SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients

Christian Stoppe, Bernard McDonald, Steffen Rex, William Manzanares, Richard Whitlock, Stephen Fremes, Robert Fowler, Yoan Lamarche, Patrick Meybohm, Christoph Haberthür, Rolf Rossaint, Andreas Goetzenich, Gunnar Elke, Andrew Day, Daren K Heyland, Christian Stoppe, Bernard McDonald, Steffen Rex, William Manzanares, Richard Whitlock, Stephen Fremes, Robert Fowler, Yoan Lamarche, Patrick Meybohm, Christoph Haberthür, Rolf Rossaint, Andreas Goetzenich, Gunnar Elke, Andrew Day, Daren K Heyland

Abstract

Background: Cardiac surgery has been shown to result in a significant decrease of the antioxidant selenium, which is associated with the development of multiorgan dysfunction and increased mortality. Thus, a large-scale study is needed to investigate the effect of perioperative selenium supplementation on the occurrence of postoperative organ dysfunction.

Methods/design: We plan a prospective, randomized double-blind, multicenter controlled trial, which will be conducted in North and South America and in Europe. In this trial we will include 1,400 high-risk patients, who are most likely to benefit from selenium supplementation. This includes patients scheduled for non-emergent combined and/or complex procedures, or with a predicted operative mortality of ≥ 5% according to the EuroSCORE II. Eligible patients will be randomly assigned to either the treatment group (bolus infusion of 2,000 μg sodium selenite immediately prior to surgery, followed by an additional dosage of 2,000 μg at ICU admission, and a further daily supplementation of 1,000 μg up to 10 days or ICU discharge) or to the control group (placebo administration at the same time points).The primary endpoint of this study is a composite of 'persistent organ dysfunction' (POD) and/or death within 30 days from surgery (POD + death). POD is defined as any need for life-sustaining therapies (mechanical ventilation, vasopressor therapy, mechanical circulatory support, continuous renal replacement therapy, or new intermittent hemodialysis) at any time within 30 days from surgery.

Discussion: The SUSTAIN-CSX™ study is a multicenter trial to investigate the effect of a perioperative high dosage sodium selenite supplementation in high-risk cardiac surgical patients.

Trial registration: This trial was registered at Clinicaltrials.gov (identifier: NCT02002247) on 28 November 2013.

Figures

Figure 1
Figure 1
Multiple stimulus and treatment approaches in cardiac surgery. The present figure was modified and reproduced with permission from Hall [2]. CPB = cardiopulmonary bypass; IL = interleukin; TNF = tumor necrosis factor; PAI = Plasminogen activator inhibitor; NAC = N-acetylcysteine.
Figure 2
Figure 2
Perioperative time course of whole blood concentrations of selenium. The shaded area indicates the reference range for whole blood selenium concentration in Germany. BL: Baseline before induction of anesthesia; AD: admission to the ICU; 4 hrs: 4 hours after admission to ICU. *P <0.05 versus baseline. **P <0.01 versus baseline. This picture was taken from [11]. The shaded area indicates the reference range. Data are given as means ± SD.

References

    1. Grover A, Gorman K, Dall TM, Jonas R, Lytle B, Shemin R, Wood D, Kron I. Shortage of cardiothoracic surgeons is likely by 2020. Circulation. 2009;120:488–494. doi: 10.1161/CIRCULATIONAHA.108.776278.
    1. Hall R. Identification of inflammatory mediators and their modulation by strategies for the management of the systemic inflammatory response during cardiac surgery. J Cardiothorac Vasc Anesth. 2013;27:983–1033. doi: 10.1053/j.jvca.2012.09.013.
    1. Laffey JG, Boylan JF, Cheng DCH. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97:215–252. doi: 10.1097/00000542-200207000-00030.
    1. Klotz L-O, Kröncke K-D, Buchczyk DP, Sies H. Role of copper, zinc, selenium and tellurium in the cellular defense against oxidative and nitrosative stress. J Nutr. 2003;133:1448S–1451S.
    1. Steinbrenner H, Sies H. Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta. 2009;1790:1478–1485. doi: 10.1016/j.bbagen.2009.02.014.
    1. Venardos KM, Perkins A, Headrick J, Kaye DM. Myocardial ischemia-reperfusion injury, antioxidant enzyme systems, and selenium: a review. Curr Med Chem. 2007;14:1539–1549. doi: 10.2174/092986707780831078.
    1. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med. 2004;31:327–337. doi: 10.1007/s00134-004-2522-z.
    1. Forman HJ, Torres M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med. 2002;166:S4–S8. doi: 10.1164/rccm.2206007.
    1. Koszta G, Kacska Z, Szatmári K, Szerafin T, Fülesdi B. Lower whole blood selenium level is associated with higher operative risk and mortality following cardiac surgery. J Anesth. 2012;26:812–821. doi: 10.1007/s00540-012-1454-y.
    1. Stoppe C, Schälte G, Rossaint R, Coburn M, Graf B, Spillner J, Marx G, Rex S. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients. Crit Care Med. 2011;39:1879–1885. doi: 10.1097/CCM.0b013e3182190d48.
    1. Stoppe C, Spillner J, Rossaint R, Coburn M, Schälte G, Wildenhues A, Marx G, Rex S. Selenium blood concentrations in patients undergoing elective cardiac surgery and receiving perioperative sodium selenite administration. Nutrition. 2013;29:158–165. doi: 10.1016/j.nut.2012.05.013.
    1. Motoyama T, Okamoto K, Kukita I, Hamaguchi M, Kinoshita Y, Ogawa H. Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Crit Care Med. 2003;31:1048–1052. doi: 10.1097/01.CCM.0000055371.27268.36.
    1. Silberman S, Bitran D, Fink D, Tauber R, Merin O. Very prolonged stay in the intensive care unit after cardiac operations: early results and late survival. Ann Thorac Surg. 2013;96:15–21. doi: 10.1016/j.athoracsur.2013.01.103.
    1. Alexander KP, Newby LK, Cannon CP, Armstrong PW, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM, American Heart Association Council on Clinical Cardiology, Society of Geriatric Cardiology Acute coronary care in the elderly, part I: non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2549–2569. doi: 10.1161/CIRCULATIONAHA.107.182615.
    1. Manzanares W, Biestro A, Galusso F, Torre MH, Mañáy N, Facchin G, Hardy G. High-dose selenium for critically ill patients with systemic inflammation: Pharmacokinetics and pharmacodynamics of selenious acid: a pilot study. Nutrition. 2010;26:634–640. doi: 10.1016/j.nut.2009.06.022.
    1. Angstwurm MWA, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strau R, Meier-Hellmann A, Insel R, Radke J, Schüttler J, Gärtner R, Selenium in Intensive Care (SIC) Results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock*. Crit Care Med. 2007;35:118–126. doi: 10.1097/01.CCM.0000251124.83436.0E.
    1. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–1762. doi: 10.1001/jama.291.14.1753.
    1. Kosinski M, Keller SD, Hatoum HT, Kong SX, Ware JE. The SF-36 Health Survey as a generic outcome measure in clinical trials of patients with osteoarthritis and rheumatoid arthritis: tests of data quality, scaling assumptions and score reliability. Med Care. 1999;37:MS10–MS22.
    1. Heyland DK, Muscedere J, Drover J, Jiang X, Day AG, Canadian Critical Care Trials Group Persistent organ dysfunction plus death: a novel, composite outcome measure for critical care trials. Crit Care. 2011;15:R98. doi: 10.1186/cc10110.
    1. Williams MR, Wellner RB, Hartnett EA, Thornton B, Kavarana MN, Mahapatra R, Oz MC, Sladen R. Long-term survival and quality of life in cardiac surgical patients with prolonged intensive care unit length of stay. Ann Thorac Surg. 2002;73:1472–1478. doi: 10.1016/S0003-4975(02)03464-1.
    1. Schoenfeld DA, Bernard GR, ARDS Network Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med. 2002;30:1772–1777. doi: 10.1097/00003246-200208000-00016.
    1. Heart N, Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795–803. doi: 10.1001/jama.2012.137.
    1. Rice TW, Wheeler AP, Thompson BT, de Boisblanc BP, Steingrub J, Rock P, NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators, NHLBI ARDS Clinical Trials Network Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306:1574–1581. doi: 10.1001/jama.2011.1435.
    1. Moher D, Schulz KF, Altman D, CONSORT Group (Consolidated Standards of Reporting Trials) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987–1991. doi: 10.1001/jama.285.15.1987.
    1. Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG, Canadian Critical Care Trials Group A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489–1497. doi: 10.1056/NEJMoa1212722.
    1. Moreno-Reyes R, Mathieu F, Boelaert M, Begaux F, Suetens C, Rivera MT, Neve J, Perlmutter N, Vanderpas J. Selenium and iodine supplementation of rural Tibetan children affected by Kashin-Beck osteoarthropathy. Am J Clin Nutr. 2003;78:137–144.
    1. Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R. Selenium in human health and disease. Antioxida Redox Signal. 2011;14:1337–1383. doi: 10.1089/ars.2010.3275.
    1. Holzer R, Bockenkamp B, Booker P, Newland P, Ciotti G, Pozzi M. The impact of cardiopulmonary bypass on selenium status, thyroid function, and oxidative defense in children. Pediatr Cardiol. 2004;25:522–528. doi: 10.1007/s00246-004-0659-8.
    1. Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care. 2012;16:R66. doi: 10.1186/cc11316.
    1. Vincent J-L, Forceville X. Critically elucidating the role of selenium. Curr Opin Anaesthesiol. 2008;21:148–154. doi: 10.1097/ACO.0b013e3282f49afe.
    1. Maehira F, Miyagi I, Eguchi Y. Selenium regulates transcription factor NF-kappaB activation during the acute phase reaction. Clin Chim Acta. 2003;334:163–171. doi: 10.1016/S0009-8981(03)00223-7.
    1. Chung YW, Kim TS, Lee SY, Lee SH, Choi Y, Kim N, Min B-M, Jeong D-W, Kim IY. Selenite-induced apoptosis of osteoclasts mediated by the mitochondrial pathway. Toxicol Lett. 2006;160:143–150. doi: 10.1016/j.toxlet.2005.06.019.
    1. Wang Z, Forceville X, Antwerpen PV, Piagnerelli M, Ahishakiye D, Macours P, Backer DD, Neve J, Vincent J-L. A large-bolus injection, but not continous infusion of sodium selenite improves outcome in peritonitis. Shock. 2009;32:140–146. doi: 10.1097/SHK.0b013e318193c35d.
    1. Hardy G, Hardy I, Manzanares W. Selenium supplementation in the critically ill. Nutr Clin Pract. 2012;27:21–33. doi: 10.1177/0884533611434116.
    1. Manzanares W, Biestro A, Torre MH, Galusso F, Facchin G, Hardy G. High-dose selenium reduces ventilator-associated pneumonia and illness severity in critically ill patients with systemic inflammation. Intensive Care Med. 2011;37:1120–1127. doi: 10.1007/s00134-011-2212-6.
    1. Valenta J, Brodska H, Drabek T, Hendl J, Kazda A. High-dose selenium substitution in sepsis: a prospective randomized clinical trial. Intensive Care Med. 2011;37:808–815. doi: 10.1007/s00134-011-2153-0.
    1. Mishra V, Baines M, Perry SE, McLaughlin PJ, Carson J, Wenstone R, Shenkin A. Effect of selenium supplementation on biochemical markers and outcome in critically ill patients. Clin Nutr. 2007;26:41–50. doi: 10.1016/j.clnu.2006.10.003.
    1. Andrews PJD, Avenell A, Noble DW, Campbell MK, Croal BL, Simpson WG, Vale LD, Battison CG, Jenkinson DJ, Cook JA, and the SIGNET (Scottish Intensive care Glutamine or seleNium Evaluative Trial) Trials Group Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011;342:d1542. doi: 10.1136/bmj.d1542.
    1. Alhazzani W, Jacobi J, Sindi A, Hartog C, Reinhart K, Kokkoris S, Gerlach H, Andrews P, Drabek T, Manzanares W, Cook DJ, Jaeschke RZ. The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2013;41:1555–1564. doi: 10.1097/CCM.0b013e31828a24c6.
    1. Huang T-S, Shyu Y-C, Chen H-Y, Lin L-M, Lo C-Y, Yuan S-S, Chen P-J. Effect of parenteral selenium supplementation in critically ill patients: a systematic review and meta-analysis. PLoS One. 2013;8:e54431. doi: 10.1371/journal.pone.0054431.
    1. Leong J-Y, van der Merwe J, Pepe S, Bailey M, Perkins A, Lymbury R, Esmore D, Marasco S, Rosenfeldt F. Perioperative metabolic therapy improves redox status and outcomes in cardiac surgery patients: a randomised trial. Heart Lung Circ. 2010;19:584–591. doi: 10.1016/j.hlc.2010.06.659.
    1. Sandre C, Agay D, Ducros VR, Faure H, Cruz C, Alonso A, Chancerelle Y, Roussel A-M. Kinetic changes of oxidative stress and selenium status in plasma and tissues following burn injury in selenium-deficient and selenium-supplemented rats. J Trauma. 2006;60:627–634. doi: 10.1097/01.ta.0000205640.82459.d6.

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