Prevalence of vitamin D deficiency in critically ill patients and its influence on outcome: experience from a tertiary care centre in North India (an observational study)
© Azim et al.; licensee BioMed Central Ltd. 2013
Received: 6 September 2013
Accepted: 27 November 2013
Published: 20 December 2013
Limited studies are available on prevalence and severity of vitamin D deficiency in a critically ill population. To the best of our knowledge, this the first study of its kind in an Indian intensive care set-up.
One hundred fifty-eight critically ill patients were prospectively enrolled for over 2 years. Demographic profile and clinical characteristics were noted. Blood sample for serum 25 (OH) D was collected on admission (4 ml). Serum 25 (OH) D was measured using radioimmunoassay kit. Vitamin D deficiency was labelled as insufficient (31–60 nmol/l), deficient (15–30 nmol/l) and undetectable (<15 nmol/l). Statistical tests used were t test, chi-square test and binary logistic regression.
Vitamin D deficiency (<60 nmol/l) was present in 127 patients (80.4%). Twenty-six patients had (20.47%) undetectable vitamin D levels. The mean vitamin D level was higher amongst survivors (43.17 + 39.22) than in non-survivors (39.72 + 29.31). Vitamin D was not significantly associated with mortality in univariate analysis. Multiple logistic regression showed admission APACHE II (p = 0.008), lactate (p = 0.013) and pre-ICU hospital stay (p = 0.041) as independent predictors of mortality in critically ill patients (p < 0.05).
Vitamin D deficiency is highly prevalent in critically ill patients. A causal association between vitamin D deficiency and mortality was not found in our study. Larger studies are needed to understand the relationship between vitamin D deficiency and ICU outcome.
The pandemic of vitamin D deficiency even in effluent societies has pointed out the growing distance of human race from nature. Recent research has generated interest in pleiotropic actions of vitamin D all over the world.
Vitamin D receptors are found in nearly all types of immune cells . Its action on innate immunity is stimulatory, while its action on adaptive immunity is mainly considered to be modulatory . Various clinical studies and trials have shown correlation between vitamin D and systemic infections. Its deficiency has been associated with acute respiratory tract infections [3, 4], cardiovascular diseases and other chronic illnesses . Scientists are now exploring its possible association with acute life-threatening illnesses. A large US-based study reviewing national database of hospital discharge from 1979 to 2003 showed seasonal variation in incidence of sepsis and severe sepsis paralleling the seasonal fluctuation in 25(OH) D levels [6, 7]. A recently published study showed that vitamin D deficiency prior to hospital admission predisposes for acute kidney injury in critically ill patients . We conducted this study to analyse the prevalence and severity of vitamin D deficiency in a critically ill Indian population as there is paucity in Indian literature.
It is a prospective single-centre study conducted in the department of critical care medicine of a tertiary care public referral hospital. The intensive care unit (ICU) admits both medical and surgical cases. Ethical clearance was obtained from the ethical committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences before conducting the study. Informed consent was taken from next of kin of all enrolled patients. This study was conducted between May 2010 and May 2012.
All consecutive critically ill patients requiring ICU admission were screened for enrolment for the study. Exclusion criteria included age less than 18 years, pregnancy, patients on corticosteroid therapy, patients with history of malabsorption syndrome, patients with chronic kidney disease (CKD), patients on drugs interfering with vitamin D metabolism and patients already on vitamin D supplementation. A total of 158 patients (out of 480 admissions) met the inclusion criteria, and data was analysed for them.
Blood samples for laboratory measurements of serum 25 (OH) D were collected on patients' admission (4 ml), which were then immediately transferred to the endocrinology laboratory. Serum 25 (OH) D was measured using a radioimmunoassay kit technique using the 12 well gamma Counter machine (STRATEC, Birkenfeld, Germany). Till the samples were not processed, they were stored at −20°C temperature after separating the serum. Vitamin D deficiency was defined as values less than 60 nmol/l. Severity of vitamin D deficiency was labelled as insufficient if the level was between 31 and 60 nmol/l, deficient if the level was between 15 and 30 nmol/l and undetectable if the level was less than 15 nmol/l. The demographic profile (age/sex, co-morbidities), admission diagnosis, clinical characteristics and biochemical parameters of each patient were noted at the time of enrolment in the study. Severity of critical illness was assessed by admission acute physiological and chronic health evaluation (APACHE II) score and sequential organ failure assessment (SOFA) score. Levels and severity of vitamin D deficiency were compared between survivors and non-survivors and correlated with the outcome. Vitamin D was also compared to other predictors of outcome like APACHE II, SOFA and total days of mechanical ventilation. Laboratory and clinical management was done as per the treating team.
Data was analysed using SPSS 16.0, and results were expressed as mean ± standard deviation or median (interquartile range) as appropriate. Sample size was decided based on significance level (alpha) = 0.05. Student's t test was used between survivors and non-survivors. Non-parametric test like chi-square test was used for comparison between two groups for ranked observation. Actual p values were reported, and a p value <0.05 was taken as significant. Multivariate analysis by binary logistic regression was used. All the study variables were considered, and the best model with five variables which gave 90.5% overall correct classification was used.
Results and discussion
Patients demography ( n = 158)
48.50 ± 16.49
Others (poisoning, snakebite, etc.)
Other ICUs/HDUs (including post-operative ICU)
Admission SOFA score
9.56 ± 4.32
Admission APACHE II score
15.35 ± 6.14
Vitamin D levels (nmol/l)
41.53 ± 34.29
Length of ICU stay (days)
16.84 ± 18.44
Days of mechanical ventilation
13.35 ± 17.01
Patient characteristics: survivors vs non-survivors
(n = 75)
(n = 83)
(Mean ± SD)
(Mean ± SD)
47.01 ± 15.78
50.08 ± 17.05
7.96 ± 4.21
11.00 ± 3.94
APACHE II score
12.89 ± 5.39
17.50 ± 5.94
14.14 ± 41.29
21.01 ± 60.35
2.74 ± 0.59
2.61 ± 0.59
2.17 ± 2.20
2.78 ± 1.97
16.66 ± 9.72
24.31 ± 18.41
Vitamin D (nmol/l)
43.17 ± 39.22
39.72 ± 29.31
Pre-ICU hospital stay (days)
6.0 ± 6.02
10.67 ± 14.54
ICU length of stay
19.03 ± 20.98
14.90 ± 15.75
Days of MV
10.05 ± 19.55
15.99 ± 13.49
Vitamin D deficiency (<60 nmol/l) was present in 127 patients (80.4%). Fifty-three patients (41.73%) were in the insufficient group, 48 patients (37.79%) were in the deficient group and 26(20.47%) patients had undetectable vitamin D levels.
Multivariate analysis of significant variables
Logistic regression coefficient (beta)
Standard error of regression coefficient (beta)
Significance of beta
95% CI of OR
Days of mechanical analysis
Vitamin D deficiency is highly prevalent in the general population all over the world. Prevalence of levels <50 nmol/l is reported between 36% and 57% in the USA and even higher (between 28% and 100%) in European studies depending upon the group of population tested and cut-off levels used for normal range . Even Indian literature suggests vitamin D deficiency between 50% and 90% in the general population [10, 11].
Cut-off value of normal range of vitamin D remains a debatable topic, and whether levels considered normal for general population can be applied to critically ill patients remains unclear [12, 13]. In our study, we have used 60 nmol/l as the cut-off value based on the study published by Lee et al. in 2009 . However, in a recent meta-analysis of prospective cohort studies, Zitterman and colleagues reported 75–87.5 nmol/l as the optimal concentration in the general population and even showed a non-linear decrease in mortality as circulating 25 (OH) D level increases .
Vitamin D deficiency and its relation with increased mortality in the general population are well established. Almost all chronic illnesses associated with ageing are adversely affected by vitamin D deficiency [16, 17]. A meta-analysis published in 2007 showed that ordinary dose vitamin D supplementation is associated with reduction in total mortality in the general population . Melamed and colleagues reported that vitamin D <17.5 ng/l is independently associated with mortality in the general population . Review of literature and clinical studies on end-stage renal disease patients have shown that vitamin D supplementation is associated with decreased mortality . A recently published meta-analysis of 10 studies with a cohort of 6,853 patients concluded that higher vitamin D levels correlates with improved survival in CKD patients .
Vitamin D deficiency in critical illnesses can be multifactorial and can influence the sepsis cascade through several mechanisms. These mechanisms may include immune modulation, suppression of exaggerated inflammatory response, enhanced phagocytosis, chemotaxis, increased production of antimicrobial peptide cathelicidin, and calcium and glucose homeostasis [22, 23].
Deficiency of vitamin D in a critically ill population has also been studied, though to a lesser extent. Its association with mortality in this population subgroup remains unclear. Studies have shown a vitamin D deficiency of more than 90% in a critically ill population [24, 25]. Lee et al. reported undetectable levels in 17.5% of patients admitted to the ICU . Data regarding vitamin D deficiency in the critically ill population in the Indian scenario is lacking. In our study, we found that 80.4% of patients were deficient (level <60 nmol/l) in vitamin D levels on admission to the intensive care unit, with 20.48% having undetectable levels (level <15 nmol/l). However, we could not find a causal relationship between vitamin D deficiency and mortality.
Cecchi et al. conducted a single-centre study on 170 patients, out of which 92 were severe sepsis/septic shock patients and 72 were trauma patients . Vitamin D levels were significantly lower in the septic group but did not prove to be a mortality predictor on multivariate analysis. In contrast, a few studies have shown a significant association between vitamin D levels and mortality in critically ill patients [27, 28]. Mathews et al. studied the effect of vitamin D deficiency in 258 surgical ICU patients and reported an inverse relation between vitamin D deficiency and length of ICU stay, cost of therapy and mortality . Braun et al. studied pre-admission 25(OH) D levels drawn 7 to 365 days prior to ICU admission in a large cohort of 2,399 patients . They reported vitamin D as a strong predictor of ICU mortality. It is postulated that acute fluid shifts seen in severe sepsis and septic shock can influence the assessment of correct vitamin D levels . Venkatesh et al. pointed out the wide fluctuation in vitamin D level occurring in critically ill patients for hours . This could be one of the causes of different findings in various studies.
Larger studies are needed to understand the role of vitamin D level in critical illness, to define supplementation strategy, in monitoring frequency and in effect of replacement on outcome. Moreover, redesigning of ICU set-ups in such a way that all patients get adequate sunlight might be a topic of debate in modern medicine.
The authors conclude that this study shows high prevalence of vitamin D deficiency in critical care settings even in tropical countries like India. We also found that APACHE II, lactate and pre-ICU hospital stay are independent predictors of mortality in critically ill patients. We could not find a causal association between vitamin D deficiency and mortality.
We are grateful to DR SK Mandal for his guidance and valuable inputs in our research.
- Aranow C: Vitamin D and the immune system. J Investig Med. 2011, 59 (6): 881-886.PubMed CentralPubMedGoogle Scholar
- Kempker JA, Han JE, Tangpricha V, Ziegler TR, Martin GS: Vitamin D and sepsis: an emerging relationship. Dermatoendocrinol. 2012, 4 (2): 101-108. 10.4161/derm.19859.PubMed CentralView ArticlePubMedGoogle Scholar
- Ginde AA, Mansbach JM, Camargo CA: Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009, 169: 384-390. 10.1001/archinternmed.2008.560.PubMed CentralView ArticlePubMedGoogle Scholar
- Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML: Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010, 5: e11088-10.1371/journal.pone.0011088.PubMed CentralView ArticlePubMedGoogle Scholar
- Anagnostis P, Athyros VG, Adamidou F, Florentin M, Karagiannis A: Vitamin D and cardiovascular disease: a novel agent for reducing cardiovascular risk?. Curr Vasc Pharmacol. 2010, 8 (5): 720-730. 10.2174/157016110792006978.View ArticlePubMedGoogle Scholar
- Danai PA, Sinha S, Moss M, Haber MJ, Martin GS: Seasonal variation in the epidemiology of sepsis. Crit Care Med. 2007, 35: 410-415. 10.1097/01.CCM.0000253405.17038.43.View ArticlePubMedGoogle Scholar
- Maxwell JD: Seasonal variation in vitamin D. Proc Nutr Soc. 1994, 53: 533-543. 10.1079/PNS19940063.View ArticlePubMedGoogle Scholar
- Braun AB, Litonjua AA, Moromizato T, Gibbons FK, Giovannucci E, Christopher KB: Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill. Crit Care Med. 2012, 40 (12): 1-7.View ArticleGoogle Scholar
- Holick MF: High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006, 81 (3): 353-373. 10.4065/81.3.353.View ArticlePubMedGoogle Scholar
- Goswami R, Mishra SK, Kochupillai N: Prevalence & potential significance of vitamin D deficiency in Asian Indians. Indian J Med Res. 2008, 127 (3): 229-238.PubMedGoogle Scholar
- Harinarayan CV, Joshi SR: Vitamin D status in India—its implications and remedial measures. J Assoc Physicians India. 2009, 57: 40-48.PubMedGoogle Scholar
- Lee P: How deficient are vitamin D deficient critically ill patients?. Crit Care. 2011, 15: 154-10.1186/cc10126.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee P: Vitamin D metabolism and deficiency in critical illness. Best Pract Res Clin Endocrinol Metab. 2011, 25 (5): 769-781. 10.1016/j.beem.2011.03.001.View ArticlePubMedGoogle Scholar
- Lee P, Eisman JA, Center JR: Vitamin D deficiency in critically ill patients. N Engl J Med. 2009, 360: 1912-1914. 10.1056/NEJMc0809996.View ArticlePubMedGoogle Scholar
- Zittermann A, Iodice S, Pilz S, Grant BW, Bagnardi V, Gandini S: Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012, 95: 91-100. 10.3945/ajcn.111.014779.View ArticlePubMedGoogle Scholar
- Raiten DJ, Picciano MF: Vitamin D and health in the 21st century: bone and beyond. Executive summary. Am J Clin Nutr. 2004, 80: 1673S-1677S.PubMedGoogle Scholar
- Holick MF: Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004, 79: 362-371.PubMedGoogle Scholar
- Autier P, Gandini S: Vitamin D supplementation and total mortality. Arch Intern Med. 2007, 167 (16): 1730-1737. 10.1001/archinte.167.16.1730.View ArticlePubMedGoogle Scholar
- Melamed M, Michos E, Post W, Astor B: 25-Hydroxyl vitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008, 168 (15): 1629-1637. 10.1001/archinte.168.15.1629.PubMed CentralView ArticlePubMedGoogle Scholar
- Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernán MA, Camargo CA, Thadhani R: Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005, 16 (4): 1115-1125. 10.1681/ASN.2004070573.View ArticlePubMedGoogle Scholar
- Pilz S, Iodice S, Zittermann A, Grant WB, Gandini S: Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am J Kidney Dis. 2011, 58 (3): 374-382.View ArticlePubMedGoogle Scholar
- Lee P, Nair P, Eisman JA, Center JR: Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality?. Intensive Care Med. 2009, 35 (12): 2028-2032. 10.1007/s00134-009-1642-x.View ArticlePubMedGoogle Scholar
- Hewison M: Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin N Am. 2010, 39: 365-379. 10.1016/j.ecl.2010.02.010.View ArticleGoogle Scholar
- Lucidarme O, Messai E, Mazzoni T, Arcade M, du Cheyron D: Incidence and risk factors of vitamin D deficiency in critically ill patients: results from a prospective observational study. J Intensive Care Med. 2010, 36 (9): 1609-1611. 10.1007/s00134-010-1875-8.View ArticleGoogle Scholar
- Flynn L, Zimmerman LH, McNorton K, Dolman M, Tyburski J, Baylor A, Wilson R, Dolman H: Effects of vitamin D deficiency in critically ill surgical patients. Am J Surg. 2012, 203 (3): 379-382. 10.1016/j.amjsurg.2011.09.012.View ArticlePubMedGoogle Scholar
- Cecchi A, Bonizzoli M, Douar S, Mangini M, Paladini S, Gazzini B, Degl’Innocenti S, Linden M, Zagli G, Peris A: Vitamin D deficiency in septic patients at ICU admission is not a mortality predictor. Minerva Anestesiol. 2011, 77 (12): 1184-1189.PubMedGoogle Scholar
- Braun AB, Gibbons FK, Litonjua AA, Giovannucci E, Christopher KB: Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality. Crit Care Med. 2012, 40: 63-72. 10.1097/CCM.0b013e31822d74f3.PubMed CentralView ArticlePubMedGoogle Scholar
- Arnson Y, Gringauz I, Itzhaky D, Amital H: Vitamin D deficiency is associated with poor outcomes and increased mortality in severely ill patients. Q J Med. 2012, 105: 633-639. 10.1093/qjmed/hcs014.View ArticleGoogle Scholar
- Matthews LR, Ahmed Y, Wilson KL, Griggs DD, Danner OK: Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients. Am J Surg. 2012, 204 (1): 37-43. 10.1016/j.amjsurg.2011.07.021.PubMed CentralView ArticlePubMedGoogle Scholar
- Braun A, Chang D, Mahadevappa K, Gibbons FK, Liu Y, Giovannucci E, Christopher KB: Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit Care Med. 2011, 39: 671-677. 10.1097/CCM.0b013e318206ccdf.PubMed CentralView ArticlePubMedGoogle Scholar
- Krishnan 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 patient. Crit Care. 2010, 14 (6): R216-10.1186/cc9341.PubMed CentralView ArticlePubMedGoogle Scholar
- Venkatesh B, Davidson B, Robinson K, Pascoe R, Appleton C, Jones M: Do random estimations of vitamin D3 and parathyroid hormone reflect the 24-h profile in the critically ill?. Intensive Care Med. 2012, 38: 177-179. 10.1007/s00134-011-2415-x. Suggests that 25(OH)D levels fluctuate widely during critical illnessView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.