Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial

Karin Amrein, Christian Schnedl, Andrea Berghold, Thomas R Pieber, Harald Dobnig, Karin Amrein, Christian Schnedl, Andrea Berghold, Thomas R Pieber, Harald Dobnig

Abstract

Background: Vitamin D deficiency is associated with multiple adverse health outcomes including increased morbidity and mortality in the general population and in critically ill patients. However, no randomized controlled trial has evaluated so far whether treatment with sufficiently large doses of vitamin D can improve clinical outcome of patients in an intensive care setting.

Methods/design: The VITdAL@ICU trial is an investigator-initiated, non-commercial, double-blind, placebo-controlled randomized clinical trial. This study compares high-dose oral cholecalciferol (vitamin D3) versus placebo treatment in a mixed population of 480 critically ill patients with low 25-hydroxyvitamin-D levels at study enrollment (≤ 20ng/ml). Following an initial loading dose of 540,000 IU of vitamin D3, patients receive 90,000 IU of vitamin D3 on a monthly basis for 5 months. The study is designed to compare clinical outcome in the two study arms with the primary endpoint being length of hospital stay. Secondary endpoints include among others length of ICU stay, the percentage of patients with 25(OH)D levels > 30 ng/ml at day 7, ICU and hospital mortality and duration of mechanical ventilation. We describe here the VITdAL@ICU study protocol for the primary report.

Discussion: This trial is designed to evaluate whether high-dose vitamin D3 is able to improve morbidity and mortality in a mixed population of adult critically ill patients and correct vitamin D deficiency safely.

Trial registration: ClinicalTrials: NCT01130181.

Figures

Figure 1
Figure 1
Trial procedures flow sheet.
Figure 2
Figure 2
CONSORT flow diagram. All adult patients admitted to five intensive care units (ICU; medical, neurological, cardiac surgery and two mixed surgery units) from May 4, 2010 onward were eligible for inclusion.

References

    1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. doi: 10.1056/NEJMra070553.
    1. Holick MF. Vitamin D deficiency in 2010: health benefits of vitamin D and sunlight: a D-bate. Nat Rev Endocrinol. 2011;7:73–75. doi: 10.1038/nrendo.2010.234.
    1. Rosen CJ. Clinical practice Vitamin D insufficiency. N Engl J Med. 2011;364:248–254. doi: 10.1056/NEJMcp1009570.
    1. Souberbielle JC, Body JJ, Lappe JM. et al.Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 2010;9:709–715. doi: 10.1016/j.autrev.2010.06.009.
    1. Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26–34.
    1. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776. doi: 10.1210/er.2008-0004.
    1. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340–1349. doi: 10.1001/archinte.168.12.1340.
    1. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168:1629–1637. doi: 10.1001/archinte.168.15.1629.
    1. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2011. p. CD007470.
    1. Samuel S, Sitrin MD. Vitamin D's role in cell proliferation and differentiation. Nutr Rev. 2008;66:S116–S124.
    1. Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med. 2009;360:1912–1914. doi: 10.1056/NEJMc0809996.
    1. Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003;88:4623–4632. doi: 10.1210/jc.2003-030358.
    1. 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. doi: 10.1097/CCM.0b013e318206ccdf.
    1. 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. doi: 10.1097/CCM.0b013e31822d74f3.
    1. 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. Intensive Care Med. 2010;36:1609–1611. doi: 10.1007/s00134-010-1875-8.
    1. Amrein K, Amrein S, Holl A, Waltensdorfer A, Pieber THD. Vitamin D, parathyroid hormone and serum calcium levels and their association with hospital mortality in critically ill patients. Crit Care. 2010;14(Suppl 1):P589. doi: 10.1186/cc8821.
    1. Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, Hollis BW, Agan AA, Randolph AG. Vitamin D Deficiency in Critically Ill Children. Pediatrics. 2012;130(3):421–428. doi: 10.1542/peds.2011-3328. Epub 2012 Aug 6.
    1. McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, Doherty DR. The Association of Vitamin D Status With Pediatric Critical Illness. Pediatrics. 2012;130(3):429–436. doi: 10.1542/peds.2011-3059. Epub 2012 Aug 6.
    1. Heaney RP. Assessing vitamin D status. Curr Opin Clin Nutr Metab Care. 2011;14:440–444. doi: 10.1097/MCO.0b013e328348ed85.
    1. Lee P. Vitamin D metabolism and deficiency in critical illness. Best Pract Res Clin Endocrinol Metab. 2011;25:769–781. doi: 10.1016/j.beem.2011.03.001.
    1. 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. doi: 10.1007/s00134-009-1642-x. Epub 2009 Sep 15.
    1. McKinney JD, Bailey BA, Garrett LH, Peiris P, Manning T, Peiris AN. Relationship between vitamin D status and ICU outcomes in veterans. J Am Med Dir Assoc. 2011;12:208–211. doi: 10.1016/j.jamda.2010.04.004.
    1. Venkatram S, Chilimuri S, Adrish M, Salako A, Patel M, Diaz-Fuentes G. Vitamin D deficiency is associated with mortality in the medical intensive care unit. Crit Care. 2011;15:R292. doi: 10.1186/cc10585.
    1. Higgins DM, Wischmeyer PE, Queensland KM, Sillau SH, Sufit AJ, Heyland DK. Relationship of Vitamin D Deficiency to Clinical Outcomes in Critically Ill Patients. JPEN J Parenter Enteral Nutr. 2012;36(6):713–720. doi: 10.1177/0148607112444449. Epub 2012 Apr 20.
    1. Amrein K, Sourij H, Wagner G, Holl A, Pieber TR, Smolle KH, Stojakovic T, Schnedl C, Dobnig H. Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study. Crit Care. 2011;15:R104. doi: 10.1186/cc10120.
    1. Ingels C, Van Cromphaut S, Wouters P, Moller H, Van Herck E, Jans I, Bouillon R, van den Berghe G. Effect of restoration of 25OHD3 status in prolonged critical illness on serum innate immunity parameters LL-37 and sCD163. Crit Care. 2010;14(Suppl 1):590. doi: 10.1186/cc8822.
    1. Mata-Granados JM, Vargas-Vasserot J, Ferreiro-Vera C, Luque de Castro MD, Pavon RG, Quesada Gomez JM. Evaluation of vitamin D endocrine system (VDES) status and response to treatment of patients in intensive care units (ICUs) using an on-line SPE-LC-MS/MS method. J Steroid Biochem Mol Biol. 2010;121:452–455. doi: 10.1016/j.jsbmb.2010.03.078.
    1. Carlstedt F, Lind L, Rastad J, Stjernstrom H, Wide L, Ljunghall S. Parathyroid hormone and ionized calcium levels are related to the severity of illness and survival in critically ill patients. Eur J Clin Invest. 1998;28:898–903. doi: 10.1046/j.1365-2362.1998.00391.x.
    1. Forsythe RM, Wessel CB, Billiar TR, Angus DC, Rosengart MR. Parenteral calcium for intensive care unit patients. Cochrane Database Syst Rev. 2008. p. CD006163.
    1. Hastbacka J, Pettila V. Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand. 2003;47:1264–1269. doi: 10.1046/j.1399-6576.2003.00236.x.
    1. Canaff L, Zhou X, Hendy GN. The proinflammatory cytokine, interleukin-6, up-regulates calcium-sensing receptor gene transcription via Stat1/3 and Sp1/3. J Biol Chem. 2008;283(20):13586–13600. doi: 10.1074/jbc.M708087200. Epub 2008 Mar 17.
    1. Kelly A, Levine MA. Hypocalcemia in the Critically Ill patient. J Intensive Care Med. 2011. 2011 Aug 12. [Epub ahead of print]
    1. Lee P, Milliken S, Center JR. Hypocalcaemic cardiac failure post BMT secondary to unrecognized vitamin D deficiency. Bone Marrow Transplant. 2008;42:363–364. doi: 10.1038/bmt.2008.178.
    1. Lee P, Samaras K, Glanville AR, Center JR. Transplant recipients on the edge of the hypocalcemia abyss. J Heart Lung Transplant. 2009;28:93–95. doi: 10.1016/j.healun.2008.09.010.
    1. Pilz S, Tomaschitz A, Marz W. et al.Vitamin D, cardiovascular disease and mortality. Clin Endocrinol (Oxf) 2011;75(5):575–584. doi: 10.1111/j.1365-2265.2011.04147.x.
    1. Maiya S, Sullivan I, Allgrove J. et al.Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart. 2008;94:581–584. doi: 10.1136/hrt.2007.119792.
    1. Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005;288:E125–E132.
    1. Pilz S, Marz W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008;93:3927–3935. doi: 10.1210/jc.2008-0784.
    1. Kim HW, Park CW, Shin YS, Kim YS, Shin SJ, Choi EJ, Chang YS, Bang BK. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract. 2006;102:c21–c29. doi: 10.1159/000088295.
    1. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754–759.
    1. Nibbelink KA, Tishkoff DX, Hershey SD, Rahman A, Simpson RU. 1,25(OH)2-vitamin D3 actions on cell proliferation, size, gene expression, and receptor localization, in the HL-1 cardiac myocyte. J Steroid Biochem Mol Biol. 2007;103:533–537. doi: 10.1016/j.jsbmb.2006.12.099.
    1. Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology. 2008;149:558–564.
    1. Bikle DD. Vitamin D and the immune system: role in protection against bacterial infection. Curr Opin Nephrol Hypertens. 2008;17:348–352. doi: 10.1097/MNH.0b013e3282ff64a3.
    1. Liu PT, Stenger S, Li H. et al.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773. doi: 10.1126/science.1123933.
    1. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3) J Cyst Fibros. 2007;6:403–410. doi: 10.1016/j.jcf.2007.03.003.
    1. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:28. doi: 10.1186/1479-5876-7-28.
    1. Danai PA, Sinha S, Moss M, Haber MJ, Martin GS. Seasonal variation in the epidemiology of sepsis. Crit Care Med. 2007;35:410–415. doi: 10.1097/01.CCM.0000253405.17038.43.
    1. Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2009;20:315–322. doi: 10.1007/s00198-008-0662-7.
    1. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005;20:187–192. doi: 10.1159/000087203.
    1. Fosnight SM, Zafirau WJ, Hazelett SE. Vitamin D supplementation to prevent falls in the elderly: evidence and practical considerations. Pharmacotherapy. 2008;28:225–234. doi: 10.1592/phco.28.2.225.
    1. Ross AC, Manson JE, Abrams SA. 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. doi: 10.1210/jc.2010-2704.
    1. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930. doi: 10.1210/jc.2011-0385.
    1. Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care. 2012;15(2):188–193. doi: 10.1097/MCO.0b013e32834f0027.
    1. Kempker JA, Tangpricha V, Ziegler TR, Martin GS. Vitamin D in sepsis: from basic science to clinical impact. Crit Care. 2012;16:316. doi: 10.1186/cc11252.
    1. Sprung CL, Annane D, Keh D. et al.Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124. doi: 10.1056/NEJMoa071366.
    1. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785–792. doi: 10.1056/NEJM199909093411102.
    1. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6–18.
    1. Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D'Erasmo E, Carnevale V, Scillitani A, Minisola S. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab. 2008;93:3015–3020. doi: 10.1210/jc.2008-0350.
    1. von Restorff C, Bischoff-Ferrari HA, Theiler R. High-dose oral vitamin D3 supplementation in rheumatology patients with severe vitamin D3 deficiency. Bone. 2009;45:747–749. doi: 10.1016/j.bone.2009.06.012.
    1. Cipriani C, Romagnoli E, Scillitani A. et al.Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study. J Clin Endocrinol Metab. 2010;95:4771–4777. doi: 10.1210/jc.2010-0502.
    1. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815–1822. doi: 10.1001/jama.2010.594.
    1. Amrein K, Schilcher G, Fahrleitner-Pammer A. Hypercalcaemia in asymptomatic sarcoidosis unmasked by a vitamin D loading dose. Eur Respir J. 2011;37:470–471. doi: 10.1183/09031936.00136910.
    1. Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab. 2010;95:3111–3117. doi: 10.1210/jc.2009-2673.

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