Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial

Lars W Andersen, Mathias J Holmberg, Katherine M Berg, Maureen Chase, Michael N Cocchi, Christopher Sulmonte, Julia Balkema, Mary MacDonald, Sophia Montissol, Venkatachalam Senthilnathan, David Liu, Kamal Khabbaz, Adam Lerner, Victor Novack, Xiaowen Liu, Michael W Donnino, Lars W Andersen, Mathias J Holmberg, Katherine M Berg, Maureen Chase, Michael N Cocchi, Christopher Sulmonte, Julia Balkema, Mary MacDonald, Sophia Montissol, Venkatachalam Senthilnathan, David Liu, Kamal Khabbaz, Adam Lerner, Victor Novack, Xiaowen Liu, Michael W Donnino

Abstract

Background: Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism.

Methods: We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay.

Results: Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p < 0.001). There was no difference between the groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p = 0.75). Relative pyruvate dehydrogenase activity was lower immediately after the surgery in the thiamine group as compared to the placebo group (15% [11, 37] vs. 28% [15, 84], p = 0.02). Patients receiving thiamine had higher post-operative global oxygen consumption 1 hour after the surgery (difference: 0.37 mL/min/kg [95% CI: 0.03, 0.71], p = 0.03) as well as cellular oxygen consumption. We found no differences in clinical outcomes.

Conclusions: There were no differences in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. Post-operative oxygen consumption was significantly increased among patients receiving thiamine.

Trial registration: clinicaltrials.gov NCT02322892, December 14, 2014.

Keywords: Aerobic; Anaerobic; Cardiac surgery; Coronary artery bypass grafting; Lactate; Metabolism; Oxygen consumption; Pyruvate dehydrogenase; Thiamine.

Figures

Fig. 1
Fig. 1
Simplified graphical presentation of PDH’s and thiamine’s role in aerobic metabolism. Aerobic metabolism occurs when pyruvate enters the mitochondria through pyruvate decarboxylation to acetyl-coenzyme A, facilitated by the rate-limiting enzyme pyruvate dehydrogenase (PDH). Adapted with permission from Andersen et al. [12]. ATP adenosine triphosphate, CoA coenzyme A, TCA tricarboxylic acid
Fig. 2
Fig. 2
CONSORT diagram. Out of 275 patients screened, 69 were randomized and 64 were analyzed per the modified intention-to-treat analysis. No patients discontinued the intervention or were lost to follow-up. CABG coronary artery bypass grafting, EuroSCORE European System for Cardiac Operative Risk Evaluation
Fig. 3
Fig. 3
Lactate levels over time between the two groups. There was no difference between the thiamine and placebo groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p = 0.75). The boxplots represent the 1st quartiles, median, and 3rd quartile. The whiskers represent the 10th and 90th percentile and outliers are marked with dots
Fig. 4
Fig. 4
PDH values. Relative PDH activity (a), quantity (b) and specific activity (c) post-surgery and 6 hours post-surgery. Values were calculated as relative to the pre-surgery level, which was set at 100 %. The y-axis is logarithmic to better illustrate the findings. The boxplots represent the 1st quartiles, median, and 3rd quartile. The whiskers represent the 10th and 90th percentile and outliers are marked with dots
Fig. 5
Fig. 5
Cellular oxygen consumption. We found a significant difference in post-surgery relative basal oxygen consumption between groups (99 % [89, 126] vs. 85 % [66, 136], p = 0.04) and a significant difference in cellular maximal oxygen consumption between groups (107 % [86, 155] vs. 90 % [54, 125], p = 0.02). The boxplots represent the 1st quartiles, median, and 3rd quartile. The whiskers represent the 10th and 90th percentile and outliers are marked with dots. The y-axis is logarithmic to better illustrate the findings

References

    1. Hall MJ, DeFrances CJ, Williams SN, Golosinskiy A, Schwartzman A. National Hospital Discharge Survey: 2007 summary. Nat Health Stat Rep. 2010;29:1–20. 24.
    1. Frost L, Molgaard H, Christiansen EH, Hjortholm K, Paulsen PK, Thomsen PE. Atrial fibrillation and flutter after coronary artery bypass surgery: epidemiology, risk factors and preventive trials. Int J Cardiol. 1992;36(3):253–61. doi: 10.1016/0167-5273(92)90293-C.
    1. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367(1):30–9. doi: 10.1056/NEJMoa1112923.
    1. Silber JH, Rosenbaum PR, Schwartz JS, Ross RN, Williams SV. Evaluation of the complication rate as a measure of quality of care in coronary artery bypass graft surgery. JAMA. 1995;274(4):317–23. doi: 10.1001/jama.1995.03530040045039.
    1. Maillet JM, Le Besnerais P, Cantoni M, Nataf P, Ruffenach A, Lessana A, et al. Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery. Chest. 2003;123(5):1361–6. doi: 10.1378/chest.123.5.1361.
    1. Toraman F, Evrenkaya S, Yuce M, Aksoy N, Karabulut H, Bozkulak Y, et al. Lactic acidosis after cardiac surgery is associated with adverse outcome. Heart Surg Forum. 2004;7(2):E155–9. doi: 10.1532/HSF98.20041002.
    1. Hajjar LA, Almeida JP, Fukushima JT, Rhodes A, Vincent JL, Osawa EA, et al. High lactate levels are predictors of major complications after cardiac surgery. J Thorac Cardiovasc Surg. 2013;146(2):455–60. doi: 10.1016/j.jtcvs.2013.02.003.
    1. Lindsay AJ, Xu M, Sessler DI, Blackstone EH, Bashour CA. Lactate clearance time and concentration linked to morbidity and death in cardiac surgical patients. Ann Thorac Surg. 2013;95(2):486–92. doi: 10.1016/j.athoracsur.2012.07.020.
    1. Badreldin AM, Doerr F, Elsobky S, Brehm BR, Abul-dahab M, Lehmann T, et al. Mortality prediction after cardiac surgery: blood lactate is indispensible. Thorac Cardiovasc Surg. 2013;61(8):708–17. doi: 10.1055/s-0032-1324796.
    1. Andersen LW, Holmberg MJ, Doherty M, Khabbaz K, Lerner A, Berg KM, Donnino MW. Postoperative lactate levels and hospital length of stay after cardiac surgery. J Cardiothorac Vasc Anesth. 2015;29:1454–60. doi: 10.1053/j.jvca.2015.06.007.
    1. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567–73. doi: 10.1097/CCM.0000000000000742.
    1. Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013;88(10):1127–40. doi: 10.1016/j.mayocp.2013.06.012.
    1. Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit Care. 2002;6(6):491–9. doi: 10.1186/cc1824.
    1. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988;94(6):1176–86. doi: 10.1378/chest.94.6.1176.
    1. Rivers EP, Rady MY, Martin GB, Fenn NM, Smithline HA, Alexander ME, et al. Venous hyperoxia after cardiac arrest. Characterization of a defect in systemic oxygen utilization. Chest. 1992;102(6):1787–93. doi: 10.1378/chest.102.6.1787.
    1. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330(24):1717–22. doi: 10.1056/NEJM199406163302404.
    1. Patel MS, Korotchkina LG. Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans. 2006;34(Pt 2):217–22. doi: 10.1042/BST0340217.
    1. Linn TC, Pettit FH, Reed LJ. Alpha-keto acid dehydrogenase complexes. X. Regulation of the activity of the pyruvate dehydrogenase complex from beef kidney mitochondria by phosphorylation and dephosphorylation. Proc Natl Acad Sci U S A. 1969;62(1):234–41. doi: 10.1073/pnas.62.1.234.
    1. Andersen LW, Liu X, Peng TJ, Giberson TA, Khabbaz KR, Donnino MW. Pyruvate dehydrogenase activity and quantity decreases after coronary artery bypass grafting: a prospective observational study. Shock. 2015;43(3):250–4. doi: 10.1097/SHK.0000000000000306.
    1. Kobayashi K, Neely JR. Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts. J Mol Cell Cardiol. 1983;15(6):359–67. doi: 10.1016/0022-2828(83)90320-6.
    1. Patel TB, Olson MS. Regulation of pyruvate dehydrogenase complex in ischemic rat heart. Am J Physiol. 1984;246(6 Pt 2):H858–64.
    1. Lewandowski ED, Johnston DL. Reduced substrate oxidation in postischemic myocardium: 13C and 31P NMR analyses. Am J Physiol. 1990;258(5 Pt 2):H1357–65.
    1. Rao V, Merante F, Weisel RD, Shirai T, Ikonomidis JS, Cohen G, et al. Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyocytes from simulated ischemia. J Thorac Cardiovasc Surg. 1998;116(3):485–94. doi: 10.1016/S0022-5223(98)70015-7.
    1. Merante F, Mickle DA, Weisel RD, Li RK, Tumiati LC, Rao V, et al. Myocardial aerobic metabolism is impaired in a cell culture model of cyanotic heart disease. Am J Physiol. 1998;275(5 Pt 2):H1673–81.
    1. Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Kuroda Y. Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex. Eur J Pediatr. 1998;157(8):648–52. doi: 10.1007/s004310050903.
    1. Donnino MW, Cocchi MN, Smithline H, Carney E, Chou PP, Salciccioli J. Coronary artery bypass graft surgery depletes plasma thiamine levels. Nutrition. 2010;26(1):133–6. doi: 10.1016/j.nut.2009.06.004.
    1. Society of Thoracic Surgeons National Database - Data Collection. Available from: . Accessed date Dec 22 2015.
    1. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064–89. doi: 10.1161/STR.0b013e318296aeca.
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020–35. doi: 10.1161/CIR.0b013e31826e1058.
    1. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–33.
    1. The Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994.
    1. Campeau L. Letter: grading of angina pectoris. Circulation. 1976;54(3):522–3.
    1. EuroSCORE II calculator. Available from: . Accessed date Dec 22 2015.
    1. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE) Eur J Cardiothorac Surg. 1999;16(1):9–13. doi: 10.1016/S1010-7940(99)00134-7.
    1. Carnero-Alcazar M, Silva Guisasola JA, Reguillo Lacruz FJ, Maroto Castellanos LC, Cobiella Carnicer J, Villagran Medinilla E, et al. Validation of EuroSCORE II on a single-centre 3800 patient cohort. Interact Cardiovasc Thorac Surg. 2013;16(3):293–300. doi: 10.1093/icvts/ivs480.
    1. Biancari F, Vasques F, Mikkola R, Martin M, Lahtinen J, Heikkinen J. Validation of EuroSCORE II in patients undergoing coronary artery bypass surgery. Ann Thorac Surg. 2012;93(6):1930–5. doi: 10.1016/j.athoracsur.2012.02.064.
    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(2):377–81. doi: 10.1016/j.jbi.2008.08.010.
    1. Liu X, Pervez H, Andersen LW, Uber A, Montissol S, Patel P, et al. Immunocapture and microplate-based activity and quantity measurement of pyruvate dehydrogenase in human peripheral blood mononuclear cells. Bioanalysis. 2015;7(5):583–92. doi: 10.4155/bio.14.302.
    1. Lib M, Rodriguez-Mari A, Marusich MF, Capaldi RA. Immunocapture and microplate-based activity measurement of mammalian pyruvate dehydrogenase complex. Anal Biochem. 2003;314(1):121–7. doi: 10.1016/S0003-2697(02)00645-0.
    1. McLellan S, Walsh T, Burdess A, Lee A. Comparison between the Datex-Ohmeda M-COVX metabolic monitor and the Deltatrac II in mechanically ventilated patients. Intensive Care Med. 2002;28(7):870–6. doi: 10.1007/s00134-002-1323-5.
    1. Donaldson L, Dodds S, Walsh TS. Clinical evaluation of a continuous oxygen consumption monitor in mechanically ventilated patients. Anaesthesia. 2003;58(5):455–60. doi: 10.1046/j.1365-2044.2003.03123.x.
    1. Ferrick DA, Neilson A, Beeson C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Discov Today. 2008;13(5-6):268–74. doi: 10.1016/j.drudis.2007.12.008.
    1. Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345:e5840. doi: 10.1136/bmj.e5840.
    1. Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia. 2007;50(10):2164–70. doi: 10.1007/s00125-007-0771-4.
    1. Larkin JR, Zhang F, Godfrey L, Molostvov G, Zehnder D, Rabbani N, et al. Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes. PLoS One. 2012;7(12):e53175. doi: 10.1371/journal.pone.0053175.
    1. Fergusson D, Aaron SD, Guyatt G, Hebert P. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ. 2002;325(7365):652–4. doi: 10.1136/bmj.325.7365.652.
    1. Luger M, Hiesmayr M, Koppel P, Sima B, Ranz I, Weiss C, et al. Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery: a double-blinded, randomised controlled pilot study. Eur J Anaesthesiol. 2015;32(8):543–8. doi: 10.1097/EJA.0000000000000205.
    1. Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360–7. doi: 10.1097/CCM.0000000000001572.
    1. Atherton HJ, Schroeder MA, Dodd MS, Heather LC, Carter EE, Cochlin LE, et al. Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS. NMR Biomed. 2011;24(2):201–8. doi: 10.1002/nbm.1573.
    1. Berg KM, Gautam S, Salciccioli JD, Giberson T, Saindon B, Donnino MW. Intravenous thiamine is associated with increased oxygen consumption in critically ill patients with preserved cardiac index. Ann Am Thorac Soc. 2014;11(10):1597–601. doi: 10.1513/AnnalsATS.201406-259BC.
    1. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18(5):503. doi: 10.1186/s13054-014-0503-3.

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