Kasr Al Ainy Medical Journal

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 23  |  Issue : 1  |  Page : 6--11

Vitamin D deficiency in critically ill children


Nora El Said Badawi1, Hebat Allah Fadel Algebaly2, Riham El Sayed3, Eman Sayed Abu Zeid2,  
1 Department of Pediatrics and Pediatric Endocrinology, Cairo University, Cairo, Egypt
2 Department of Pediatrics & Pediatric Intensive Care, Cairo University, Cairo, Egypt
3 Department of Clinical and Chemical Pathology, Cairo University, Cairo, Egypt

Correspondence Address:
Hebat Allah Fadel Algebaly
Department of Pediatrics, Faculty of Medicine, Specialized New Children Hospital, Cairo University, 11562 Ali Basha Ebrahim St. Cairo
Egypt

Abstract

Context Vitamin D is needed for the proper function of different organs of the body. A few studies have assessed vitamin D status in critically ill children and reported the prevalence of vitamin D deficiency (VDD) in the range of 30–71%. Aim The objectives of this study were to assess the prevalence of VDD in a pediatric ICU (PICU) patients and to determine whether there is any relationship between VDD and illness severity, mortality, or length of PICU stay. Design and settings We carried out a cross-sectional study of serum 25(OH)-vitamin D levels, measured during the first day of admission to a 10-bedded medical PICU at the Children’s Cairo University. Materials and methods We analyzed demographic data, pediatric risk of mortality III, and pediatric logistic organ dysfunction between normal and VDD groups in the PICU. Results The prevalence of VDD was 44% and that of severe VDD was 34% in critically ill Egyptian children at the onset of critical illness. The median level of vitamin D in the whole group was 59 nmol/l and in deficient group it was 17 nmol/l. Infants had higher median vitamin D levels than those above 1 year of age, but with no statistical difference. VDD patients had higher pediatric logistic organ dysfunction (12 vs. 10; P=0.001) and lower platelet counts (240 vs. 331; P=0.021). Pediatric risk of mortality III, inotropes, sepsis, ventilation, duration of PICU stay, and mortality were not related to VDD. Conclusion VDD is highly prevalent in critically ill children and is observed to be associated with organ dysfunction on admission.



How to cite this article:
Badawi NE, Fadel Algebaly HA, El Sayed R, Abu Zeid ES. Vitamin D deficiency in critically ill children.Kasr Al Ainy Med J 2017;23:6-11


How to cite this URL:
Badawi NE, Fadel Algebaly HA, El Sayed R, Abu Zeid ES. Vitamin D deficiency in critically ill children. Kasr Al Ainy Med J [serial online] 2017 [cited 2017 Nov 25 ];23:6-11
Available from: http://www.kamj.eg.net/text.asp?2017/23/1/6/207191


Full Text

 Introduction



The role of vitamin D in metabolism and homeostasis in the general population is well established, but there is now growing interest in its potential association with acute and critical illness [1]. Acute drops in serum concentrations of vitamin D during critical illness due to increasing tissue demands and impaired compensation by concurrent inflammation and organ dysfunction may prolong critical illness pathophysiology [2]. The question about whether vitamin D deficiency (VDD) is involved in multiple organ dysfunction is not yet answered. Seven studies from different pediatric ICUs (PICUs) around the world have been published thus far, including North America, Atlanta, Canada, Australia, Spain, and two Indian PICUs. All these studies showed a high prevalence of VDD in the range of 30–71%. Only Ponnarmeni et al. [3] from north India limited his study to critically ill children with sepsis. This study investigated the hypothesis that VDD might be related to higher severity scores and organ dysfunction. The primary objective of this study was to estimate the prevalence of VDD in a group of critically ill children, and the secondary objectives was to correlate vitamin D status with pediatric logistic organ dysfunction (PELOD) and pediatric risk of mortality III (PRISM III) scores.

 Materials and methods



We included 88 children from 1 month to 12 years of age, admitted to a 10-bedded medical PICU at the Children’s Cairo University. The Children’s Cairo University institutional review board approved the study. After obtaining informed consent, parents were interviewed about the order of the child among his or her siblings, time spent outdoor exposed to the sun, and intake of vitamin D-containing foods and supplements during weaning. Parents of infants younger than 1 year provided a breastfeeding or artificial formula history. We recorded height and weight percentiles and calculated BMI. Sepsis grade was determined according to the definitions of the International Pediatric Sepsis Consensus Conference [4]: sepsis, Systemic inflammatory response syndrome (SIRS) in the presence or as a result of suspected or proven infection; severe sepsis, sepsis plus one of the following: cardiovascular dysfunction, acute respiratory distress syndrome, or two or more organ dysfunctions; and septic shock, sepsis and cardiovascular organ dysfunction.

Severity of illness was assessed within the first 24 h of PICU admission with the PRISM III score using 16 variables [5], and organ dysfunction was assessed by the PELOD score including six organ systems (neurologic, cardiovascular, renal, respiratory, hematologic, and hepatic), each with up to three variables (total 12 variables). Each variable was assigned points (0, 1, 10, or 20) on the basis of the level of severity [6]. The maximum level of vasopressor used during PICU stay was calculated by using the Sequential Organ Failure Assessment Cardiovascular (CV-SOFA) score [7]. Venous blood samples for the detection of total serum calcium and phosphorus were analyzed at the same time as for vitamin D, but unfortunately ionized calcium was not available at that time in the hospital laboratory. Vitamin D biological samples were collected within the first 24 h of admission to the PICU. Samples were stored at −80 and analysis performed using enzyme-linked immunosorbent assay developed by Immunodiagnostic, Bensheim and Biomedical (Immunodiagnostik AG, Stubenwald-Allee 8a, D Benshieum, Bergstrabe distriction, Germany). A total of 200 µl of prediluted serum sample and control standard were incubated separately for 1 h at 8–10°C after washing; 100 µl of enzyme conjugate was added into each well and incubated for 1 h at 8–10°C; and after washing, 200 µl of the substrate solution was added into each well and incubated for 30 min at room temperature without shaking (protected from direct sunlight). Finally, 50 µl of stop solution was added to each well, and the absorbance was read at 450 nm. VDD was defined as 25(OH) D concentrations below 50 nmol/l, and severe deficiency was defined as concentrations below 30 nmol/l [8],[9],[10].

Descriptive statistics are presented with results for continuous variables, provided as means with SDs or medians with minimum and maximum or interquartile ranges and percentages. Associations between vitamin D, patient characteristics, and outcome variables were measured by Fisher’s tests for categorical variables and the Mann–Whitney or the Kruskal–Wallis tests for continuous variables, where appropriate. Survival analysis was performed using the Kaplan–Meier procedure to compare the time to death or discharge in the deficient versus normal level vitamin D group.

 Results



Prevalence of vitamin D deficiency in the study

Thirty-nine out of 88 (44%) critical children had VDD (level<50 nmol/l), with median vitamin D levels of 17 nmol/l (95% confidence interval: 12–25) in the VDD group as shown in [Table 1], whereas 30/88 (34%) children had serious deficiency (<30 nmol/l) ([Table 3]).{Table 1}

Demographic variables of the study population

The age range was from 1 month to 12 years with a median of 36 months; 43% were girls and 57% were boys. Respiratory disorders were the most common diagnosis in 45% (43% pneumonia and 2% for status asthmaticus), neurological disorders in 22.7% (coma in 15.9%, Guillain–Barré syndrome 4.5%, status epilepticus 2.3%), heart failure in 10.5%, diabetic ketoacidosis in 6.8%, elective postoperative illness in 4.5%, acute hemolytic crises in 3.4%, inborn errors of metabolism in 2.2%, hepatic encephalopathy in 2.2%, septic shock in 1.1%, aplastic crisis in 1.1%, and diabetic ketoacidosis in 6.8%, as shown in [Table 2]. Patients with chronic disorders represented 42% of the patients, and the majority of them were admitted to the PICU for acute infections along with their chronic conditions. In all, 86% of the admitted infants were exclusively breast fed, and 35% received vitamin D supplementation before admission. Sepsis was present in 82% of cases, and ventilated patients represented 49% of the admissions. The median duration of stay was 6 days, and the maximum PICU stay was 83 days.{Table 2}{Table 3}

Characteristics of the vitamin D deficiency group

The study sample was categorized according to age: above and below 1 year of age. After analyzing vitamin D levels, the median was observed to be higher in infants below 1 year of age, but with no statistical difference (46 vs. 62) (P=0.138). VDD was more common among children with no vitamin D supplementation (P=0.01) and no exposure to the sun (P<0.001) before the PICU admission determined by history taking. It was observed that VDD was prominent with increasing number of organ dysfunction but with only a weak correlation with PELOD scores on admission (P=0.001, r=−0.370) ([Figure 1]). Children with cardiomyopathy and chronic hepatitis admitted to the PICU had relatively lower vitamin D levels, but their number was not feasible for statistical comparison. [Table 4] and [Table 5] show the comparisons between VDD and normal vitamin D groups: no relation could be observed between VDD and order among siblings, BMI, ventilation, inotropes use, PRISM III ([Figure 3]), calcium, phosphorus, and alkaline phosphatase. VDD patients also had lower platelet counts (P=0.003, r=0.321) as seen in [Figure 2]. The majority of study patients had associated sepsis, but this had no statistical relation to VDD. No relation could be observed between mortality or PRISM III and VDD. The VDD group tended to survive for fewer days in the PICU than those with sufficient levels, but there was no statistical difference between deficient and normal vitamin D groups in the survival analysis ([Table 5] and [Figure 4]).{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Table 4}{Table 5}

 Discussion



Nearly half of the studied PICU patients (44%) had vitamin D levels less than 50 nmol/l (deficiency) and 30% had severe deficiency with levels below 30 nmol/l. This high prevalence is similar to other published studies from different PICUs around the world: 40% of PICU patients in North America [11], 60% of PICU patients in Atlanta [12], 34.5% in Australia [13], and 29.5% in Spain [14]. Higher prevalence was observed in other studies, reaching 69% in Canada and 71.4% in India [2],[15]. Ponnarmeni et al. [3] observed 50% prevalence of VDD among their septic critical children in a north Indian PICU. Dayal et al. [16] detected 25% VDD among 92 children admitted to a ward and could detect significant fall in vitamin D levels during hospitalization.

Egypt, similar to other Middle Eastern countries, enjoys a good deal of sunny weather, and therefore it would be expected to have normal levels of vitamin D. However, some of the few studies conducted in Egypt concluded that adult Egyptian females might be at higher risk of VDD, and this was not attributed to concealed clothes [17].

Admission diagnoses among the studied children included a variety of medical critical conditions, whereas postoperative patients comprised only 4% with the exclusion of cardiac surgical patients, unlike McNally and Ripple; both had a large category of postoperative cardiac and surgical diagnoses. Madden et al. [11] excluded cardiac surgical cases because of the effect of cardiac bypass on vitamin D levels. Rey and colleagues demonstrated a link between vitamin D and respiratory, metabolic, and renal diagnoses. Hebbar and colleagues observed significant VDD in critically ill asthmatic children. In our study, the recorded values of vitamin D showed noticeably lower levels among patients with diabetic ketoacidosis, cardiomyopathy, and hepatic failure, but this was just an observation that was not feasible for statistical analysis because of the small sample size of the subgroups. In chronic hepatic patients who presented with fulminant hepatitis, parents provided a history of routine vitamin D supplementation with vitamin D3. The role of vitamin D in the pathogenesis of diabetes is well known [18], but whether the marked deficiency had a role in diabetic ketoacidosis precipitation or whether this is a sequence of the critical illness still needs to be investigated. One patient with dilated cardiomyopathy had unrecordable vitamin D levels and died. Further research in category-specific critical illness would be helpful to explore the possible relation between VDD and deterioration of chronic illnesses such as cardiomyopathy and chronic hepatic patients.

Children older than 1 year had lower median vitamin D levels in our group, but this difference had no statistical significance. However, published studies have shown controversial results. Although Madden et al. [11] and Rey et al. [11],[14] reported relevance of VDD with age, others found no relation between age and VDD [2],[3],[13]. Sun exposure and vitamin D supplementation were strongly protective against deficiency. An explanation for this may be that acute stress and critical illness are a state of mismatch between substrate supply and tissue requirement, and those with good reserve may have sufficient stores despite maximal stimulation. Variations in individual patient responses to acute stress and critical illness may therefore depend on baseline vitamin D levels and the extent of tissue requirement [19]. All of the previous pediatric critical care studies, with the exception of the study by Madden et al. [11] and Hebbar et al. [12], could not document a seasonal difference for VDD.

In our study, only admission PELOD was higher with VDD. Studies from the Boston Children’s Hospital and Canada have demonstrated that VDD is associated with only increased illness severity measured by PRISM III and generally reflected longer hospital stays [2],[11]. Ayulo et al. [20] did not find a significant correlation between PELOD score and vitamin D levels in critically ill children. Reye, Ripple, Lodha, and Ponnarmeni could not find an association between mortality risk prediction, mortality, or hospital stay and vitamin D levels. Dayal could not find any relation between patients who required ventilation and inotropes and with nosocomial sepsis and VDD among 92 patients admitted to the ward. It is noted that the PELOD score is used as an indicator of organ dysfunction unlike the PRISM III, which is validated as a good predictor for mortality.

The high mortality of 28% has many contributing factors such as delayed PICU admission due lack of beds, poor access to appropriate care, high percentage of multiple organ failure, and septic shock. Gemke and Bonsel [21] in a multicenter study showed a mean 7.1% mortality (range=1–10%) in PICU patients; one of the reasons for this variable mortality was related to the different severity of disorders. El-Nawawy [22] showed 38% PICU mortality, but in India this was 35% [23] and in Argentina it was lower (2.6%) [24].

There was a tendency toward less ICU stay in the VDD group, as the cases were either discharged or died earlier than those with sufficient vitamin D, but this finding was not statistically significant.

Limitation of the study

The present study included small groups of cardiomyopathy, liver failure, and diabetic ketoacidosis patients and could not document the clinical observation of VDD as a contributing factor for their deteriorating medical condition. In addition, the VDD mortality group was observed to survive less in the ICU, but this also was not statistically different. We had no baseline data about vitamin D levels in the general Egyptian pediatric population, and 16% of the patients had vitamin D levels above 150 nmol/l because of the faulty outpatient practice of using repeated large doses of intramuscular cholecalciferol (vitamin D) based on clinical manifestations of rickets without a baseline vitamin D assay.

 Conclusion



VDD prevalence was reported in about half of the critically ill patients, and it was observed to be related to multiple organ dysfunctions and rapid clinical deterioration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr 2008; 88:491S–499S.
2McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, Doherty DR, Canadian Critical Care Trials Group The association of vitamin D status with pediatric critical illness. Pediatrics 2012; 130:429–436.
3Ponnarmeni S, Angurana SK, Singhi S, Bansal A, Dayal D, Kaur R et al. Vitamin D deficiency in critically ill children with sepsis. Paediatr Int Child Health 2016; 36:15–21.
4Goldstein B, Giroir B, Randolph A. International Consensus Conference Panel. International pediatric severe sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8.
5Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med 1996; 24:743–752.
6Leteurtre S, Martinot A, Duhamel A, Gauvin F, Grandbastien B, Nam TV et al. Development of a pediatric multiple organ dysfunction score: use of two strategies. Med Decis Making 1999; 19:399–410
7Acharya SP, Pradhan B, Marhatta MN. Application of ‘the Sequential Organ Failure Assessment (SOFA) score’ in predicting outcome in ICU patients with SIRS. KUMJ 2007; 5:475–483.
8Thacher TD, Clarke BL Vitamin D insufficiency. Mayo Clin Proc 2011; 86:50–60.
9Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008; 122:1142–1152.
10Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96:53–58.
11Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM et al. Vitamin D deficiency in critically ill children. Pediatrics 2012 130:421–428.
12Hebbar KB, Wittkamp M, Alvarez JA, McCracken CE, Tangpricha V. Vitamin D deficiency in pediatric critical illness. J Clin Transl Endocrinol 2014; 1:170–175.
13Rippel C, South M, Butt WW, Shekerdemian LS. Vitamin D status in critically ill children. Intensive Care Med 2013; 38:2055–2062.
14Rey C, Sánchez-Arango D, López-Herce J, Martínez-Camblor P, García-Hernández I, Prieto B, Pallavicini Z Vitamin D deficiency at pediatric intensive care admission. J Pediatr (Rio J) 2014; 90:135–142.
15Lodha R, Shah R, Gupta N, Irshad XX, Kabra SK. Vitamin D levels in critically ill children [abstract]. Pediatr Crit Care Med 2014; 15:59–60.
16Dayal D, Kumar S, Sachdeva N, Kumar R, Singh M, Singhi S. Fall in vitamin D levels during hospitalization in children. Int J Pediatr 2014; 2014:291856.
17Fawzi Maggie M, Swelam E, Said NS. Plasma levels of 25-hydroxyvitamin D and dress style in a sample of Egyptian female university students. Life Sci 2012; 9:763–767.
18Mutlu A, Mutlu GY, Özsu E, Çizmecioğlu FM, Hatun Ş. Vitamin D deficiency in children and adolescents with type 1 diabetes. J Clin Res Pediatr Endocrinol 2011; 3:179–183.
19Krishnan A, Ochola J, Mundy J, Jones M, Kruger P, Duncan E, Venkatesh B Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients. Crit Care 2010; 14:R216.
20Ayulo M Jr, Katyal CH, Agarwal CH, Sweberg T, Rastogi D, Markowitz M, Ushay HM. The prevalence of vitamin D deficiency and its relationship with disease severity in an urban pediatric critical care unit. Endocr Regul 2014; 48:69–76.
21Gemke RJ, Bonsel GJ. Comparative assessment of pediatric intensive care: a −23. 17 national multicenter study. Pediatric Intensive Care Assessment of Outcome (PICASSO) Study Group. Crit Care Med 1995; 23:238–245.
22El-Nawawy A. Evaluation of the outcome of patients admitted to the pediatric intensive care unit in Alexandria using the pediatric risk of mortality (PRISM) score. J Trop Pediatr 2003; 49:109–114.
23Thukral A, Lodha XX, Irshad M, Arora NK. Performance of pediatric risk of mortality (PRISM), pediatric index of mortality(PIM) and PIM2 in a pediatric intensive care unit in a developing country. Pediatr Crit Care Med 2006; 7:356–361.
24Eulmesekian PG, Pérez A, Minces PG, Ferrero H. Validation of pediatric index of mortality 2 (PIM2) in a single pediatric intensive care unit of Argentina. Pediatr Crit Care Med 2007; 8:54–57.