Vitamin D status and its association with season, hospital and sepsis mortality in critical illness

Karin Amrein, Paul Zajic, Christian Schnedl, Andreas Waltensdorfer, Sonja Fruhwald, Alexander Holl, Tadeja Purkart, Gerit Wünsch, Thomas Valentin, Andrea Grisold, Tatjana Stojakovic, Steven Amrein, Thomas R Pieber, Harald Dobnig, Karin Amrein, Paul Zajic, Christian Schnedl, Andreas Waltensdorfer, Sonja Fruhwald, Alexander Holl, Tadeja Purkart, Gerit Wünsch, Thomas Valentin, Andrea Grisold, Tatjana Stojakovic, Steven Amrein, Thomas R Pieber, Harald Dobnig

Abstract

Introduction: Vitamin D plays a key role in immune function. Deficiency may aggravate the incidence and outcome of infectious complications in critically ill patients. We aimed to evaluate the prevalence of vitamin D deficiency and the correlation between serum 25-hydroxyvitamin D (25(OH) D) and hospital mortality, sepsis mortality and blood culture positivity.

Methods: In a single-center retrospective observational study at a tertiary care center in Graz, Austria, 655 surgical and nonsurgical critically ill patients with available 25(OH) D levels hospitalized between September 2008 and May 2010 were included. Cox regression analysis adjusted for age, gender, severity of illness, renal function and inflammatory status was performed. Vitamin D levels were categorized by month-specific tertiles (high, intermediate, low) to reflect seasonal variation of serum 25(OH) D levels.

Results: Overall, the majority of patients were vitamin D deficient (<20 ng/ml; 60.2%) or insufficient (≥20 and <30 ng/dl; 26.3%), with normal 25(OH) D levels (>30 ng/ml) present in only 13.6%. The prevalence of vitamin D deficiency and mean 25(OH) D levels was significantly different in winter compared to summer months (P <0.001). Hospital mortality was 20.6% (135 of 655 patients). Adjusted hospital mortality was significantly higher in patients in the low (hazard ratio (HR) 2.05, 95% confidence interval (CI) 1.31 to 3.22) and intermediate (HR 1.92, 95% CI 1.21 to 3.06) compared to the high tertile. Sepsis was identified as cause of death in 20 of 135 deceased patients (14.8%). There was no significant association between 25(OH) D and C-reactive protein (CRP), leukocyte count or procalcitonin levels. In a subgroup analysis (n = 244), blood culture positivity rates did not differ between tertiles (23.1% versus 28.2% versus 17.1%, P = 0.361).

Conclusions: Low 25(OH) D status is significantly associated with mortality in the critically ill. Intervention studies are needed to investigate the effect of vitamin D substitution on mortality and sepsis rates in this population.

Figures

Figure 1
Figure 1
Seasonal variation of the prevalence of vitamin D deficiency and mean 25(OH) D values. The prevalence of vitamin D deficiency was higher in winter compared to the summer/autumn months. In August, only 29% were classified as vitamin D deficient, while in or after winter months, the prevalence reached more than 80% (March, 84%, October 87% and November 83%). 25(OH) D, 25-hydroxyvitamin D.
Figure 2
Figure 2
Seasonal cutoff levels and mean 25(OH) D values for month-specific tertiles. The highest mean value was observed in August (n = 75, 28.0 ± 13.9 ng/ml). This was significantly and almost two-fold higher than the lowest mean level found in March (n = 90, 15.4 ± 8.4 ng/ml, P <0.001), October (n = 16, 15.3 ± 4.9 ng/ml, P <0.001) and November (n = 23, 14.8 ± 9.0 ng/ml, P <0.001). 25(OH) D, 25-hydroxyvitamin D.
Figure 3
Figure 3
Unadjusted Kaplan-Meier plot for hospital survival stratified by definition of vitamin D deficiency (a) and month-specific vitamin D tertiles (b). Using the log-rank test, hospital mortality was significantly different between vitamin D sufficiency, insufficiency and deficiency (P = 0.034) and vitamin D tertiles (P = 0.004).
Figure 4
Figure 4
Unadjusted Kaplan-Meier plot for ICU survival stratified by definition of vitamin D deficiency (a) and month-specific vitamin D tertiles (b). Using the log-rank test, ICU mortality was not significantly different between groups (P = 0.893 for vitamin D sufficiency/insufficiency/deficiency classification and 0.164 for tertiles).

References

    1. Schaub N, Frei R, Muller C. Addressing unmet clinical needs in the early diagnosis of sepsis. Swiss Med Wkly. 2011;141:w13244.
    1. Shimaoka M, Park EJ. Advances in understanding sepsis. Eur J Anaesthesiol Suppl. 2008;42:146–153.
    1. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–1377. doi: 10.1056/NEJMoa010307.
    1. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–150. doi: 10.1056/NEJMra021333.
    1. To KB, Napolitano LM. Common complications in the critically ill patient. Surg Clin North Am. 2012;92:1519–1557. doi: 10.1016/j.suc.2012.08.018.
    1. Martin SJ, Yost RJ. Infectious diseases in the critically ill patients. J Pharm Pract. 2011;24:35–43. doi: 10.1177/0897190010388906.
    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. 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. 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. 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. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. doi: 10.1056/NEJMra070553.
    1. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807–1820. doi: 10.1007/s00198-009-0954-6.
    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. 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;130:429–436. doi: 10.1542/peds.2011-3059.
    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;130:421–428. doi: 10.1542/peds.2011-3328.
    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. 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. Ginde AA, Camargo CA Jr, Shapiro NI. Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection. Acad Emerg Med. 2011;18:551–554. doi: 10.1111/j.1553-2712.2011.01047.x.
    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. Verstuyf A, Carmeliet G, Bouillon R, Mathieu C. Vitamin D: a pleiotropic hormone. Kidney Int. 2010;78:140–145. doi: 10.1038/ki.2010.17.
    1. Hewison M. Vitamin D and innate and adaptive immunity. Vitam Horm. 2011;86:23–62.
    1. Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol. 2011;7:337–345. doi: 10.1038/nrendo.2010.226.
    1. Cluse ZN, Fudge AN, Whiting MJ, McWhinney B, Parkinson I, O'Loughlin PD. Evaluation of 25-hydroxy vitamin D assay on the immunodiagnostic systems iSYS analyser. Ann Clin Biochem. 2012;49:159–165. doi: 10.1258/acb.2011.011018.
    1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med. 2003;29:530–538. doi: 10.1007/s00134-003-1662-x.
    1. Amrein K, Schnedl C, Berghold A, Pieber TR, Dobnig H. Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial. BMC Endocr Disord. 2012;12:27. doi: 10.1186/1472-6823-12-27.
    1. Grmec S, Gasparovic V. Comparison of APACHE II, MEES and Glasgow coma scale in patients with nontraumatic coma for prediction of mortality. Acute physiology and chronic health evaluation. Mainz emergency evaluation system. Crit Care. 2001;5:19–23. doi: 10.1186/cc973.
    1. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–35. doi: 10.1002/1097-0142(1950)3:1<32::AID-CNCR2820030106>;2-3.
    1. Schisterman EF, Perkins NJ, Liu A, Bondell H. Optimal cut-point and its corresponding Youden Index to discriminate individuals using pooled blood samples. Epidemiology. 2005;16:73–81. doi: 10.1097/.
    1. Heaney RP. Assessing vitamin D status. Curr Opin Clin Nutr Metab Care. 2011;14:440–444. doi: 10.1097/MCO.0b013e328348ed85.
    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, 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. Annweiler C, Pochic S, Fantino B, Legrand E, Bataille R, Montero-Odasso M, Beauchet O. Serum vitamin D concentration and short-term mortality among geriatric inpatients in acute care settings. Adv Ther. 2010;27:245–249. doi: 10.1007/s12325-010-0025-6.
    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;36:713–720. doi: 10.1177/0148607112444449.
    1. Moromizato T, Litonjua AA, Braun AB, Gibbons FK, Giovannucci E, Christopher KB. Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill. Crit Care Med. 2014;42:97–107. doi: 10.1097/CCM.0b013e31829eb7af.
    1. 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;204:37–43. doi: 10.1016/j.amjsurg.2011.07.021.
    1. 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 patients. Crit Care. 2010;14:R216. doi: 10.1186/cc9341.
    1. Duncan A, Talwar D, McMillan DC, Stefanowicz F, O'Reilly DS. Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements. Am J Clin Nutr. 2012;95:64–71. doi: 10.3945/ajcn.111.023812.
    1. Heijboer AC, Blankenstein MA, Kema IP, Buijs MM. Accuracy of 6 routine 25-hydroxyvitamin D assays: influence of vitamin D binding protein concentration. Clin Chem. 2012;58:543–548. doi: 10.1373/clinchem.2011.176545.
    1. Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 2012;76:315–325. doi: 10.1111/j.1365-2265.2011.04261.x.
    1. Durr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758:1408–1425. doi: 10.1016/j.bbamem.2006.03.030.
    1. Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia. Respirology. 2011;16:611–616. doi: 10.1111/j.1440-1843.2011.01924.x.
    1. Hertting O, Holm A, Luthje P, Brauner H, Dyrdak R, Jonasson AF, Wiklund P, Chromek M, Brauner A. Vitamin D induction of the human antimicrobial peptide cathelicidin in the urinary bladder. PLoS One. 2010;5:e15580. doi: 10.1371/journal.pone.0015580.
    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;35:2028–2032. doi: 10.1007/s00134-009-1642-x.
    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. Youssef DA, Ranasinghe T, Grant WB, Peiris AN. Vitamin D's potential to reduce the risk of hospital-acquired infections. Dermatoendocrinol. 2012;4:167–175. doi: 10.4161/derm.20789.
    1. Maxwell JD. Seasonal variation in vitamin D. Proc Nutr Soc. 1994;53:533–543. doi: 10.1079/PNS19940063.
    1. van der Mei IA, Ponsonby AL, Engelsen O, Pasco JA, McGrath JJ, Eyles DW, Blizzard L, Dwyer T, Lucas R, Jones G. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environ Health Perspect. 2007;115:1132–1139. doi: 10.1289/ehp.9937.
    1. Andersen R, Brot C, Jakobsen J, Mejborn H, Molgaard C, Skovgaard LT, Trolle E, Tetens I, Ovesen L. Seasonal changes in vitamin D status among Danish adolescent girls and elderly women: the influence of sun exposure and vitamin D intake. Eur J Clin Nutr. 2013;67:270–274. doi: 10.1038/ejcn.2013.3.
    1. Pittaway JK, Ahuja KD, Beckett JM, Bird ML, Robertson IK, Ball MJ. Make vitamin D while the sun shines, take supplements when it doesn't: a longitudinal, observational study of older adults in Tasmania. Australia. PLoS One. 2013;8:e59063. doi: 10.1371/journal.pone.0059063.
    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. White AN, Ng V, Spain CV, Johnson CC, Kinlin LM, Fisman DN. Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia. Pennsylvania. BMC Infect Dis. 2009;9:196. doi: 10.1186/1471-2334-9-196.
    1. Zittermann A, Kuhn J, Dreier J, Knabbe C, Gummert JF, Borgermann J. Vitamin D status and the risk of major adverse cardiac and cerebrovascular events in cardiac surgery. Eur Heart J. 2013;34:1358–1364. doi: 10.1093/eurheartj/ehs468.
    1. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88:582S–586S.
    1. Carter GD. Accuracy of 25-hydroxyvitamin D assays: confronting the issues. Curr Drug Targets. 2011;12:19–28. doi: 10.2174/138945011793591608.
    1. Krishnan A, Venkatesh B. Vitamin D measurement in the intensive care unit: methodology, clinical relevance and interpretation of a random value. Inflamm Allergy Drug Targets. 2013;12:230–238. doi: 10.2174/18715281113129990050.

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