A multicenter randomized placebo-controlled trial of intravenous thyroxine for heart-eligible brain-dead organ donors

Rajat Dhar, Dean Klinkenberg, Gary Marklin, Rajat Dhar, Dean Klinkenberg, Gary Marklin

Abstract

Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid-stimulating hormone) may contribute to hemodynamic instability, and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy.

Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain-dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12 h or saline placebo. The primary study hypotheses are that thyroxine treatment will result in a higher proportion of hearts transplanted and that these hearts will have non-inferior function to hearts not treated with thyroxine. Additional outcome measures are the time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography.

Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment in organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether intravenous thyroxine treatment increases hearts transplanted and/or provides hemodynamic benefits for donor management.

Trial registration: ClinicalTrials.gov NCT04415658 . Registered on June 4, 2020.

Keywords: Brain death; Donor management; Heart transplant; Organ donation; Thyroid hormone.

Conflict of interest statement

RD is a consultant for Mid-America Transplant but did not receive any support for any aspect of the study. GM is an employee of Mid-America Transplant. DK is a consultant for Mid-America Transplant, the sponsor of this study. The other authors have no competing interests.

© 2021. The Author(s).

References

    1. Szabó G. Physiologic changes after brain death. J Heart Lung Transplant. 2004;23:S223–S226. doi: 10.1016/j.healun.2004.04.005.
    1. Dujardin KS, McCully RB, Wijdicks EF, Tazelaar HD, Seward JB, McGregor CG, et al. Myocardial dysfunction associated with brain death: clinical, echocardiographic, and pathologic features. J Heart Lung Transplant. 2001;20(3):350–357. doi: 10.1016/S1053-2498(00)00193-5.
    1. Tryon D, Hasaniya NW, Jabo B, Razzouk AJ, Bailey LL, Rabkin DG. Effect of left ventricular dysfunction on utilization of donor hearts. J Heart Lung Transplant. 2018;37(3):349–357. doi: 10.1016/j.healun.2017.07.015.
    1. Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH. Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy. Transplantation. 1989;47(5):828–834. doi: 10.1097/00007890-198905000-00016.
    1. Novitzky D, Cooper DK. Thyroid hormone and the stunned myocardium. J Endocrinol. 2014;223(1):R1–R8. doi: 10.1530/JOE-14-0389.
    1. Novitzky D, Cooper DKC, Rosendale JD, Kauffman HM. Hormonal therapy of the brain-dead organ donor: experimental and clinical studies. Transplantation. 2006;82:1396–1401. doi: 10.1097/01.tp.0000237195.12342.f1.
    1. Novitzky D, Mi Z, Sun Q, Collins JF, Cooper DK. Thyroid hormone therapy in the management of 63,593 brain-dead organ donors: a retrospective analysis. Transplantation. 2014;98(10):1119–1127. doi: 10.1097/TP.0000000000000187.
    1. Cooper LB, Milano CA, Williams M, Swafford W, Croezen D, Van Bakel AB, et al. Thyroid hormone use during cardiac transplant organ procurement. Clin Transplant. 2016;30(12):1578–1583. doi: 10.1111/ctr.12860.
    1. Rosendale JD, Kauffman HM, McBride MA, Chabalewski FL, Zaroff JG, Garrity ER, et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation. 2003;75:1336–1341. doi: 10.1097/01.TP.0000062839.58826.6D.
    1. Macdonald PS, Aneman A, Bhonagiri D, Jones D, O'Callaghan G, Silvester W, et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Critical care medicine. 2012;40:1635–1644. doi: 10.1097/CCM.0b013e3182416ee7.
    1. Goarin JP, Cohen S, Riou B, Jacquens Y, Guesde R, Le Bret F, et al. The effects of triiodothyronine on hemodynamic status and cardiac function in potential heart donors. Anesth Analg. 1996;83(1):41–47. doi: 10.1213/00000539-199607000-00008.
    1. Dhar R, Stahlschmidt E, Yan Y, Marklin G. A randomized trial comparing triiodothyronine (T3) with thyroxine (T4) for hemodynamically unstable brain-dead organ donors. Clin Transplant. 2019;33(3):e13486. doi: 10.1111/ctr.13486.
    1. Cooper DK, Novitzky D, Wicomb WN, Basker M, Rosendale JD, Myron KH. A review of studies relating to thyroid hormone therapy in brain-dead organ donors. Front Biosci (Landmark Ed). 2009;14:3750–3770. doi: 10.2741/3486.
    1. Dhar R, Stahlschmidt E, Marklin G. A randomized trial of intravenous thyroxine for brain-dead organ donors with impaired cardiac function. Prog Transplant. 2020;30(1):48–55. doi: 10.1177/1526924819893295.
    1. Sally M, Malinoski D. Current research on organ donor management. Anesthesiology clinics. 2013;31:737–748. doi: 10.1016/j.anclin.2013.08.004.
    1. Minambres E, Perez-Villares JM, Chico-Fernandez M, Zabalegui A, Duenas-Jurado JM, Misis M, et al. Lung donor treatment protocol in brain dead-donors: a multicenter study. J Heart Lung Transplant. 2015;34(6):773–780. doi: 10.1016/j.healun.2014.09.024.
    1. Angel LF, Levine DJ, Restrepo MI, Johnson S, Sako E, Carpenter A, et al. Impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes. Am J Respir Crit Care Med. 2006;174(6):710–716. doi: 10.1164/rccm.200603-432OC.
    1. Dhar R, Stahlschmidt E, Paramesh A, Marklin G. A randomized controlled trial of naloxone for optimization of hypoxemia in lung donors after brain death. Transplantation. 2019;103(7):1433–1438. doi: 10.1097/TP.0000000000002511.
    1. Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield M, et al. Therapeutic hypothermia in deceased organ donors and kidney-graft function. N Engl J Med. 2015;373(5):405–414. doi: 10.1056/NEJMoa1501969.
    1. Schnuelle P, Gottmann U, Hoeger S, Boesebeck D, Lauchart W, Weiss C, et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA. 2009;302:1067–1075. doi: 10.1001/jama.2009.1310.
    1. Ware LB, Landeck M, Koyama T, Zhao Z, Singer J, Kern R, et al. A randomized trial of the effects of nebulized albuterol on pulmonary edema in brain-dead organ donors. Am J Transplant. 2014;14:621–628. doi: 10.1111/ajt.12564.
    1. Kotloff RM, Blosser S, Fulda GJ, Malinoski D, Ahya VN, Angel L, et al. Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement. Crit Care Med. 2015;43(6):1291–1325. doi: 10.1097/CCM.0000000000000958.
    1. Swanson EA, Adams T, Patel MS, De La Cruz S, Hutchens M, Khush K, et al. Impact of deceased donor management on donor heart use and recipient graft survival. J Am Coll Surg. 2020;231(3):351–60 e5. doi: 10.1016/j.jamcollsurg.2020.05.025.
    1. Abdelnour T, Rieke S. Relationship of hormonal resuscitation therapy and central venous pressure on increasing organs for transplant. J Heart Lung Transplant. 2009;28:480–485. doi: 10.1016/j.healun.2009.01.018.
    1. Snyder JJ, Salkowski N, Kim SJ, Zaun D, Xiong H, Israni AK, et al. Developing statistical models to assess transplant outcomes using national registries: the process in the United States. Transplantation. 2016;100(2):288–294. doi: 10.1097/TP.0000000000000891.
    1. Ardehali A, Esmailian F, Deng M, Soltesz E, Hsich E, Naka Y, et al. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet. 2015;385(9987):2577–2584. doi: 10.1016/S0140-6736(15)60261-6.
    1. Zuppa AF, Nadkarni V, Davis L, Adamson PC, Helfaer MA, Elliott MR, et al. The effect of a thyroid hormone infusion on vasopressor support in critically ill children with cessation of neurologic function. Crit Care Med. 2004;32(11):2318–2322. doi: 10.1097/01.CCM.0000146133.52982.17.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться