral and Enteral Nutrition is 200 IU of vitamin D (cholecalciferol, D2) daily by the intravenous route. This is considered a maintenance dose for this vitamin and does not take into account patients who have deficiency or insufficiency and need to receive supplementation. The daily dose of 200 IU vitamin D (cholecalciferol) was shown to be ineffective in normalizing vitamin D concentrations of patients who were VDD. In this10-day trial, serum concentrations of 25(OH)D were significantly higher on days 2, 6, and 7 (P = 0.05) for a group receiving higher doses of vitamin D (500 IU of ergocalciferol, D3) daily compared with the standard dose of 200 IU cholecalciferol daily. Unfortunately, 25(OH)D serum concentrations remained below normal in all treatment groups during the 10-day trial. Use of both vitamin D2 and D3 in this supplementation study was a confounding variable. Lower concentrations of 25(OH)D were observed in nonsurvivors in critically ill patients [45].

Mata-Granados et al. [46] administered two 60 000 IU 25(OH)D oral doses to a group of critically ill septic patients, which resulted in a significant increase in serum 25(OH)D concentration from baseline: 4–46 ng/ml 25(OH)D (P = 0.0001). A single oral dose of 540 000 IU of cholecalciferol was used to treat critically ill patients in a randomized, double-blind pilot study. The aim was to correct VDD by achieving 25(OH)D levels of 30 ng/ml or greater by day 7. In the vitamin D-supplemented group, the mean baseline 25(OH)D concentration was 13.1 ng/ml and it increased to a mean of 38.2 ng/ml on day 7, which was significantly greater than the placebo group in which no significant change was observed. Concentrations increased within 2 days after one mega-dose of cholecalciferol in most patients without causing adverse effects of hypercalcemia or hypercalcuria. The study also observed that daily maintenance doses of 200 IU of calciferol did not significantly affect 25(OH)D concentrations. The authors could not exclude that smaller more frequent doses would not be able to achieve the same results. Clinical outcomes such as mortality could not be evaluated because of the small sample size. This is the first randomized-controlled trial to study the short-term effects of high-dose vitamin D in the critically ill population [46].

The recommended daily dose of 200 IU intravenously or even doubling this dose to 500 IU of vitamin D intravenously did not have any significant effects on serum 25(OH)D concentrations [45]. However, in the studies that evaluated the effect of larger doses, two oral doses of 60 000 IU and one oral dose of 540 000 IU 25(OH)D led to a significant increase in 25(OH)D concentrations [5],[46]. Only short-term effects have been evaluated in the ICU; thus, large randomized-controlled trials are needed to determine the long-term effects and clinical outcomes of high-dose vitamin D supplementation. It is notable that a dose of 10 000 IU per day in healthy men is safe. Monitoring for toxicity (e.g., hypercalcemia) would be prudent in patients receiving large doses of vitamin D [47].


  Conclusion Top


Our review concludes that vitamin D is now recognized to be a pleiotropic hormone with major effects on innate immune response, cell growth, differentiation, and apoptosis affecting the course of several critical diseases in the body such as critical diseases of the cardiovascular, respiratory, CNS, endocrine, renal systems etc.

Vitamin D levels decrease further during ICU stay, which can be explained by insufficient replacement of vitamin D by enteral or parenteral nutrition in the absence of UV-B exposure.

Pre-ICU vitamin D status shows a negative association with the severity of the condition and the duration of stay of the case admitted in ICU.

VDD is associated strongly with high mortality rates among critically ill patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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