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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 2  |  Page : 61-68

Calcium, phosphate, and Vitamin D abnormalities in critically ill children


1 Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
2 Department of Biochemistry, Maulana Azad Medical College, New Delhi, India

Date of Submission22-Jan-2020
Date of Decision22-Feb-2020
Date of Acceptance29-Feb-2020
Date of Web Publication10-Apr-2020

Correspondence Address:
Dr. Urmila Jhamb
Department of Pediatrics, Maulana Azad Medical College, New Delhi - 110 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_9_20

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  Abstract 


Background and Aims: Calcium, phosphate, and Vitamin D abnormalities are common in critically ill children, which may affect their outcome. However, data regarding the prevalence of these abnormalities are scarce from developing countries. This study assessed the prevalence of calcium, phosphate, and Vitamin D abnormalities in critically ill children and their association with the outcome.
Materials and Methods: This was a prospective, cross-sectional study of children aged 1 month to 12 years admitted to the pediatric intensive care unit of a tertiary care public hospital. Relevant clinical information and PRISM III score were recorded, and blood sample for the estimation of serum calcium, phosphate, Vitamin D, and other relevant parameters were collected at admission. Children were followed up till final outcome.
Results: A total of 135 children were included with a median age of 36 months. Total and ionized hypocalcemia were present in 9.6% and 22.9%, respectively, and both were associated with higher mortality (P = 0.006 and 0.03, respectively). Children with total hypocalcemia more often had sepsis and required significantly more fluid boluses and inotropes. Hypophosphatemia and hyperphosphatemia were present in 28.8% and 10.3%, respectively, and were also associated with significantly higher mortality. 85.6% of the children were Vitamin D deficient, but no significant association with severity and outcome was found.
Conclusion: Calcium, phosphate, and Vitamin D abnormalities were common in critically ill children. Higher mortality was associated with hypocalcemia and abnormal phosphate levels but not with Vitamin D deficiency. There was significant association of hypocalcemia with sepsis, fluid bolus, and inotrope requirement.

Keywords: Critically ill children, hypocalcemia, mortality, pediatric intensive care unit stay, Vitamin D level


How to cite this article:
Agrwal S, Jhamb U, Kaushik S. Calcium, phosphate, and Vitamin D abnormalities in critically ill children. J Pediatr Crit Care 2020;7:61-8

How to cite this URL:
Agrwal S, Jhamb U, Kaushik S. Calcium, phosphate, and Vitamin D abnormalities in critically ill children. J Pediatr Crit Care [serial online] 2020 [cited 2020 Sep 25];7:61-8. Available from: http://www.jpcc.org.in/text.asp?2020/7/2/61/282233




  Introduction Top


Abnormalities of calcium, phosphate, and Vitamin D are common in critically ill children admitted to the pediatric intensive care unit (PICU), but data are scarce from developing countries. Critically ill children have various metabolic derangements which predispose them for hypocalcemia, e.g., hypoalbuminemia, renal failure, Vitamin D deficiency, and hypoparathyroidism.[1] Some studies have shown association of hypocalcemia with the duration of stay, ventilation, severity of illness, and mortality.[2],[3],[4],[5] Critically ill children also have various risk factors for developing hypophosphatemia, e.g. malnutrition, sepsis, diuretics, and steroid use, and this has been shown to be associated with increased duration of stay and sepsis in some studies, while others have failed to find any such association.[6],[7],[8] Occurrence of hypercalcemia and hyperphosphatemia is less in critically ill children, and the association of these abnormalities with the outcome has not been studied in detail. Studies have shown that Vitamin D deficiency is common among critically ill children, and there are variable results of studies regarding its association with severity of illness, sepsis, duration of ventilation, and PICU stay.[9],[10],[11],[12],[13],[14],[15] High incidence of Vitamin D deficiency has been found even in healthy Indian children.[16],[17]

The present study aims to analyze the prevalence of abnormalities in serum calcium, phosphate, and 25-hydroxyvitamin D levels in the children admitted to the PICU and to study the association of these abnormalities with the outcome.


  Materials and Methods Top


This prospective, cross-sectional study was conducted in the seven-bedded PICU of a tertiary care hospital in Delhi. Children aged 1 month to 12 years admitted to the PICU were consecutively enrolled. Children with known renal or parathyroid dysfunction or those taking Vitamin D were excluded. Taking prevalence of 40%, precision of 10%, and 95% confidence interval, using the formula for sample size calculation for qualitative, cross-sectional study, a sample size of minimal 96 was calculated.

Demographic data, history including drug intake, anthropometry, examination findings, primary diagnosis at admission, PRISM III score, requirement of mechanical ventilation, and its duration, fluid boluses or inotropic support, outcome, and duration of stay were recorded. Blood sample for the estimation of serum calcium (total and ionized), phosphate, sodium, potassium, alkaline phosphatase, blood urea, serum creatinine, serum albumin, and Vitamin D was collected within 24 h of admission ( first morning). Methods used for analysis were O-cresolphthalein complexone for serum calcium, phosphomolybdate for serum phosphate, and electrochemiluminescence immunoassay method for Vitamin D.

Cutoff values were taken as follows:

  • Hypocalcemia – Total serum calcium <8.5 mg/dL and ionized calcium level <1 mmol/L[3]
  • Hypercalcemia – Total serum calcium >11 mg/dL and ionized serum calcium >1.25 mmol/L[18]
  • Hypophosphatemia – Serum phosphate <3.7 mg/dL[19]
  • Hyperphosphatemia – >6.5 mg/dL[19]
  • Vitamin D deficiency – serum 25 hydroxyvitamin D <20 ng/mL[20]
  • Hypervitaminosis D – 25 hydroxyvitamin D >100 ng/mL.


Serum calcium value was corrected for serum albumin.

Data were analyzed using SPSS 16.0 software (Copyright 2007, SPSS Inc, Chicago, IL, USA). A P < 0.05 was considered statistically significant. For comparison of categorical variables, Chi-square/Fisher's exact test was applied. Mann–Whitney/Student's t-test was applied for comparison of categorical with quantitative variables. Pearson and Spearman correlation coefficients were used to determine the correlation of the quantitative variables.

The study was approved by the institutional ethical committee. Informed written consent was taken from the parents.


  Results Top


A total of 226 children were admitted in the PICU during the study period (March–September 2014), and 135 were included in the study. Ninety-one were excluded for various reasons, e.g. death or transfer out of PICU before the sample was drawn, consent not given, previous kidney disease, age <1 month, and readmission. Ninety-three (68.1%) were males and 42 (31.9%) were females. Median age of the study population was 36 months. 33.3% of the children were <1 year of age, 29.7% were between 1 and 5 years of age, and 37% were more than 5 years of age. Sixty-five (48.1%) children required ventilator support, and mortality in the study population was 22.2%. Primary system involved was central nervous system in 24%, respiratory system in 17%, cardiovascular system in 15.5%, and gastrointestinal system in 10.5%. Fourteen percent were postoperative patients, and the remaining 7.4% had other miscellaneous diagnosis.

[Table 1] shows the prevalence of various serum abnormalities in the study population. 17 (12.6%) children had history of prior calcium supplementation. There was no significant difference in the occurrence of hypocalcemia among those who had received prior calcium supplementation (P = 0.93). The study showed a very high incidence of Vitamin D deficiency (85.9%). 74% of children had levels Vitamin D <10 ng/mL. None of them had hypervitaminosis D.
Table 1: Prevalence of metabolic abnormalities in the study population

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Association of calcium abnormalities with demography, PICU morbidities, and outcome is shown in [Table 2]. Median age of the children with total hypocalcemia was significantly lower (P = 0.006). They were more likely to have sepsis (P < 0.001) and required more fluid boluses (P = 0.007) and inotropes support (P = 0.012). Mean calcium was significantly lower among the children with sepsis (P = 0.004). Mortality was higher in the children with total hypocalcemia (P = 0.006) and ionized hypocalcemia (P = 0.03), but no association was found with hypercalcemia. There was no statistically significant difference in gender distribution, need for mechanical ventilation, duration of PICU stay, and duration of ventilation between the normal and abnormal calcium levels.
Table 2: Correlation of calcium abnormalities with patient characteristics, severity of illness, sepsis, and biochemical parameters

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We did not find any significant association of abnormal serum phosphate levels with various morbidities, such as sepsis, fluid bolus, inotrope, and ventilation requirement. PRISM III score and mortality were significantly higher among the children with abnormal serum phosphate levels. The study did not find any significant association of Vitamin D deficiency with requirement and duration of mechanical ventilation, duration of PICU stay, biochemical abnormalities of calcium or phosphate, sepsis, requirement of fluid bolus or inotropes, and mortality as shown in [Table 3] and [Table 4].
Table 3: Association of Vitamin D levels with outcome and calcium/phosphate levels

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Table 4: Association of Vitamin D deficiency with biochemical abnormalities and outcome

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Comparison of the biochemical abnormalities between survivors and nonsurvivors is shown in [Figure 1]. Total and ionized hypocalcemia were significantly more among the nonsurvivors (P value 0.012 and 0.047, respectively). Hypophosphatemia and hyperphosphatemia were also significantly more in the nonsurvivor group (P = 0.048 and 0.018, respectively). There was no significant difference in the rate of Vitamin D deficiency (not shown in figure).
Figure 1: Biochemical abnormalities among survivors and nonsurvivors

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  Discussion Top


Hypocalcemia has been reported in 18%–65% of the critically ill children and adults.[2],[3],[4],[5],[21] We found hypocalcemia at admission in 24.4%; however, when corrected for albumin, it was 9.6%. One gram per deciliter decrease in serum albumin decreases the total calcium by 0.8 mg/day, and we considered serum albumin levels of <4 mg/dL as hypoalbuminemia. In our study, 122 (90%) children had serum albumin <4 mg/dL. Occurrence of total hypocalcemia at admission in our study was lower than the study by Singhi et al.[3] (35%) and Cardenas-Rivero et al.[5] (49%). Singhi et al.[3] found that an additional 13% of the patients developed hypocalcemia during PICU stay. Ionized hypocalcemia at admission in our study was higher than the study by Broner et al.[4] (12.5%) and Cardenas-Rivero et al.[5] (17.9%), while it was lower than the study by Naik and Dandge[21] (47.5%). We did not check calcium levels again during the PICU stay. Children with hypocalcemia had significantly higher incidence of sepsis and those with sepsis had lower mean calcium levels. Higher incidence of sepsis among the hypocalcemic patients was found by Chernow et al.[2] (P = 0.01 for total hypocalcemia) and Cardenas-Rivero et al.[5] (P = 0.03 for ionized hypocalcemia). Hypocalcemia was found in 57% and 83% of the children with sepsis in studies by Singhi et al.[3] and Naik and Dandge, respectively.[21] Calcium level in the setting of sepsis has been found to be inversely related to the levels of inflammatory mediators, e.g. tumor necrosis factor, interleukin-6, and procalcitonin.[22] Raised calcitonin precursors have also been implicated as a cause of hypocalcemia in septic patients.[23]

Calcium is an important cation for neuromuscular transmission, muscle contraction, and membrane stability. Studies have shown significant association of hypocalcemia with hypotension and requirement of cardiovascular support.[3],[5],[21],[24] Vincent et al.[25] showed that infusion of intravenous calcium in the critically ill patients was associated with significant increase in mean arterial pressure that lasted for about 1 h. We also found significant association of hypocalcemia with fluid and inotrope requirement. Children with hypocalcemia had significantly higher mortality compared to those with normal or high serum calcium. Our observation was consistent with other studies.[3],[4],[5],[21]

Higher proportion of the children with hypocalcemia required mechanical ventilation compared to those with normal serum calcium, but the difference was not statistically significant. We did not find any significant association of total hypocalcemia with the PRISM III score. This was in contrast to other studies which showed higher severity of illness among hypocalcemic patients.[5],[26],[27] The children with ionized hypocalcemia had significantly higher PRISM scores. Patients with hypocalcemia have been shown to stay in the PICU for longer period, but we did not find any association of hypocalcemia with the duration of ventilation or ICU stay.[2],[3],[21] Our study did not show any significant association of hypercalcemia with severity of illness, duration of ventilation or PICU stay, need for cardiovascular support, or mortality.

Hypophosphatemia is a common metabolic abnormality in critically ill children and adults. Hypophosphatemia is known to develop during the ICU stay, and studies have shown that 60%–75% children developed hypophosphatemia during the PICU stay.[6],[7],[28] We analyzed phosphate levels only at the PICU admission. The incidence of hypophosphatemia in our study was lower than the study by Santana e Meneses et al.[28] Malnutrition has been described as an independent risk factor for the occurrence of hypophosphatemia.[6],[28] In our study, malnutrition was present in 43.6% of the hypophosphatemic patients which was similar to the findings of de Menezes et al. and Santana e Meneses et al.[6],[28] Hypophosphatemia was significantly associated with malnutrition in the study of de Menezes et al.[6] (P = 0.04), but our study did not show any significant association (P = 0.73).

We did not find any significant association of hypophosphatemia with requirement and duration of mechanical ventilation and duration of PICU stay. Our findings were similar to those of de Menezes et al.[6] and Ruiz Magro et al.[8] while Kilic et al.[7] found significant association of hypophosphatemia with the duration of mechanical ventilation and ICU stay (P = 0.02 and 0.001, respectively).

Studies have reported the incidence of hypophosphatemia among patients with sepsis to be up to 80%.[7],[29] Our study showed that 35% of the children with sepsis had hypophosphatemia and 13.5% had hyperphosphatemia. High levels of inflammatory cytokines are associated with hypophosphatemia.[29] In our study, 23% of normophosphatemic and 33% of hypophosphatemic patients had sepsis (P = 0.24). This observation was in contrast to Kilic et al.[7]

Bollaert et al.[30] showed a significant increase in the left ventricular stroke volume and arterial pressure immediately after intravenous phosphate infusion, and it was also associated with increase in arterial pH. However, we did not find any significant association of hypophosphatemia with the requirement of fluid bolus and inotrope among the critically ill children. This observation was similar to de Menezes et al.[6]

In our study, the median PRISM III score was significantly higher among the hypophosphatemic (P = 0.013) and hyperphosphatemic children (P = 0.008) compared to the normophosphatemic patients. de Menezes et al.[6] did not find any such association. In the study by Kilic et al.,[7] the mean PRISM score was higher among the hypophosphatemic patients, but the difference was not significant. We could not find any study comparing the incidence of hyperphosphatemia with duration of ventilation, occurrence of sepsis, PRISM score, and mortality.

We found higher mortality among the children with abnormal serum phosphate levels. Incidence of hypophosphatemia and hyperphosphatemia was significantly higher among nonsurvivors. Suzuki et al.[31] showed that patients with at least one episode of hypophosphatemia had higher mortality, but on multivariate regression analysis, hypophosphatemia was not an independent predictor of mortality. Severe hypophosphatemia has been found to be associated with eightfold increase in risk of mortality in septic patients.[32] Haider et al.[33] found that hyperphosphatemia was significantly associated with mortality. The deleterious effect of low serum phosphate can be explained by its effect on myocardial function, response to vasopressors, and ATP generation.

Incidence of Vitamin D deficiency in critically ill children ranges from 28% to 71%.[9],[34],[35] Incidence of Vitamin D deficiency in our study (85.9% deficient and 7.4% insufficient) was higher than the other Indian study by Lodha et al.[35] (71%). Some studies from the same city have shown that the incidence of Vitamin D deficiency in healthy children is 85%–90%.[16],[17] It is difficult to state whether the high incidence of Vitamin D deficiency in our study population is due to critical illness or only a reflection of the population prevalence. In the critically ill children, Vitamin D levels may decline further during the ICU stay due to insufficient replacement and the absence of ultraviolet-B exposure.[14] We, however, did not repeat the vitamin levels during PICU stay.

The effects of Vitamin D are mediated through Vitamin D receptor. Vitamin D acts on both the adaptive and innate immunity systems. Vitamin D deficiency has been implicated in various immune disorders, e.g. inflammatory bowel disease, asthma, and type one diabetes.[36],[37] Studies have shown significant association of Vitamin D deficiency with occurrence of sepsis in children as well as in adults.[12],[38] We did not find any significant association of Vitamin D deficiency with the occurrence of sepsis. Similar observation was made by Amrein et al.[13] Vitamin D deficiency has been found to be associated with a higher requirement of cardiorespiratory support.[9],[10] Severe Vitamin D deficiency is associated with decreased muscle strength and may lead to prolonged ventilation requirement and difficulty in weaning.[39] Some studies have found association of Vitamin D deficiency with a longer duration of stay,[9] while others have failed to demonstrate such association.[13], 15, [39],[40],[41] We did not find any significant association of Vitamin D deficiency with the cardiorespiratory support requirement, duration of PICU stay, and duration of mechanical ventilation, and this observation was similar to other studies.[10],[14],[15] Amrein et al.[14] found that the mortality was lower among the adult ICU patients who were on Vitamin D supplementation compared to those on placebo. We did not find any significant association of Vitamin D deficiency with mortality.

Strength of our study was that it was a prospective study and we analyzed calcium, phosphate, and Vitamin D together and tried to find a correlation among them. The limitations of our study were small sample size and that we did not analyzed parathyroid hormone levels as a cause of calcium and phosphate abnormalities. In our study, most of the patients had Vitamin D deficiency or insufficiency. Very small number of patients in our study had normal Vitamin D levels, and this may be the reason for not finding any significant association with the outcome.


  Conclusion Top


Our study provides data regarding the prevalence of calcium, phosphate, and Vitamin D abnormalities in critically ill children in a developing country. Calcium deficiency has a significant association with cardiovascular morbidity and incidence of sepsis. Abnormality of calcium and phosphate is associated with poorer outcome in critically ill children. We found very high incidence of Vitamin D deficiency. In view of very low number of patients having sufficient Vitamin D levels group, the association of Vitamin D deficiency with various PICU morbidities could not be analyzed accurately.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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