Nutr Res Pract.  2020 Feb;14(1):12-19. 10.4162/nrp.2020.14.1.12.

Association of vitamin D deficiency with clinical outcomes in critically ill Korean children

• Jhang WK
• Kim DH
• Park SJ

• KMID: 2468508
• DOI: http://doi.org/10.4162/nrp.2020.14.1.12

Abstract

BACKGROUND/OBJECTIVES
Vitamin D is a pleiotropic hormone that affects various body organ systems. We evaluated the prevalence of a vitamin D deficiency (VDD) and its potential role in the clinical condition of critically ill Korean children.
SUBJECTS/METHODS
Patients under 18 years old with a 25(OH) vitamin D measurement on the first day of PICU admission were included from among the children admitted to the pediatric intensive care unit (PICU) of our tertiary children's hospital between October 2017 and January 2019.
RESULTS
A total of 172 pediatric patients were enrolled. The mean 25(OH) vitamin D level was 17.5 ± 12.8 ng/mL. There was a 65.1% prevalence of VDD (25(OH) vitamin D level < 20 ng/mL). VDD was associated with age at PICU admission, gastrointestinal/hepatobiliary disorders, International Society of Thrombosis and Hemostasis disseminated intravascular coagulation (ISTH DIC) score, pediatric multiple organ dysfunction syndrome (pMODS) score and with several laboratory test findings including hemoglobin, platelet, C-reactive protein, serum albumin, total bilirubin, prothrombin time, and anti-thrombin III levels. Most of these parameters also showed significant linear correlations with the 25(OH) vitamin D level (P < 0.05). However, no statistically meaningful association was found between VDD and other clinical conditions such as the need for a mechanical ventilator, requirement for vasoactive drugs, duration of the PICU and hospital stays, or PICU mortality.
CONCLUSION
There is a high prevalence of VDD in critically ill Korean children. There were significant associations between the 25(OH) vitamin D level and gastrointestinal/hepatobiliary disorders, the pMODS score and with coagulation related factors. Further large-scale studies with more specific subgroup analyses are required to more precisely assess the clinical implications of VDD in critically ill pediatric patients.

Keyword

Vitamin D; pediatrics

MeSH Terms

Bilirubin
Blood Platelets
C-Reactive Protein
Child*
Critical Illness*
Disseminated Intravascular Coagulation
Hemostasis
Humans
Intensive Care Units
Length of Stay
Mortality
Multiple Organ Failure
Pediatrics
Prevalence
Prothrombin Time
Serum Albumin
Thrombosis
Ventilators, Mechanical
Vitamin D Deficiency*
Vitamin D*
Vitamins*
Bilirubin
C-Reactive Protein
Serum Albumin
Vitamin D
Vitamins

Figure

• 

  Fig. 1 Comparisons of the mean values for several parameters among the severe VDD, VDD and non-VDD groups.VDD, vitamin D deficiency; CRP, C-reactive peptide; ISTH DIC score, International Society on Thrombosis and Hemostasis disseminated intravascular coagulation score; pMODS, pediatric multiple organ dysfunction syndrome.

Reference

1. Kim SY. The pleiomorphic actions of vitamin D and its importance for children. Ann Pediatr Endocrinol Metab. 2013; 18:45–54. PMID: 24904851.

2. Massey K, Dickerson R, Brown R. A review of vitamin D deficiency in the critical care population. Pharmacy. 2014; 2:40–49.

3. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008; 122:398–417. PMID: 18676559.

4. Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res. 2009; 65:106R–113R.

5. Banerjee A, Khemka VK. Augmentation of anticoagulant effect with vitamin D: possible therapeutic target for venous thromboembolism. Int J Hematol Blo Dis. 2017; 2:1–5.

6. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl). 2010; 88:441–450. PMID: 20119827.

7. Kaur G, Singh J, Kumar J. Vitamin D and cardiovascular disease in chronic kidney disease. Pediatr Nephrol. Forthcoming 2018.

8. Hirschler V, Molinari C, Maccallini G, Intersimone P, Gonzalez CD. Vitamin D levels and cardiometabolic markers in indigenous argentinean children living at different altitudes. Glob Pediatr Health. 2019; 6:2333794X18821942.

9. 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. PMID: 14985208.

10. Helou M, Ning Y, Yang S, Irvine P, Bachmann LM, Godder K, Massey G. Vitamin d deficiency in children with cancer. J Pediatr Hematol Oncol. 2014; 36:212–217. PMID: 23823117.

11. McNally JD, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol. 2009; 44:981–988. PMID: 19746437.

12. Koven NS, Cadden MH, Murali S, Ross MK. Vitamin D and long-term memory in multiple sclerosis. Cogn Behav Neurol. 2013; 26:155–160. PMID: 24077575.

13. 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. PMID: 21926604.

14. Amrein K, Zajic P, Schnedl C, Waltensdorfer A, Fruhwald S, Holl A, Purkart T, Wünsch G, Valentin T, Grisold A, Stojakovic T, Amrein S, Pieber TR, Dobnig H. Vitamin D status and its association with season, hospital and sepsis mortality in critical illness. Crit Care. 2014; 18:R47. PMID: 24661739.

15. 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; 77:1184–1189. PMID: 21720281.

16. Sankar J, Lotha W, Ismail J, Anubhuti C, Meena RS, Sankar MJ. Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study. Ann Intensive Care. 2016; 6:3. PMID: 26745966.

17. Ponnarmeni S, Kumar Angurana S, Singhi S, Bansal A, Dayal D, Kaur R, Patial A, Verma Attri S. Vitamin D deficiency in critically ill children with sepsis. Paediatr Int Child Health. 2016; 36:15–21. PMID: 26120004.

18. McNally JD, Menon K, Lawson ML, Williams K, Doherty DR. 1,25-Dihydroxyvitamin D levels in pediatric intensive care units: risk factors and association with clinical course. J Clin Endocrinol Metab. 2015; 100:2942–2945. PMID: 26052726.

19. Sankar J, Ismail J, Das R, Dev N, Chitkara A, Sankar MJ. Effect of severe vitamin D deficiency at admission on shock reversal in children with septic shock: a prospective observational study. J Intensive Care Med. 2019; 34:397–403. PMID: 28335672.

20. McNally JD, Nama N, O'Hearn K, Sampson M, Amrein K, Iliriani K, McIntyre L, Fergusson D, Menon K. Vitamin D deficiency in critically ill children: a systematic review and meta-analysis. Crit Care. 2017; 21:287. PMID: 29169388.

21. Becker P, Carney LN, Corkins MR, Monczka J, Smith E, Smith SE, Spear BA, White JV. Academy of Nutrition and Dietetics. American Society for Parenteral and Enteral Nutrition. Consensus statement of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition: indicators recommended for the identification and documentation of pediatric malnutrition (undernutrition). Nutr Clin Pract. 2015; 30:147–161. PMID: 25422273.

22. Mehta NM, Corkins MR, Lyman B, Malone A, Goday PS, Carney LN, Monczka JL, Plogsted SW, Schwenk WF. American Society for Parenteral and Enteral Nutrition Board of Directors. Defining pediatric malnutrition: a paradigm shift toward etiology-related definitions. JPEN J Parenter Enteral Nutr. 2013; 37:460–481. PMID: 23528324.

23. Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357:266–281. PMID: 17634462.

24. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:1911–1930. PMID: 21646368.

25. Rusińska A, Płudowski P, Walczak M, Borszewska-Kornacka MK, Bossowski A, Chlebna-Sokół D, Czech-Kowalska J, Dobrzańska A, Franek E, Helwich E, Jackowska T, Kalina MA, Konstantynowicz J, Książyk J, Lewiński A, Łukaszkiewicz J, Marcinowska-Suchowierska E, Mazur A, Michałus I, Peregud-Pogorzelski J, Romanowska H, Ruchała M, Socha P, Szalecki M, Wielgoś M, Zwolińska D, Zygmunt A. Vitamin D supplementation guidelines for general population and groups at risk of vitamin D deficiency in Poland-recommendations of the Polish Society of Pediatric Endocrinology and Diabetes and the Expert Panel With Participation of National Specialist Consultants and Representatives of Scientific Societies-2018 update. Front Endocrinol (Lausanne). 2018; 9:246. PMID: 29904370.

26. 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. PMID: 22869836.

27. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med. 1996; 24:743–752. PMID: 8706448.

28. Graciano AL, Balko JA, Rahn DS, Ahmad N, Giroir BP. The Pediatric Multiple Organ Dysfunction Score (P-MODS): development and validation of an objective scale to measure the severity of multiple organ dysfunction in critically ill children. Crit Care Med. 2005; 33:1484–1491. PMID: 16003052.

29. Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children. JAMA Pediatr. 2017; 171:e172352. PMID: 28783810.

30. Rippel C, South M, Butt WW, Shekerdemian LS. Vitamin D status in critically ill children. Intensive Care Med. 2012; 38:2055–2062. PMID: 23052958.

31. Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics. 2009; 124:1404–1410. PMID: 19951983.

32. Levis S, Gomez A, Jimenez C, Veras L, Ma F, Lai S, Hollis B, Roos BA. Vitamin d deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab. 2005; 90:1557–1562. PMID: 15634725.

33. Hebbar KB, Wittkamp M, Alvarez JA, McCracken CE, Tangpricha V. Vitamin D deficiency in pediatric critical illness. J Clin Transl Endocrinol. 2014; 1:170–175. PMID: 25580380.

34. Kimlin MG, Lucas RM, Harrison SL, van der Mei I, Armstrong BK, Whiteman DC, Kricker A, Nowak M, Brodie AM, Sun J. The contributions of solar ultraviolet radiation exposure and other determinants to serum 25-hydroxyvitamin D concentrations in Australian adults: the AusD Study. Am J Epidemiol. 2014; 179:864–874. PMID: 24573539.

35. Al-Othman A, Al-Musharaf S, Al-Daghri NM, Krishnaswamy S, Yusuf DS, Alkharfy KM, Al-Saleh Y, Al-Attas OS, Alokail MS, Moharram O, Sabico S, Chrousos GP. Effect of physical activity and sun exposure on vitamin D status of Saudi children and adolescents. BMC Pediatr. 2012; 12:92. PMID: 22759399.

36. Holick MF, Chen TC, Lu Z, Sauter E. Vitamin D and skin physiology: a D-lightful story. J Bone Miner Res. 2007; 22 Suppl 2:V28–V33. PMID: 18290718.

37. Weishaar T, Rajan S, Keller B. Probability of vitamin D deficiency by body weight and race/ethnicity. J Am Board Fam Med. 2016; 29:226–232. PMID: 26957379.

38. Mostafa WZ, Hegazy RA. Vitamin D and the skin: focus on a complex relationship: a review. J Adv Res. 2015; 6:793–804. PMID: 26644915.

39. Newton DA, Baatz JE, Kindy MS, Gattoni-Celli S, Shary JR, Hollis BW, Wagner CL. Vitamin D binding protein polymorphisms significantly impact vitamin D status in children. Pediatr Res. Forthcoming 2019.

40. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, Powe NR, Thadhani R. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013; 369:1991–2000. PMID: 24256378.

41. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008; 88:582S–586S. PMID: 18689406.

42. Abou-Zahr R, Kandil SB. A pediatric critical care perspective on vitamin D. Pediatr Res. 2015; 77:164–167. PMID: 25314583.

43. Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab. 1986; 63:954–959. PMID: 3745408.

44. Iruzubieta P, Terán Á, Crespo J, Fábrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol. 2014; 6:901–915. PMID: 25544877.

45. Langer-Gould A, Lucas RM, Xiang AH, Wu J, Chen LH, Gonzales E, Haraszti S, Smith JB, Quach H, Barcellos LF. Vitamin D-binding protein polymorphisms, 25-hydroxyvitamin D, sunshine and multiple sclerosis. Nutrients. 2018; 10:E184. PMID: 29414925.

46. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Järvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppönen E, Spector TD. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010; 376:180–188. PMID: 20541252.

47. Bahrami A, Sadeghnia HR, Tabatabaeizadeh SA, Bahrami-Taghanaki H, Behboodi N, Esmaeili H, Ferns GA, Mobarhan MG, Avan A. Genetic and epigenetic factors influencing vitamin D status. J Cell Physiol. 2018; 233:4033–4043. PMID: 29030989.

48. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010; 19:2739–2745. PMID: 20418485.

49. Moy KA, Mondul AM, Zhang H, Weinstein SJ, Wheeler W, Chung CC, Männistö S, Yu K, Chanock SJ, Albanes D. Genome-wide association study of circulating vitamin D-binding protein. Am J Clin Nutr. 2014; 99:1424–1431. PMID: 24740207.

50. Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, Doria A, Cervera R, Miesbach W, Stojanovich L, Barak V, Porat-Katz BS, Amital H, Shoenfeld Y. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis. 2011; 70:145–150. PMID: 20980705.

51. Targher G, Pichiri I, Lippi G. Vitamin D, thrombosis, and hemostasis: more than skin deep. Semin Thromb Hemost. 2012; 38:114–124. PMID: 22314609.

52. Elbers LP, Wijnberge M, Meijers JC, Poland DC, Brandjes DP, Fliers E, Gerdes VE. Coagulation and fibrinolysis in hyperparathyroidism secondary to vitamin D deficiency. Endocr Connect. 2018; 7:325–333. PMID: 29317405.

53. Lee JY, So TY, Thackray J. A review on vitamin d deficiency treatment in pediatric patients. J Pediatr Pharmacol Ther. 2013; 18:277–291. PMID: 24719588.