Prevention of vitamin D deficiency in children following cardiac surgery: study protocol for a randomized controlled trial

J Dayre McNally, Katie O'Hearn, Margaret L Lawson, Gyaandeo Maharajh, Pavel Geier, Hope Weiler, Stephanie Redpath, Lauralyn McIntyre, Dean Fergusson, Kusum Menon, Canadian Critical Care Trials Groups, J Dayre McNally, Katie O'Hearn, Margaret L Lawson, Gyaandeo Maharajh, Pavel Geier, Hope Weiler, Stephanie Redpath, Lauralyn McIntyre, Dean Fergusson, Kusum Menon, Canadian Critical Care Trials Groups

Abstract

Background: Vitamin D is a pleiotropic hormone important for the recovery of organ systems after critical illness. Recent observational studies have suggested that three out of every four children are vitamin D deficient following cardiac surgery, with inadequate preoperative intake and surgical losses playing important contributory roles. Observed associations between postoperative levels, cardiovascular dysfunction and clinical course suggest that perioperative optimization of vitamin D status could improve outcome. With this two-arm, parallel, double blind, randomized controlled trial (RCT), we aim to compare immediate postoperative vitamin D status in children requiring cardiopulmonary bypass for congenital heart disease who receive preoperative daily high dose vitamin D supplementation (high-dose arm) with those who receive usual intake (low-dose arm).

Methods/design: Eligibility requirements include age (>36 weeks, <18 years) and a congenital heart defect requiring cardiopulmonary bypass surgical correction. Enrollment of 62 participants will take place at a single Canadian tertiary care center over a period of 2 years. Children randomized to the high-dose group will receive age-based dosing that was informed by the Institute of Medicine (IOM) daily tolerable upper intake level (<1 year old = 1,600 IU/day, >1 year old = 2,400 IU/day). Children in the low-dose arm will receive usual care based on IOM recommendations (<1 year old = 400 IU, >1 year old = 600 IU). The primary outcome measure is immediate postoperative vitamin D status, using blood 25(OH)D.

Discussion: Maintaining adequate postoperative vitamin D levels following surgery could represent an effective therapy to speed recovery following CHD surgery. The proposed research project will determine whether preoperative supplementation with a dosing regimen based on the IOM recommended daily upper tolerable intake will prevent postoperative vitamin-D deficiency in the majority of children. The results will then be used to inform the design of a large international RCT exploring whether preoperative optimization of vitamin D status might improve short and long-term outcomes in this vulnerable population.

Trial registration: Clinicaltrials.gov Identifier--NCT01838447 Date of registration: 11 April 2013.

Figures

Fig. 1
Fig. 1
Flow chart of study-related procedures and measurements. Patients and/or caregiver may decline initiation blood work and urine samples and still participate. Postoperatively, urine will only be collected at PICU admission if it was not collected in the operating room. Participants with isolated postoperative hypercalciuria will only have renal ultrasound at the request of nephrology. CHD, congenital heart disease; PICU, Pediatric Intensive Care Unit; POD, postoperative day

References

    1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–900. doi: 10.1016/S0735-1097(02)01886-7.
    1. Brix-Christensen V. The systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children. Acta Anaesthesiol Scand. 2001;45:671–9. doi: 10.1034/j.1399-6576.2001.045006671.x.
    1. Gazit AZ, Huddleston CB, Checchia PA, Fehr J, Pezzella AT. Care of the pediatric cardiac surgery patient--part 1. Curr Probl Surg. 2010;47:185–250. doi: 10.1067/j.cpsurg.2009.11.006.
    1. McEwan A. Aspects of bleeding after cardiac surgery in children. Paediatr Anaesth. 2007;17:1126–33. doi: 10.1111/j.1460-9592.2007.02265.x.
    1. Dyke PC, Yates AR, Cua CL. Increased calcium supplementation is associated with morbidity and mortality in the infant postoperative cardiac patient*. Pediatric Critical Care. 2007;8:254–7. doi: 10.1097/01.PCC.0000260784.30919.9E.
    1. Maiya S, Sullivan I, Allgrove J, Yates R, Malone M, Brain C, et al. Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart. 2008;94:581–4. doi: 10.1136/hrt.2007.119792.
    1. Mehrotra P, Marwaha RK, Aneja S, Seth A, Singla BM, Ashraf G, et al. Hypovitaminosis d and hypocalcemic seizures in infancy. Indian Pediatr. 2010;47:581–6. doi: 10.1007/s13312-010-0131-1.
    1. McNally JD, Menon K, Lawson ML, Williams KA, Doherty DR. 1, 25 dihydroxyvitamin D deficiency in critically ill children: risk factors and association with clinical course. J Endocrinol Metab. 2015;100:2942–5. doi: 10.1210/jc.2014-4471.
    1. Holick MF. Vitamin D, status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19:73–8. doi: 10.1016/j.annepidem.2007.12.001.
    1. Lee P. Vitamin D, metabolism and deficiency in critical illness. Best Pract Res Clin Endocrinol Metab. 2011;25:769–81. doi: 10.1016/j.beem.2011.03.001.
    1. Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med. 2009;360:1912–4. doi: 10.1056/NEJMc0809996.
    1. Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care. 2012;15:188–93. doi: 10.1097/MCO.0b013e32834f0027.
    1. Lucidarme O, Messai E, Mazzoni T, Arcade M, DuCheyron D. Incidence and risk factors of vitamin D deficiency in critically ill patients: results from a prospective observational study. Intensive Care Med. 2010;36:1609–11. doi: 10.1007/s00134-010-1875-8.
    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;12:208–11. doi: 10.1016/j.jamda.2010.04.004.
    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;36:713–20. doi: 10.1177/0148607112444449.
    1. Braun A, Chang D, Mahadevappa K, Gibbons FK, Liu Y, Giovannucci E, et al. Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit Care Med. 2011;39:671–7. doi: 10.1097/CCM.0b013e318206ccdf.
    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. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340–9. doi: 10.1001/archinte.168.12.1340.
    1. Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, et al. 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;93:3927–35. doi: 10.1210/jc.2008-0784.
    1. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174–80. doi: 10.1001/archinte.168.11.1174.
    1. Amrein K, Schnedl C, Holl A, Riedl R, Christopher KB, Pachler C, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. Jama. 2014;312:1520–30. doi: 10.1001/jama.2014.13204.
    1. McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, et al. The association of vitamin D status with pediatric critical illness. Pediatrics. 2012;130:429–36. doi: 10.1542/peds.2011-3059.
    1. Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, et al. Vitamin D deficiency in critically ill children. Pediatrics. 2012;130:421–8. doi: 10.1542/peds.2011-3328.
    1. McNally JD, Iliriani K, Pojsupap S, Sampson M, O’Hearn K, McIntyre L, et al. Rapid Normalization of Vitamin D Levels: A Meta-Analysis. Pediatrics. 2015;135:e152–66. doi: 10.1542/peds.2014-1703.
    1. Graham EM, Taylor SN, Zyblewski SC, Wolf B, Bradley SM, Hollis BW, et al. Vitamin D status in neonates undergoing cardiac operations: relationship to cardiopulmonary bypass and association with outcomes. J Pediatr. 2013;162:823–6. doi: 10.1016/j.jpeds.2012.10.013.
    1. McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, et al. Impact of anesthesia and surgery for congenital heart disease on the vitamin d status of infants and children: a prospective longitudinal study. Anesthesiology. 2013;119:71–80. doi: 10.1097/ALN.0b013e31828ce817.
    1. Krishnan A, Ochola J, Mundy J, Jones M. Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients. Crit Care. 2010;14:R216-R. doi: 10.1186/cc9341.
    1. Gauthier B, Trachtman H, Di Carmine F, Urivetsky M, Tobash J, Chasalow F, et al. Hypocalcemia and hypercalcitoninemia in critically ill children. Crit Care Med. 1990;18:1215–9. doi: 10.1097/00003246-199011000-00005.
    1. Broner CW, Stidham GL, Westenkirchner DF, Tolley EA. Hypermagnesemia and hypocalcemia as predictors of high mortality in critically ill pediatric patients. Crit Care Med. 1990;18:921–8. doi: 10.1097/00003246-199009000-00004.
    1. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr. 1989;114:946–51. doi: 10.1016/S0022-3476(89)80435-4.
    1. Olgun H, Ceviz N, Ozkan B. A case of dilated cardiomyopathy due to nutritional vitamin D deficiency rickets. Turk J Pediatr. 2003;45:152–4.
    1. Price DI, Stanford LC, Braden DS, Ebeid MR, Smith JC. Hypocalcemic rickets: an unusual cause of dilated cardiomyopathy. Pediatr Cardiol. 2003;24:510–2. doi: 10.1007/s00246-002-0251-z.
    1. Verma S, Khadwal A, Chopra K, Rohit M, Singhi S. Hypocalcemia nutritional rickets: a curable cause of dilated cardiomyopathy. J Trop Pediatr. 2011;57:126–8. doi: 10.1093/tropej/fmq044.
    1. Shedeed SA. Vitamin D, supplementation in infants with chronic congestive heart failure. Pediatr Cardiol. 2012;33:713–9. doi: 10.1007/s00246-012-0199-6.
    1. Kozik DJ, Tweddell JS. Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2006;81:S2347–54. doi: 10.1016/j.athoracsur.2006.02.073.
    1. Jaggers J, Lawson JH. Coagulopathy and inflammation in neonatal heart surgery: mechanisms and strategies. Ann Thorac Surg. 2006;81:S2360–6. doi: 10.1016/j.athoracsur.2006.02.072.
    1. Baeke F, Gysemans C, Korf H, Mathieu C. Vitamin D insufficiency: implications for the immune system. Pediatric nephrology (Berlin, Germany) 2010;25:1597–606. doi: 10.1007/s00467-010-1452-y.
    1. Rigby WF, Denome S, Fanger MW. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J Clin Invest. 1987;79:1659–64. doi: 10.1172/JCI113004.
    1. Bhalla AK, Amento EP, Serog B, Glimcher LH. 1,25-dihydroxyvitamin D3 inhibits antigen-induced T cell activation. Journal of immunology (Baltimore, Md : 1950) 1984;133:1748–54.
    1. Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, et al. Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008;122:829–31. doi: 10.1016/j.jaci.2008.08.020.
    1. Gombart AF, Borregaard N, Koeffler HP. cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19:1067–77. doi: 10.1096/fj.04-3284com.
    1. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Journal of Translational Medicine. 2009; 7:28.
    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. Zittermann A, Schleithoff SS, Götting C, Fuchs U, Kuhn J, Kleesiek K, et al. Calcitriol deficiency and 1-year mortality in cardiac transplant recipients. Transplantation. 2009;87:118–24. doi: 10.1097/TP.0b013e31818c2708.
    1. Borgermann J, Lazouski K, Kuhn J, Dreier J, Schmidt M, Gilis-Januszewski T, et al. 1,25-dihydroxyvitamin D fluctuations in cardiac surgery are related to age and clinical outcome. Crit Care Med. 2012;40:2073–81. doi: 10.1097/CCM.0b013e31824e8c42.
    1. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, 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;96:53–8. doi: 10.1210/jc.2010-2704.
    1. Pierpont ME, Basson CT, Benson DW, Jr, Gelb BD, Giglia TM, Goldmuntz E, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115:3015–38. doi: 10.1161/CIRCULATIONAHA.106.183056.
    1. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–52. doi: 10.1016/S0140-6736(07)61601-8.
    1. Cunniff C, Frias JL, Kaye CI, Moeschler J. Health care supervision for children with Williams syndrome. Pediatrics. 2001;107:1192–204.
    1. Zeigler VL. Congenital heart disease and genetics. Crit Care Nurs Clin North Am. 2008;20:159–69. doi: 10.1016/j.ccell.2008.01.008.
    1. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials. 2010;11:32. doi: 10.1186/1745-6215-11-32.
    1. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158:200–7. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. Chang HY, Hsu CH, Tsai JD, Li ST, Hung HY, Kao HA, et al. Renal calcification in very low birth weight infants. Pediatr Neonatol. 2011;52:145–9. doi: 10.1016/j.pedneo.2011.03.004.
    1. Gimpel C, Krause A, Franck P, Krueger M, von Schnakenburg C. Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm infants. Pediatr Int. 2010;52:51–6. doi: 10.1111/j.1442-200X.2009.02886.x.
    1. Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011;365:410–21. doi: 10.1056/NEJMoa1103864.
    1. Holmlund-Suila E, Viljakainen H, Hytinantti T, Lamberg-Allardt C, Andersson S, Makitie O. High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. J Clin Endocrinol Metab. 2012;97:4139–47. doi: 10.1210/jc.2012-1575.
    1. Gallo S, Comeau K, Vanstone C, Agellon S, Sharma A, Jones G, et al. Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. Jama. 2013;309:1785–92. doi: 10.1001/jama.2013.3404.
    1. Emel T, Doğan DA, Erdem G, Faruk O, Faruk Ö. Therapy strategies in vitamin D deficiency with or without rickets: efficiency of low-dose stoss therapy. J Pediatric Endocrinol Metabolism. 2012;25:107–10. doi: 10.1515/jpem-2011-0368.
    1. Diamond TH, Ho KW, Rohl PG, Meerkin M. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Aust. 2005;183:10–2.
    1. Markestad T, Hesse V, Siebenhuner M, Jahreis G, Aksnes L, Plenert W, et al. Intermittent high-dose vitamin D prophylaxis during infancy: effect on vitamin D metabolites, calcium, and phosphorus. Am J Clin Nutr. 1987;46:652–8.
    1. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clinic Proceedings Mayo Clinic. 2011;86:50–60. doi: 10.4065/mcp.2010.0567.
    1. Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357:266–81. doi: 10.1056/NEJMra070553.
    1. Maunsell Z, Wright DJ, Rainbow SJ. Routine isotope-dilution liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3. Clin Chem. 2005;51:1683–90. doi: 10.1373/clinchem.2005.052936.
    1. Gallo S, Comeau K, Sharma A, Vanstone CA, Agellon S, Mitchell J, et al. Redefining normal bone and mineral clinical biochemistry reference intervals for healthy infants in Canada. Clin Biochem. 2014;47:27–32. doi: 10.1016/j.clinbiochem.2014.07.012.
    1. Erol I, Buyan N, Ozkaya O, Sahin F, Beyazova U, Söylemezoğlu O, et al. Reference values for urinary calcium, sodium and potassium in healthy newborns, infants and children. Turk J Pediatr. 2009;51:6–13.
    1. Matos V, van Melle G, Boulat O, Markert M, Bachmann C. Guignard J-p. Uriary phosphate/creatinie, calcium/creatinine, and Magnesium / creatinine ratios in a healthy pediatric population. J Pediatrics. 1997;131:252–7. doi: 10.1016/S0022-3476(97)70162-8.
    1. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: Vitamin D-mediated human antimicrobial activity against myocbacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007;179:2060. doi: 10.4049/jimmunol.179.4.2060.
    1. Bowron A, Barton A, Scott J, Stansbie D. Serum 25 hydroxyvitamin D is unaffected by multiple freeze thaw cycles. Clin Chem. 2005;51:258–9.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81. doi: 10.1016/j.jbi.2008.08.010.
    1. Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg. 2002;123:110–8. doi: 10.1067/mtc.2002.119064.
    1. Pollack MM, Patel KM, Ruttimann UE. The Pediatric Risk of Mortality III--Acute Physiology Score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients. J Pediatr. 1997;131:575–81. doi: 10.1016/S0022-3476(97)70065-9.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅