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Indian Pediatr 2016;53:
479-484 |
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Vitamin D Deficiency and Parathyroid Response
in Critically-ill Children: Association with Illness Severity
and Clinical Outcomes
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Satish Kumar Shah, Sushil Kumar Kabra,
*Nandita Gupta,
Gautham Pai and Rakesh Lodha
From Departments of Pediatrics and *Endocrinology,
All India Institute of Medical Sciences, New Delhi, India.
Correspondence to: Dr Rakesh Lodha,
Additional Professor, Department of Pediatrics, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi 110 029, India.
Email:
[email protected]
Received: August 22, 2015;
Initial review: October 20, 2015;
Accepted: April 19, 2016.
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Objective: To determine the
prevalence of vitamin D deficiency in critically ill children, and to
study its association with parathyroid response, severity of illness and
clinical outcomes.
Design: Prospective observational
study.
Setting: Medical Pediatric
Intensive Care Unit of a tertiary care centre of Northern India.
Participants: 154 children
in-patients: August 2011-January 2013.
Main outcome measures: Vitamin D
deficient children were (serum 25-hydroxy vitamin D <20 µg/mL) divided
into "parathyroid-responder" [serum parathyroid hormone >65 pg/mL with
25(OH)D<20 µg/mL and/or calcium corrected for albumin <8.5 mg/dL] and
"non parathyroid-responder.’’ Illness severity was assessed by Pediatric
Index of Mortality-2 (PIM-2) score at admission. Biochemical parameters,
illness severity scores and clinical outcomes were compared between
parathyroid-responders and non-parathyroid-responders.
Results: Vitamin D deficiency and
hypocalcemia were observed in 125 (83.1%) and 91 (59%) children,
respectively at admission. There were no differences in illness severity
score at admission, mortality rate and length of stay between vitamin
D-deficient children and 19.8% of non-vitamin D-deficient children.
Among Vitamin D-deficient children, parathyroid-responders had higher
PIM-2 score at admission compared to non-parathyroid-responder [12.8
(7.4,20.6) vs. 6.5 (2.5,12.2), P=0.01]. However, there
were no differences in other clinical outcomes between two groups.
Conclusion: Critically ill
children have high prevalence of vitamin D deficiency. Parathyroid gland
response secondary to hypocalcemia or vitamin D defiency is impaired in
critical illness.
Keywords: Calcium, Illness severity, Outcome.
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T he pleiotropic action of vitamin
D plays a central role in the critical illness pathophysiology. Vitamin
D receptor is found in B and T lymphocytes, bone marrow and cardiac
cells, and there is growing evidence regarding its cardio-protective,
immunomodulatory and antimicrobial properties [1]. Studies have
documented higher prevalence of vitamin D deficiency in critical care
settings [2-6]. Whether this deficiency is associated with severity of
illness or other clinical outcomes is unclear [10].
We hypothesized that there is impairment in the
Calcium ľParathyroid
hormone (PTH)–Vitamin D axis due to critical illness. Assessing vitamin
D deficiency in terms of PTH response and its association with illness
severity and clinical outcomes is necessary to get insight for further
interventional studies for optimizing the management of Vitamin D
deficiency, particularly in the setting where vitamin D deficiency is
highly prevalent even in healthy children. We, therefore, conducted this
study to determine the prevalence of Vitamin D deficiency and
characterize its relation with calcium and PTH, and assess the outcome
considering type of parathyroid response in vitamin D-deficient
children.
Methods
This was a prospective cohort study conducted in
Pediatric Intensive Care Unit (PICU) of All India Institute of Medical
Sciences, New Delhi, India, and was a secondary objective of data
collected as a part of ‘Hypophosphatemia in Pediatric Critical Illness’
study by the same group. In this study, all the children aged between 1
month and 15 years were eligible for inclusion. Exclusion criteria were:
known parathyroid disease, rickets, renal tubular acidosis, chronic
kidney disease (CKD) diagnosis of acute kidney injury (AKI) at
admission. Children requiring readmission and those who died within 24
hours were also excluded. Ethical approval was obtained from
Institutional ethics committee. Parents of the children fulfilling the
criteria were approached for the written informed consent for the
participation of the child in the study.
The following variables were recorded at baseline for
each patient: age, gender, season of admission, vitamin D
supplementation, type of milk-product consumption, anthropometry, and
documentation of underlying chronic illness if any. Pediatric Index of
Mortality 2 (PIM2) score was used to assess illness severity at
admission [11]. Serum 25(OH)D, PTH, total calcium, alkaline phosphatase
(ALP), albumin and phosphate levels were measured at admission,
preferably within 24 hours. Children did not receive any form of Vitamin
D supplementation prior to blood sampling. Children were followed-up
throughout the PICU stay. Evidence of sepsis, septic shock, acute
respiratory distress syndrome (ARDS), need for mechanical ventilation,
duration of mechanical ventilation, need for renal replacement therapy
(RRT), duration of PICU stay and mortality were recorded. Other standard
and relevant investigations (blood culture, blood gas, electrolytes,
kidney function test, etc) were recorded at the time of admission.
Patients with vitamin D level less than 20 ng/mL were
categorized as deficient [12-14]. Secondary hyperparathyroidism was
defined as a serum PTH level >65 pg/mL, corresponding to the upper limit
of the laboratory reference range [15]. Hypocalcemia was defined as
total serum calcium (corrected for albumin) <8.5 mg/dL [16]. To evaluate
parathyroid hormone response in the setting of hypocalcemia or
hypovitaminosis D, children were classified to have "adequate PTH
response/PTH responder" or "inadequate PTH response/PTH non-responder".
PTH-responders were defined as patients who had PTH >65 pg/mL together
with 25(OH)D <20 ng/mL and/or total calcium corrected for albumin <8.5
mg/dL based on measurements made at the time of PICU admission.
Malnutrition was defined as weight-for-age Z-score < –2 for
children up to 10 years and BMI-for-age Z-score < –2 for children
above 10 years as per World Health Organization (WHO) growth chart and
WHO reference [17]. Sepsis and septic shock were defined according to
the International Pediatric Sepsis Consensus Conference criteria [18].
Acute kidney Injury (AKI) was defined based on either urine output or
serum creatinine criteria [19]. ARDS was defined using standard
definition [20].
Illness severity and various clinical outcomes were
compared between children having vitamin D deficiency and those not
having vitamin D deficiency. Those children with vitamin D deficiency
and secondary hyperparathyroidism were classified as ‘PTH responder’.
Proportion of vitamin D deficient children showing adequate PTH response
was calculated. Illness severity score and various clinical outcomes
were assessed between PTH responder and non-PTH responder in vitamin D
deficient children.
Blood samples were transported in ice pack
immediately after collection for cold centrifugation and plasma
separation. Separated plasma samples were stored at -80 0
C, and were analyzed for 25(OH)D and PTH values in batches, every
2-weekly. Serum 25(OH)D was assayed by an auto-analyzer (DiaSorin
Liaison, Italy) using a chemiluminescent tracer, with a measuring range
of 4 to 150 ng/mL (inter- and intra-assay coefficient of variation of
10%). Serum PTH level was estimated by using electrochemiluminometric
assay using a Cobas e411 auto analyzer (Roche Diagnostics, Basel,
Switzerland), with a measuring range of 1.2 to 5000 pg/mL. Serum
calcium, phosphorus, and ALP were estimated by colorimetric method using
a Beckman Coulter Synchron-CX9 PRO clinical system (Beckman Coulter,
Inc).
Statistical analysis: Data were analyzed using
STATA 11 software (Stata Corp, College Station, TX). Differences between
groups were assessed using the chi-square test for categorical variables
and Student’s t-test or Wilcoxon ranked sum test for continuous
variables, depending on the distribution of variables. Correlation
coefficients were calculated using Spearman’s rank correlation. A P
value of less than 0.05 was considered as statistically significant.
Results
A total of 162 children out of 295 admissions met
inclusion criteria. Most common reasons for exclusion were: AKI (30),
CKD (27), readmission (26), transfer out within 24 hour (18), death
within 24 hour (16) and refusal of consent (16). Serum PTH and vitamin D
estimation could not be done in 8 children, and thus 154 children were
included in analysis. The general characteristics of study population
are shown in Table 1. The most frequent causes of
admission were Acute respiratory infection (16.8%), tropical infectious
disease (15.6%) like dengue, malaria, etc., central nervous system
disease (15.6%), congenital heart disease (9.1%), liver disease (9.7%),
genetic disorder (6.5%), gastrointestinal disorders (5.8%),
rheumatologic disorders (5.8%), and others (15%). No child received any
form of vitamin D supplementation prior to admission. Around 56% of
children had some underlying chronic illness.
TABLE I Demographic, Clinical and Biochemical Characteristics of Study Population (N=154)
Characteristics |
Value |
Age (mo) |
30 (6-102) |
Weight (kg) |
10 (5.2-19.7) |
Malnutrition, n (%) |
101 (65.6) |
Male gender, n (%) |
102 (66.2) |
PIM2 score |
7.2 (2.8-14.5) |
Need for mechanical ventilation, n (%) |
109 (70.8) |
PICU length of stay |
7 (3-16) |
Duration of ventilation |
8 (3-15) |
Serum 25(OH)D, ng/dL |
11.7 (7.1- 16.0) |
PTH, pg/mL |
33.7 (17.8-56.7) |
Calcium corrected for albumin, mg/dL |
8.2 (7.4-9.0) |
Serum phosphate, mg/dL |
3.7 (2.9-4.4) |
Serum ALP, IU/mL |
428 (296-604) |
PIM2: Pediatric Index of Mortality 2; PICU: Pediatric Intensive
Care Unit; 25(OH)D: Vitamin D; PTH: Parathyroid hormone; ALP:
Alkaline phosphatase; All values median (IQR) except otherwise
stated. |
The prevalence of vitamin D deficiency [25(OH) D <20
ng/mL] was 83.1% (95% CI 77.1, 89.0). Fourteen out of 154 children
(9.1%) had 25(OH)D levels between 20 to 29.9 ng/mL. Only 7.8% of
children had 25(OH) D ł30
ng/mL. Twenty-one children (13.6%) had 25(OH)D less than 5 ng/mL.
Hypocalcemia was common in Vitamin D deficient group. Serum calcium
corrected for albumin was lower in vitamin D deficient group compared to
non-deficient group (P=0.02). Median PTH value was higher in
vitamin D deficient compared to that of non-deficient group but not
statistically significant (Table II).
TABLE II Baseline Characteristics and Clinical Outcome of Study Population by Vitamin D Status
Characteristics |
25(OH)D <20 ng/mL |
25(OH)D ≥20 ng/mL |
P value |
|
(n=128) |
(n=26) |
|
Demographic and Clinical |
|
|
|
Median age, month (IQR) |
48 (6.5- 108) |
9.5 (6- 32) |
0.04 |
Malnutrition, n (%) |
81 (63.2) |
20 (76.9) |
0.18 |
Male gender, n (%) |
81 (63.2) |
21 (80.7) |
0.08 |
Presence of chronic illness, n (%) |
71 (55.4) |
15 (57.7) |
0.8 |
Admission season, n (%) |
|
|
|
Summer |
65 (50.7) |
18 (69.2) |
0.01 |
Winter |
37 (28.9 ) |
5 (19.2) |
|
Spring |
26 (20.3 ) |
3 (11.5 ) |
|
Major Diagnostic Category |
|
|
|
ARI, n (%) |
14.8 (19) |
26.9 (7) |
0.09 |
Cardiovascular system, n (%) |
8.6 (11) |
11.5 (3) |
|
Infection other than respiratory, n (%)
|
17.1 (22) |
7.6 (2) |
|
Neurological disease, n (%) |
|
15.6 (20) |
15.4 (4) |
Liver disease, n (%) |
10.9 (14) |
3.8 (1) |
|
Sepsis at admission, n (%) |
84 (65.6) |
16 (66.6) |
0.6 |
PIM2, median (IQR) |
7.5 (3.0-14.4) |
6.7 (1.8- 17.7) |
0.85 |
Biochemical |
|
|
|
25(OH)D, ng/mL, median (IQR) |
9.9 (6.3-13.7) |
26.5 (21.6-43.0) |
<0.001 |
PTH, pg/mL, median (IQR) |
35.8 (18.1-57.0) |
26.2 (14.6-56.4) |
0.43 |
Secondary hyperparathyroidism, n (%) |
25 (19.5) |
6 (23.1) |
0.681 |
Calcium corrected for albumin, mg/dL, median (IQR) |
8.1 (7.3-8.8) |
8.8 (8.2-9.1) |
0.02 |
Hypocalcemia, n (%) |
83 (64.8) |
8 (30.8) |
0.001 |
Serum phosphate, mg/dL, median (IQR) |
3.5 (2.9-4.4) |
3.9 (3.4- 5.0) |
0.20 |
Serum albumin, mg/dL, median (IQR) |
3.2 (2.4-3.7) |
3.3 (2.8-3.8) |
0.27 |
Serum ALP, U/ml, median (IQR) |
422 (296-611) |
465 (318-587) |
0.74 |
Clinical outcomes |
|
|
|
Mortality, n (%) |
54 (42.1) |
14 (53.8) |
0.27 |
PICU length of Stay, median (IQR) |
6.5 (3–14.5) |
11 (4 –19) |
0.07 |
Requirement of mechanical ventilation, n (%) |
87 (67.9) |
22 (84.6) |
0.08 |
Days of mechanical ventilation, median (IQR) |
7 (3-14) |
12.5 (4- 20) |
0.12 |
ARDS, n (%) |
29 (22.6) |
11 (42.3) |
0.03 |
Need for RRT during stay, n (%) |
27 (21.0) |
3 (11.5) |
0.26 |
Liver failure, n (%) |
20 (15.6) |
2 (7.7) |
0.29 |
Septic shock, n (%) |
51 (39.8) |
9 (34.6) |
0.61 |
ARI:Acute Respiratory Infection; PIM2: Pediatrics Index
Mortality 2; PTH: Parathyroid hormone; ALP: Alkaline Phosphatase;
PICU: Pediatric Intensive Care Unit; ARDS: Acute Respiratory
Distress Syndrome; RRT: Renal replacement therapy. |
ARDS was observed more often during the stay in
non-vitamin D deficient compared to vitamin D deficient group (42.3
vs. 22.6%, P=0.03). The two groups did not differ in terms of
illness severity score at admission, duration of PICU stay, need for
mechanical ventilation, duration of ventilator support, septic shock,
liver failure and need for renal replacement therapy (Table II).
Fifty-nine percent of children had hypocalcaemia at
presentation. Secondary hyperparathyroidism was present in 19.8% of
hypocalcemic and 19.5% of vitamin D deficient children. All the children
in non-vitamin D deficient group who showed secondary hyper-parathyroidism
showed evidence of hypocalcemia. PTH responders in vitamin D deficient
groups were found to have higher illness severity score at admission
compared to non-responders [12.8 (7.4,20.6) vs. 6.5 (2.5,12.2),
P=0.01]. There was no difference in mortality or other clinical
outcomes in PTH responders compared to non-responders during PICU stay (Table
III).
TABLE III Baseline Characteristics and Clinical Outcome of Patients With Vitamin D Deficiency in the Presence or
Absence of Parathyroid Hormone Response
Characteristics |
PTH responder (n=25) |
PTH non responder (n=103) |
P value |
Demographic and clinical |
Age in months, median (IQR) |
15 (5- 60) |
36 (7-108) |
0.16 |
Male gender, n (%) |
16 (64) |
65 (63.1) |
0.93 |
PIM2, median (IQR) |
12.8 (7.4- 20.6) |
6.5 (2.5-12.2) |
0.01 |
Biochemical |
25(OH)D, ng/mL, median (IQR) |
8 (6-12.9) |
10 (6.4-14) |
0.49 |
Calcium corrected for albumin, mg/dL, median (IQR) |
7.4 (6.6- 8.8) |
8.1 (7.4-8.8) |
0.06 |
Hypocalcemia, n (%) |
18 (72.0) |
73 (56.5) |
0.15 |
Serum Phosphate, mg/dL, median (IQR) |
4.2 (2.8-4.9) |
3.5 (2.9-4.2) |
0.15 |
Serum albumin, g/dL, median (IQR) |
4 (2.8- 3.4) |
3 (2.4-3.6) |
0.09 |
ALP, µ/mL,median (IQR) |
441 (300-1026) |
417 (296-576) |
0.22 |
Clinical outcomes |
Mortality, n (%) |
13 (52) |
41 (39.8) |
0.26 |
PICU Length of stay, median (IQR) |
7 (3-11) |
6 (3-15) |
0.82 |
Requirement of mechanical ventilation, n (%) |
20 (80) |
67 (65) |
0.15 |
Days of mechanical ventilation, median (IQR) |
5 (3-11.5) |
7 (3-15) |
0.30 |
ARDS, n (%) |
9 (36) |
20 (19.4) |
0.07 |
Need for RRT during stay, n (%) |
8 (32) |
19 (18.4) |
0.13 |
Liver failure, n (%) |
3 (12) |
17 (16.5) |
0.57 |
Septic shock, n (%) |
14 (56) |
37 (35.9) |
0.06 |
PIM2: Pediatric Index Mortality 2; ALP: Alkaline
phsophatase; PICU: Pediatric Intensive Care Unit; ARDS:
Acute Respiratory Distress Syndrome; RRT: Renal
replacement therapy. |
There was no correlation between admission level
vitamin D and calcium (r=0.08, P=0.3) or PTH (r=-0.14, P=0.06).
Negative correlation was observed between illness severity score and
admission level total calcium corrected for albumin (r=-0.32, P<0.001)
and admission level albumin (r= -0.31, P<0.001).
Discussion
We documented a high prevalence (83.1%) of vitamin D
deficiency in critically ill children at admission; only one-fifth of
the vitamin D deficient children showed adequate parathyroid hormone
response. Vitamin D deficiency was neither associated with higher
illness severity nor with worse clinical outcomes. However, among
vitamin D deficient children, those who showed adequate parathyroid
hormone response were sicker with no difference in mortality or other
clinical outcomes compared to those without adequate parathyroid hormone
response.
Earlier studies [2-9] have also documented a high
prevalence of vitamin D deficiency in critically ill children. Vitamin D
deficiency at initiation of critical illness may be due to pre-existing
vitamin D deficiency. We did not find association of vitamin D
deficiency with illness severity and other poor clinical outcomes. Some
studies have shown that lower level of vitamin D at initiation of care
is associated with higher admission day illness severity score [5-8].
However, none of them have showed association with mortality and
duration of PICU stay. In our study, ARDS was seen more commonly in
children with vitamin D sufficient status which is contrary to
observations in adults [21].
Only one-fifth of patients with either hypocalcemia
or vitamin D deficiency in our study showed adequate parathyroid
response. There are inadequate data regarding status of
calcium-PTH-vitamin D axis in critically ill children. Literature review
in critical care setting in adults identified that secondary
hyperparathyroidism was seen in 30-60 % [22,23]. The causes for blunted
PTH response remain unclear. Malnutrition and deficiency of magnesium in
our study children might have contributed to poor PTH response. Other
reasons could be abnormalities of calcium sensing receptor,
abnormalities of vitamin D receptor or impairment of 1
a-hydroxylation
in critical care setting. Regardless of percentage of PTH responders, it
was seen from our study and some studies in adult that vitamin D
deficient patients with adequate PTH response had paradoxically higher
illness severity score at admission compared to non-responders. There is
no clear explanation for such observation. We hypothesize that
pleiotropic actions of vitamin D in critical illness may be related to
action of 1,25 (OH)2D
at tissue level. 1,25(OH)2D
is the metabolically active form which is formed from 25(OH)D by the
activating enzyme 1 a-hydroxylase.
This conversion is under the endocrine and paracrine regulation of PTH.
Rise in PTH leads to conversion of 25(OH) D to 1,25(OH)2D
which is the biochemically active form. However, in sicker patients
secondary hyperpara-thyroidism may persist because of tissue vitamin D
deficiency. Therefore, lack of adequate PTH response may indicate better
tissue vitamin D utilization, and therefore may be associated with lower
severity score. It seems that vitamin D deficiency in conjunction with
hyperparathyroidism may be considered as marker of illness severity and
not the predictor of any clinical outcome.
There are some limitations of the study. This was a
single center study with heterogeneous groups; while the sample size is
similar to previous studies, it is still small for the subgroup
analysis. We did not measure vitamin D level at multiple time points
which would have given a better picture of vitamin D status as it has
been observed that various interventions during initial resuscitation
phase may alter vitamin D level. We could not measure 1,25(OH) 2D
and Vitamin D binding protein. Magnesium levels were also not measured,
deficiency of which might have led to impaired PTH response. In
conclusion, vitamin D deficiency is common in critically ill children.
There seems to be an impairment in calcium-PTH-Vitamin D axis in
critical illness. Vitamin D deficiency with secondary parathyroidism may
be considered as a marker of illness severity and is not a predictor of
clinical outcome.
Contributors: RL, SKK and SKS: designed the
study; RL and SKS: data interpretation, statistical analysis and drafted
the manuscript; SKS and GP: data collection; NG: helped with the vitamin
D and PTH estimation. All authors approved the final manuscript.
Funding: Intramural support from the Department
of Pediatrics, All India Institute of Medical Sciences, New Delhi.
Competing interests: None stated.
What is Already Known?
• Vitamin D deficiency is common in critical
illness.
What This Study Adds?
• There is impairment in Calcium-Parathyroid hormone-Vitamin
D axis in critically ill children.
|
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