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Episode 128: HOT TOPICS - Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors

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This week's Hot Topic is Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors and Dr Nicholas Morris is joined by Dr Raj Dhar from Washington University School of Medicine to discuss his latest New England Journal of Medicine manuscript (https://pubmed.ncbi.nlm.nih.gov/38048188/).

Contributors

  • Raj Dhar, MD, FRCP(C)

    Associate Professor, Department of Neurology
    Division of Neurocritical Care, Barnes Jewish Hospital
    Washington University in St. Louis
    St. Louis, MO

  • Nicholas A. Morris, MD

    Assistant Professor and Fellowship Director
    Division of Neurocritical Care and Emergency Neurology
    Department of Neurology
    University of Maryland School of Medicine Medicine

  1. 00:00:21
    Hello, and welcome to the Neuro
  2. 00:00:22
    Critical Care Society Hot Topics podcast.
  3. 00:00:25
    I'm your host, Dr. Nicholas Morris
  4. 00:00:27
    from the University of Maryland, Chuck
  5. 00:00:28
    Trauma Hospital. And today, I am very
  6. 00:00:31
    excited to talk to Raj Darr, Raj is a
  7. 00:00:35
    professor of neurology with the Division
  8. 00:00:36
    of Neuro Critical Care at Washington
  9. 00:00:39
    University School of Medicine, and he's
  10. 00:00:41
    here today to talk about what I think is
  11. 00:00:44
    a real triumph and a really important
  12. 00:00:46
    paper for all neurointensivists to know
  13. 00:00:47
    about his work on intravenously both
  14. 00:00:47
    eroxine for unstable brain dead heart
  15. 00:00:47
    donors, which was published in the New
  16. 00:00:48
    England Journal of
  17. 00:00:55
    Medicine in November of 2023. So, Raj,
  18. 00:00:58
    welcome to the podcast. Thanks, and
  19. 00:01:01
    thanks for that introduction.
  20. 00:01:03
    Well, first of all, congratulations on
  21. 00:01:06
    a New England Journal publication in
  22. 00:01:07
    neurocritical care. These are sort of
  23. 00:01:09
    few and far between, especially led by
  24. 00:01:10
    neurointensivists, and I think the
  25. 00:01:14
    amount of work that went into this
  26. 00:01:15
    project was. obviously immense, but
  27. 00:01:17
    this work started long before the
  28. 00:01:19
    publication of this manuscript. Can you
  29. 00:01:22
    take us back to a little bit about,
  30. 00:01:23
    when did you start thinking about this
  31. 00:01:25
    topic and what got you interested? Yeah,
  32. 00:01:28
    no, it has been a long journey and
  33. 00:01:30
    mainly a fun journey, I'll say, and
  34. 00:01:32
    unexpected as sometimes research can be,
  35. 00:01:35
    just takes you in directions that you
  36. 00:01:37
    have a clinical interest in and it just
  37. 00:01:39
    develops and sometimes the avenue
  38. 00:01:40
    doesn't develop into anything. I think
  39. 00:01:42
    we all know that and this was one area
  40. 00:01:45
    that grew and developed maybe even more
  41. 00:01:48
    than I expected. And it kind of came
  42. 00:01:50
    out of, I guess, two related avenues,
  43. 00:01:53
    one being, of course, the fact that we
  44. 00:01:54
    care for patients in the neuro ICU, who
  45. 00:01:58
    are herniating, who are brain dead even.
  46. 00:02:00
    And so we see host brain death care,
  47. 00:02:04
    even though we haven't declared the
  48. 00:02:05
    patient brain dead yet. When we manage
  49. 00:02:08
    vasopressors, we manage the
  50. 00:02:11
    hematodynamic instability and endocrine
  51. 00:02:12
    problems, lung problems. was, you
  52. 00:02:16
    know, the clinical interest was always
  53. 00:02:17
    there. And then I think the second part,
  54. 00:02:21
    which has been about 10 to 15 years now,
  55. 00:02:23
    was really working more closely with the
  56. 00:02:25
    OPO here in this region to optimize the
  57. 00:02:28
    care even after brain death. And so
  58. 00:02:30
    that started 15 years ago. And, you
  59. 00:02:35
    know, here we really have now it's no
  60. 00:02:37
    longer so unique, but at that time was
  61. 00:02:39
    a pretty unique opportunity where the
  62. 00:02:41
    OPO had its own donor care facility.
  63. 00:02:43
    Now that's becoming more common around
  64. 00:02:45
    the country and they were very
  65. 00:02:46
    interested in optimizing care,
  66. 00:02:49
    optimizing the science, which was and
  67. 00:02:51
    still is to some degree a unique aspect
  68. 00:02:55
    of OPOs. Not all OPOs looked at donor
  69. 00:02:57
    care that way from a scientific lens.
  70. 00:02:59
    And so that was appealing to me to say
  71. 00:03:02
    we know there's problems going on, we
  72. 00:03:04
    know there's issues as we can discuss,
  73. 00:03:07
    but we also have the opportunity to
  74. 00:03:09
    manage donors in an ICU, all the donors,
  75. 00:03:12
    so not just just owners at my hospital.
  76. 00:03:14
    but all the donors in the region. And
  77. 00:03:15
    so I was able to get involved with donor
  78. 00:03:18
    management at the individual donor level
  79. 00:03:20
    and also the research level really
  80. 00:03:22
    across the region. And so that was
  81. 00:03:24
    really a catalyst for some of the
  82. 00:03:26
    studies that we can talk about that I
  83. 00:03:27
    got involved in over the years. That's
  84. 00:03:30
    fantastic. And I think many of our
  85. 00:03:31
    listeners were probably well aware of
  86. 00:03:35
    sort of the ultimate inspiration here.
  87. 00:03:38
    But maybe you can help frame this work
  88. 00:03:40
    for them You know, why is it so
  89. 00:03:43
    important that we learn how to stabilize
  90. 00:03:45
    brain dead donors? Yeah, I mean, it's
  91. 00:03:48
    sort of a unique area where really, you
  92. 00:03:50
    know, obviously the patient we've been
  93. 00:03:52
    caring for is deceased. But we really
  94. 00:03:55
    have this opportunity to provide organs
  95. 00:03:58
    to save lives. And so there's a lot of
  96. 00:04:01
    instability that happens after brain
  97. 00:04:02
    death, you know, based on just the
  98. 00:04:04
    loss of brain function, the loss of
  99. 00:04:05
    input, potentially the loss of hormones.
  100. 00:04:10
    know, the more unstable a donor is,
  101. 00:04:12
    the less likely they are to be able to
  102. 00:04:13
    donate their organs. And so that
  103. 00:04:16
    potential good that can happen in this
  104. 00:04:18
    situation, when there's often a tragic
  105. 00:04:20
    situation that's occurred, really
  106. 00:04:22
    motivated me and inspired me and
  107. 00:04:24
    inspires a lot of people in this area,
  108. 00:04:26
    the opios, and less so on the
  109. 00:04:29
    intensivist side, although it's growing,
  110. 00:04:30
    to
  111. 00:04:32
    say, you know, what are the
  112. 00:04:33
    interventions we can do to make the
  113. 00:04:35
    lungs better, to make the hearts better,
  114. 00:04:37
    that ultimately can lead to those organs
  115. 00:04:40
    being transplanted. And then on top of
  116. 00:04:42
    that, the heart and lungs is mainly
  117. 00:04:44
    what I focused on in my research, but
  118. 00:04:46
    of course, if the heart and lungs are
  119. 00:04:48
    not working, the other organs don't
  120. 00:04:50
    look so good, you know, kidneys,
  121. 00:04:51
    liver, so really, it has a downstream
  122. 00:04:53
    effect in terms of, you know, if a
  123. 00:04:56
    donor has a cardiac arrest, which
  124. 00:04:58
    certainly can happen, that jeopardizes
  125. 00:05:00
    all the organs. So I think stability is
  126. 00:05:03
    really a key, a key in donor Yeah,
  127. 00:05:06
    absolutely, especially when there's
  128. 00:05:07
    such a shortage of donors out there and
  129. 00:05:10
    such a high demand for organ
  130. 00:05:12
    transplantation. What do we know about
  131. 00:05:17
    the neuro-cormonophysiology or the brain
  132. 00:05:19
    dead donor? Obviously, you're really
  133. 00:05:22
    focused in on IV lead, both hydroxine
  134. 00:05:24
    supplementation.
  135. 00:05:27
    What do we know that happens during
  136. 00:05:27
    brain death to the thyroid hormone and
  137. 00:05:27
    the pituitary axis? Yeah, no,
  138. 00:05:33
    I think it's sort of, I would say,
  139. 00:05:36
    maybe a misunderstood area or at least a
  140. 00:05:38
    controversial area because I think most
  141. 00:05:41
    of us accept that there's gonna be
  142. 00:05:42
    changes to the, and almost all donors
  143. 00:05:45
    to hypothermic function, to some degree,
  144. 00:05:48
    pituitary function, but I think what's
  145. 00:05:50
    been unclear is how much that affects
  146. 00:05:51
    downstream thyroid function, adrenal
  147. 00:05:54
    function, and then the end organs,
  148. 00:05:56
    like the heart or even the lungs to some
  149. 00:05:58
    degree with adrenal function. So
  150. 00:06:01
    there's been a lot of interest over the
  151. 00:06:02
    years
  152. 00:06:04
    how do we link the observation that is
  153. 00:06:07
    incontrovertible that donors run stable,
  154. 00:06:09
    that they have organ dysfunction, they
  155. 00:06:11
    have inflammation, and the observation
  156. 00:06:13
    that some donors have hormonal
  157. 00:06:15
    deficiencies, whether it be, you know,
  158. 00:06:17
    obviously DI, but also low levels of
  159. 00:06:21
    corticosterorides or thyroid hormone in
  160. 00:06:22
    this case, and how are those linked?
  161. 00:06:25
    And, you know, does obviously replace
  162. 00:06:27
    one of those hormones make a difference.
  163. 00:06:28
    So I think that relationship has been
  164. 00:06:32
    unclear, and, you know, it's a
  165. 00:06:34
    correlation, and that's what we want to
  166. 00:06:35
    test in the study, is they're really a
  167. 00:06:38
    meaningful therapeutic implication. And
  168. 00:06:41
    I think there was uncertainty there,
  169. 00:06:43
    both from a trial point of view, but
  170. 00:06:45
    even the physiology, I don't think it's
  171. 00:06:47
    entirely clear as we may discuss, most
  172. 00:06:49
    donors are not. In fact, that
  173. 00:06:51
    hypothyroid, you know, and that was
  174. 00:06:53
    one of the interesting things we found
  175. 00:06:55
    here. Yeah, I think that's surprising
  176. 00:06:57
    to many, perhaps some inexperienced
  177. 00:07:01
    people in the neuroIC, probably
  178. 00:07:03
    experienced people as well, 'cause I
  179. 00:07:05
    think as we talked about before we went
  180. 00:07:07
    on air, maybe this is not a patient
  181. 00:07:10
    population, if you wanna call it that,
  182. 00:07:12
    that we think much about in a much about
  183. 00:07:14
    their physiology, at least not all of
  184. 00:07:16
    us do, and probably a few of us do as
  185. 00:07:19
    intensely as you have.
  186. 00:07:23
    So this, as we said, this work didn't
  187. 00:07:26
    just come out of thin air, you'd sort
  188. 00:07:27
    of been building up to this for some
  189. 00:07:29
    time. So can you take us through some
  190. 00:07:31
    of your earlier studies and what you
  191. 00:07:33
    found and how you kind of built the case
  192. 00:07:34
    to have this large randomized trial
  193. 00:07:38
    involving multiple OPOs and really at a
  194. 00:07:41
    large scale? Yeah, no, I think it was
  195. 00:07:44
    a really interesting story in the sense
  196. 00:07:46
    of unexpected and kind of the way that
  197. 00:07:48
    research doesn't always work, but maybe
  198. 00:07:50
    sometimes fortuitously does develop and
  199. 00:07:52
    you have to have the right milieu, you
  200. 00:07:53
    have to have the right interest. And so
  201. 00:07:55
    it really did start with that one center,
  202. 00:07:57
    one question. And really the first
  203. 00:07:59
    question we actually looked at with
  204. 00:08:00
    Puerto Costa Rica.
  205. 00:08:03
    You know, just briefly, we had the
  206. 00:08:04
    observation that a lot of, and the
  207. 00:08:07
    other part of this, I guess, is a lot
  208. 00:08:08
    of donor science or donor care is not
  209. 00:08:11
    based on a lot of science. It's based
  210. 00:08:12
    in observations. It's based in, you
  211. 00:08:15
    know, transplant teams saying that,
  212. 00:08:16
    well, I think there's a lot of
  213. 00:08:17
    inflammation. Let's do this. And so
  214. 00:08:19
    there was a practice that high doses of
  215. 00:08:21
    torco steroids probably are helpful to
  216. 00:08:24
    tamp down inflammation in the lungs and
  217. 00:08:26
    the kidneys maybe. And so the practice
  218. 00:08:28
    was to give very high doses of steroids,
  219. 00:08:30
    you know, like a pulse dose,
  220. 00:08:31
    essentially So it was really nice. In a
  221. 00:08:35
    sense, it was just a bunch of
  222. 00:08:37
    intensivists, not all neurointensivists,
  223. 00:08:37
    actually sitting around a table over
  224. 00:08:40
    dinner saying, you know, we're doing
  225. 00:08:42
    this. What is the basis of this?
  226. 00:08:43
    Should we do it? We know in sepsis and
  227. 00:08:45
    in the ICU that, you know, steroids
  228. 00:08:49
    have a role maybe, although even that's
  229. 00:08:50
    not clear, but probably not this high
  230. 00:08:52
    dose of steroids, even for a
  231. 00:08:54
    hemodynamic problem, you know, that
  232. 00:08:55
    was around the same time in 2010, that
  233. 00:08:57
    a lot of those sepsis studies were
  234. 00:08:58
    coming out And so we actually started.
  235. 00:09:01
    and it wasn't randomized trial, it just
  236. 00:09:03
    shows the progression of the studies
  237. 00:09:04
    that's really nice and interesting,
  238. 00:09:06
    that we kind of did a historical control
  239. 00:09:09
    study where we kind of started using low
  240. 00:09:11
    dose sepsis, dosing of steroids and
  241. 00:09:14
    looked at things like glucose,
  242. 00:09:16
    obviously it was different in those
  243. 00:09:17
    groups, but also did the lungs work as
  244. 00:09:19
    well, it was the oxygenation did was
  245. 00:09:20
    the heart is good. And so that was kind
  246. 00:09:22
    of like the first simple study that
  247. 00:09:24
    anyone could probably relate to, just
  248. 00:09:26
    saying we did something in your ICU,
  249. 00:09:28
    like we all do sometimes and doesn't
  250. 00:09:29
    make a difference, we really need to do
  251. 00:09:31
    this in subarachnoid hemorrhage or
  252. 00:09:33
    whatever. So that was the level that we
  253. 00:09:35
    started out was, and we published that
  254. 00:09:38
    and saying that maybe these lower,
  255. 00:09:40
    lower doses of steroids, we didn't go
  256. 00:09:42
    with no steroids, which is interesting,
  257. 00:09:43
    this thyroid hormone study, we were
  258. 00:09:45
    really eventually got to the point of no
  259. 00:09:47
    hormones here, but we were not at the
  260. 00:09:49
    point back then to say, and this is
  261. 00:09:51
    mainly based on the kind of beliefs and
  262. 00:09:55
    lack of equipoise, I guess you could
  263. 00:09:56
    say, in the transplant community to say,
  264. 00:09:58
    well, we're not gonna give these donor
  265. 00:10:00
    steroids and then, you know, what
  266. 00:10:01
    happened to the recipients, right?
  267. 00:10:02
    There's a whole level of ethics that
  268. 00:10:04
    comes up in these studies that is
  269. 00:10:06
    something new for me, at least as I've
  270. 00:10:07
    got involved. We don't think of that
  271. 00:10:09
    when we do something to a patient, well,
  272. 00:10:10
    what happens to their, you know,
  273. 00:10:12
    children? Yeah, but yeah, you know,
  274. 00:10:14
    like, it's a whole different level of
  275. 00:10:16
    concern. And so we did low and high
  276. 00:10:18
    dose steroids and showed no difference
  277. 00:10:20
    in lung outcomes. And as an example,
  278. 00:10:22
    that did affect our practice and we'll
  279. 00:10:24
    come back to that with a thyroid study,
  280. 00:10:25
    I imagine And it also affected several
  281. 00:10:27
    other OPOs, not many, I'll admit. And
  282. 00:10:30
    that taught me that you can do these
  283. 00:10:32
    studies, you can find something
  284. 00:10:33
    interesting, may not be a randomized
  285. 00:10:35
    trial, but it could affect OPO practice,
  286. 00:10:38
    but it's not gonna change all OPOs
  287. 00:10:40
    practice unless you do a large
  288. 00:10:41
    randomized trial. So that's kind of
  289. 00:10:43
    right. And we did several other studies,
  290. 00:10:45
    pilot studies of thyroid hormone. We
  291. 00:10:46
    did a really, one of my favorite
  292. 00:10:48
    studies, a pro-inventilation study that
  293. 00:10:51
    we did before COVID, before proning was
  294. 00:10:53
    cool, I guess.
  295. 00:10:57
    OGs of pruning. Right, at least, you
  296. 00:10:59
    know, and it was really neat that we
  297. 00:11:00
    could just make these lungs work so much
  298. 00:11:02
    better when we prone them and like the
  299. 00:11:04
    rate of transplantation, which as you
  300. 00:11:06
    alluded to is a real deficiency,
  301. 00:11:08
    especially lungs are in great short
  302. 00:11:10
    supply. Only 20 of lungs from even
  303. 00:11:12
    young donors are utilized and it's
  304. 00:11:14
    amazing. And so the heart is maybe,
  305. 00:11:16
    you know, 40 still very low, even when
  306. 00:11:19
    you have young people becoming brain
  307. 00:11:21
    dead And so that was really, it was
  308. 00:11:25
    also not a randomized study. So at the
  309. 00:11:27
    end of that point, we really wanted to
  310. 00:11:28
    work towards this definitive study, but
  311. 00:11:30
    the pronant study was really convincing.
  312. 00:11:32
    Double and amount of lungs were
  313. 00:11:33
    transplanted. We had physiologic
  314. 00:11:35
    endpoints. We even had CT scans showing
  315. 00:11:38
    adleptosis was improved. So, you know,
  316. 00:11:40
    it was a journey. And then the final
  317. 00:11:43
    part, I'll say, which really is
  318. 00:11:44
    important to this and relevant to our
  319. 00:11:46
    community, is that there was a
  320. 00:11:48
    community of OPOs and researchers, even
  321. 00:11:51
    not in opios like myself. met and
  322. 00:11:53
    started a former collaborative, maybe
  323. 00:11:55
    like NCS is trying to do, that we would
  324. 00:11:57
    meet twice a year to talk just about
  325. 00:11:59
    research. And it was a small enough
  326. 00:12:01
    community, like near ICU is a small
  327. 00:12:03
    community, it's not thousands of
  328. 00:12:04
    hospitals, I mean, maybe it is now,
  329. 00:12:06
    but, you know, these were like 20, 30
  330. 00:12:09
    people meeting every year to talk about,
  331. 00:12:11
    well, one day we should do a thyroid
  332. 00:12:12
    hormone study, like, you know, this
  333. 00:12:14
    was, and that was called the ODRC, the
  334. 00:12:16
    Organ Donation Research Collaborative
  335. 00:12:18
    And we met, and over the years, you
  336. 00:12:21
    know, talked about these studies, and
  337. 00:12:22
    that really helped to make it a national,
  338. 00:12:26
    you know, take it from the one center
  339. 00:12:27
    of proning study, steroid study, to
  340. 00:12:29
    what we'll talk about today. And
  341. 00:12:32
    towards the end of this decade, this
  342. 00:12:34
    last decade, I guess, the
  343. 00:12:36
    2018s, I became a chair person of that
  344. 00:12:39
    collaborative, so that became kind of
  345. 00:12:40
    unexpected, like, oh, now I'm
  346. 00:12:42
    actually really involved in this, so,
  347. 00:12:44
    yeah, there was just a growth of so
  348. 00:12:46
    many things that were sort of fortuitous
  349. 00:12:48
    that brought this study to a realization.
  350. 00:12:51
    That's great. actually provided a
  351. 00:12:54
    really wonderful blueprint for sort of
  352. 00:12:56
    young faculty, junior investigators,
  353. 00:12:57
    where they start kind of with maybe
  354. 00:13:00
    retrospective, observational studies,
  355. 00:13:01
    they move into the prospective single
  356. 00:13:03
    center domain, and then they build
  357. 00:13:05
    collaborations and eventually take that
  358. 00:13:08
    to a much grander scale.
  359. 00:13:14
    Maybe we can move on a little bit to the
  360. 00:13:16
    kind of thieroxine story And so, as you
  361. 00:13:20
    said, during this work, you sort of
  362. 00:13:22
    transitioned away from corticosteroids
  363. 00:13:24
    and really focused on thyroid hormone.
  364. 00:13:27
    And in this study that we're going to
  365. 00:13:30
    get into more in depth, you infused IV
  366. 00:13:33
    levothyroxine or T4, right? But you've
  367. 00:13:37
    done some previous work because the more
  368. 00:13:39
    active form, of course, is T3. And
  369. 00:13:42
    you've, I think, done more than anyone
  370. 00:13:44
    looking at what actually happens in
  371. 00:13:46
    brain dead donors when you give them
  372. 00:13:48
    thyroid hormone, what type of thyroid
  373. 00:13:51
    Can you summarize some of your early
  374. 00:13:52
    findings for the listeners? Yeah, I
  375. 00:13:55
    mean, I think first it's important as
  376. 00:13:56
    we're alluding to with the science and
  377. 00:13:58
    the knowledge, it was pretty deficient,
  378. 00:14:00
    but when we'll do more in the detail,
  379. 00:14:01
    but there definitely wasn't a study like
  380. 00:14:03
    this, but there had been, you know,
  381. 00:14:06
    in a sort of the progression of science
  382. 00:14:07
    as well in many fields, including
  383. 00:14:09
    neuro-critical care, I feel like
  384. 00:14:10
    there's, you know, maybe animals,
  385. 00:14:12
    there's a problem, you know, which was
  386. 00:14:13
    in that case in the 1980s, heart
  387. 00:14:15
    transplantation became a bigger thing.
  388. 00:14:18
    And then there was a problem in the well,
  389. 00:14:19
    these hearts don't work that well
  390. 00:14:20
    sometimes And why don't they work? And
  391. 00:14:21
    it's the donor's fault in a way, you
  392. 00:14:23
    know? And so there was the experimental
  393. 00:14:27
    observation in monkeys, especially, or,
  394. 00:14:29
    you know, non-human primate models that
  395. 00:14:31
    maybe thyroid hormone and T3 could
  396. 00:14:33
    really jumpstart these hearts and that
  397. 00:14:35
    that deficiency that we alluded to
  398. 00:14:36
    earlier after brain death might be
  399. 00:14:39
    significant. And so, you know, I can
  400. 00:14:41
    kind of understand, and this is, you
  401. 00:14:42
    know, what, for decades ago now, that
  402. 00:14:46
    that's a pretty exciting potential that
  403. 00:14:47
    you can make a heart work in a recipient
  404. 00:14:49
    better the donor, a thyroid hormone,
  405. 00:14:53
    and there were, you know, small animal
  406. 00:14:54
    studies of that. But it kind of grew
  407. 00:14:57
    into, and that was mainly with T3, but
  408. 00:15:00
    it kind of grew over the decades into a
  409. 00:15:01
    clinical practice as these things
  410. 00:15:03
    sometimes do, you know, without having
  411. 00:15:04
    a definitive trial saying, well, that
  412. 00:15:06
    made sense. Let's start doing that.
  413. 00:15:09
    But a lot of those studies in humans
  414. 00:15:10
    were with T4,
  415. 00:15:12
    I mean, levothyroxen, and mainly
  416. 00:15:14
    because of cost, to be honest, I think
  417. 00:15:16
    it was just T3 is much more expensive
  418. 00:15:18
    and I'll come back to T3 But first of
  419. 00:15:20
    all, that use led to then, as it does
  420. 00:15:23
    in many areas, well, let's look at
  421. 00:15:25
    this retrospectively and who got
  422. 00:15:28
    whatever treatment for subarachnoid or
  423. 00:15:30
    something. And so those studies came
  424. 00:15:32
    out in the early 2000s from a decade or
  425. 00:15:35
    20, 000 donors showing the donors that
  426. 00:15:37
    got thyroid hormone mainly T4 in this
  427. 00:15:39
    case now, we're doing better in their
  428. 00:15:42
    organ function in
  429. 00:15:45
    terms of whether the heart was
  430. 00:15:45
    transplanted, whether total organs were
  431. 00:15:47
    transplanted.
  432. 00:15:50
    And so that was very appealing that the,
  433. 00:15:52
    I'd say, semi-scientific level to the
  434. 00:15:54
    OPO community and to the transplant
  435. 00:15:55
    community to say, well, this is great,
  436. 00:15:58
    you know, it's translated over to
  437. 00:15:59
    humans. And so that was the level of
  438. 00:16:02
    evidence. And then there were some
  439. 00:16:03
    studies with T3 in humans, but they
  440. 00:16:05
    were all very small up till, and we did
  441. 00:16:08
    a study that I'll mention, that really,
  442. 00:16:10
    and that's again, I think a real
  443. 00:16:11
    learning point for me and for the
  444. 00:16:12
    community is that there were these large
  445. 00:16:14
    retrospective studies, you know,
  446. 00:16:16
    looking at databases with all the biases
  447. 00:16:18
    and confounding that hopefully we know
  448. 00:16:20
    about, but then there was, you know,
  449. 00:16:22
    small randomized studies saying we're
  450. 00:16:24
    gonna give T3 to these 20 donors, look
  451. 00:16:26
    at their echoes, look at their, and
  452. 00:16:28
    none of those randomized trials showed
  453. 00:16:29
    any benefit. But yet, we all, I mean,
  454. 00:16:32
    the OPO community looked at those large
  455. 00:16:34
    retrospective as more powerful, you
  456. 00:16:37
    know, and that was kind of the world
  457. 00:16:38
    that we lived in up till we did our
  458. 00:16:39
    study was this kind of equipoise, but
  459. 00:16:42
    really people leaning towards using
  460. 00:16:44
    thyroid hormone, the guidelines mention
  461. 00:16:46
    it Uh. And then the T3 question, well,
  462. 00:16:49
    yeah, the studies didn't show a benefit.
  463. 00:16:51
    And then we did a study because we were
  464. 00:16:53
    like, if we're going to go forward with
  465. 00:16:54
    this, we want to know definitively, we
  466. 00:16:55
    don't want someone to say, well, you
  467. 00:16:57
    didn't show benefit with T4, but maybe
  468. 00:16:59
    T3 would have been better. So we did a
  469. 00:17:01
    pilot study, which was also important
  470. 00:17:03
    for, you know, sample size and all the
  471. 00:17:05
    things we think about. And where we
  472. 00:17:07
    took unstable donors sort of similar to
  473. 00:17:08
    this study and randomized them to T3 or
  474. 00:17:12
    T4, what was really cool in that study,
  475. 00:17:14
    and briefly, I'll mention one of the
  476. 00:17:16
    advantages of OPO research is you have a
  477. 00:17:18
    lot of flexibility in interventions,
  478. 00:17:21
    because, you know, these are not your
  479. 00:17:22
    patients. These are donors you're
  480. 00:17:24
    trying to optimize. So we could do
  481. 00:17:25
    echoes serially. We had the ability and
  482. 00:17:28
    the resources, to be honest, to do
  483. 00:17:30
    echoes in that small pilot study, we
  484. 00:17:32
    didn't do serial activist, large study.
  485. 00:17:33
    Unfortunately, that wasn't feasible
  486. 00:17:35
    across 15 sites. But in that small
  487. 00:17:38
    study, we actually did a baseline echo
  488. 00:17:40
    immediately after brain death
  489. 00:17:41
    declaration, which was super
  490. 00:17:43
    interesting but I think that's a
  491. 00:17:44
    neuro-intensive, is like, how do those
  492. 00:17:45
    hearts actually work? We all know about
  493. 00:17:47
    Takatsubo, and we know about Stenmayer
  494. 00:17:49
    Cardium. And we did find that in those
  495. 00:17:51
    unstable donors, again, selecting
  496. 00:17:53
    those on pressers, their incidence of
  497. 00:17:56
    low EF was very high. I think the
  498. 00:17:57
    median EF was like 40. Hmm. If you do
  499. 00:18:00
    the echo early enough, and it's
  500. 00:18:01
    interesting, as I learned on the
  501. 00:18:03
    outside of the Opio world, no one does
  502. 00:18:04
    echoes that early, 'cause no one wants
  503. 00:18:06
    to find a low EF, because who wants
  504. 00:18:08
    that heart? So, you know, that's sort
  505. 00:18:09
    of an aside. Right, right. They're
  506. 00:18:11
    sort of interesting, you know, like,
  507. 00:18:12
    oh, the echoes we do are fine. Well,
  508. 00:18:14
    that's 'cause you do them a day or two
  509. 00:18:15
    later So we did it early and then we
  510. 00:18:17
    gave T3 or T4 in a random manner in a
  511. 00:18:21
    small study, admittedly. And then we
  512. 00:18:23
    measured actors again in eight hours
  513. 00:18:24
    after intravenous infusion of both drugs.
  514. 00:18:27
    And we showed no greater rise in the EF.
  515. 00:18:29
    What was most interesting is the EF went
  516. 00:18:30
    up in both groups. So there is
  517. 00:18:32
    reversibility even over eight hours,
  518. 00:18:34
    which to me again is very interesting.
  519. 00:18:35
    So, you know, there basically has
  520. 00:18:37
    several lines of reasoning based on use,
  521. 00:18:39
    the majority of OPOs are using T4, not
  522. 00:18:41
    T3, that randomized trials now showing
  523. 00:18:43
    the benefit of T3,
  524. 00:18:47
    You know, so that was the main reasons
  525. 00:18:49
    why ultimately we ended up doing the
  526. 00:18:52
    CyROTS and not T3 studied. Great. And
  527. 00:18:57
    from a sort of logistical standpoint, I
  528. 00:19:00
    imagine this was quite an undertaking.
  529. 00:19:02
    It sounds like you were maybe able to
  530. 00:19:05
    manage this through building this
  531. 00:19:07
    collaborative that you described
  532. 00:19:08
    previously with yearly meetings and
  533. 00:19:11
    things. How did you convince the OPOs
  534. 00:19:14
    to take part? Because I think a lot of
  535. 00:19:16
    neurointensists have experience working
  536. 00:19:18
    with OPOs and if anything, they're very
  537. 00:19:21
    committed to their policies and
  538. 00:19:23
    guidelines and it can be quite difficult
  539. 00:19:25
    to change some of these really strongly
  540. 00:19:28
    held beliefs about what's helpful for
  541. 00:19:30
    the brain dead donor. So yeah, how
  542. 00:19:32
    were you able to get them all to get
  543. 00:19:34
    buy-in? Yeah, that was a key point and
  544. 00:19:37
    it did take that kind of decade. It was
  545. 00:19:39
    a decade from when we started talking
  546. 00:19:40
    about the T4 study when we did it and
  547. 00:19:43
    even even though there were 15 LPOs and
  548. 00:19:45
    I'll.
  549. 00:19:46
    If anyone's interested, I'll point them
  550. 00:19:47
    to the supplement of the paper where we
  551. 00:19:49
    have a nice map of the US and these
  552. 00:19:51
    different OPOs that participated and I
  553. 00:19:53
    was really impressed and I certainly
  554. 00:19:56
    don't take all the credit for it of
  555. 00:19:57
    getting these OPOs on board and the
  556. 00:19:59
    geographic and
  557. 00:20:02
    diversity that we got in our study was
  558. 00:20:04
    nice, but it's still 15 out of over 50
  559. 00:20:06
    OPOs to your point. That means that
  560. 00:20:08
    other ones that we approached did not
  561. 00:20:09
    participate. So it kind of shows you
  562. 00:20:11
    that there are barriers, but I think
  563. 00:20:13
    they're starting to become more open,
  564. 00:20:15
    especially if you go from within and
  565. 00:20:17
    kind of my collaborator at Gary Marklin,
  566. 00:20:20
    who's the chief medical officer here at
  567. 00:20:21
    ROPO, was also on the medical
  568. 00:20:24
    director's board. So kind of talking
  569. 00:20:26
    face to face. So definitely without him
  570. 00:20:28
    and without kind of that community of
  571. 00:20:30
    trust that this is not, you know,
  572. 00:20:32
    we're just coming from the outside and
  573. 00:20:33
    saying, you need to change your
  574. 00:20:34
    practice. We like their role, which we
  575. 00:20:38
    can identify with, but I think they do
  576. 00:20:39
    it even better than we do is mission
  577. 00:20:40
    focused. As you said, it's just we
  578. 00:20:42
    want more organs. And so you have to
  579. 00:20:44
    turn that mission into what we need to
  580. 00:20:46
    do better science to demo organs. And I
  581. 00:20:48
    think we did convince many opiods of
  582. 00:20:50
    that, that there's a benefit to knowing
  583. 00:20:52
    if what you're doing is working, you
  584. 00:20:54
    know, it's not. But yeah, that was a
  585. 00:20:56
    learning process. We did these small
  586. 00:20:58
    studies. We did small collaborative
  587. 00:21:00
    studies. We actually did a four center
  588. 00:21:01
    randomized trial that to me was
  589. 00:21:04
    interesting. There was a trial of
  590. 00:21:05
    Narcan. Narcan interestingly in animal
  591. 00:21:07
    models reverses neurogenic pulmonary
  592. 00:21:10
    edema with herniation in sheep And so a
  593. 00:21:13
    lot of OPOs were used in Narcan. And I
  594. 00:21:15
    was like, why use a Narcan? And
  595. 00:21:16
    they're like, oh yeah, based on these
  596. 00:21:17
    sheep studies. And I'm not sure that's
  597. 00:21:19
    the best basis for human treatment. I
  598. 00:21:21
    mean, it's interesting. And so doing a
  599. 00:21:23
    pilot study with just four OPOs for me
  600. 00:21:25
    to learn, how do you get them on board?
  601. 00:21:27
    How do you randomize? And we did that
  602. 00:21:29
    study and showed. And a lot of zone has
  603. 00:21:30
    no benefit in lung function after brain
  604. 00:21:33
    death and humans. So
  605. 00:21:36
    that kind of track record, and then
  606. 00:21:37
    going back, I said, we've done the
  607. 00:21:38
    Narcan study. It worked. No one kind
  608. 00:21:40
    of freaked out.
  609. 00:21:43
    It was definitely a complex building of
  610. 00:21:45
    trust of the kind of scientific mission,
  611. 00:21:49
    I guess, and then the help of Gary
  612. 00:21:52
    Marklin and others in the community was
  613. 00:21:54
    really key. And then some OPOs still
  614. 00:21:57
    didn't. I mean, to your point, some
  615. 00:21:58
    really felt that thyroid hormone works
  616. 00:22:01
    and why would we want to randomize? So
  617. 00:22:02
    you had to find OPOs that had, I
  618. 00:22:05
    will say impressively also in the
  619. 00:22:06
    supplement, there's a nice table of all
  620. 00:22:08
    the OPOs and which ones we use in
  621. 00:22:09
    thyroid hormone, which ones we're doing,
  622. 00:22:11
    you know, high dose steroids, all that
  623. 00:22:13
    kind of stuff. And except for a few,
  624. 00:22:15
    they were all used in thyroid hormone.
  625. 00:22:16
    And so I really do give credit that 12
  626. 00:22:19
    out of 15 OPOs randomized donuts or no
  627. 00:22:21
    thyroid hormone, even though that was
  628. 00:22:22
    their protocol. So to your point, I
  629. 00:22:24
    mean, it is hard, but it's somehow
  630. 00:22:25
    possible to convince OPOs to try
  631. 00:22:27
    something different as long as it's,
  632. 00:22:28
    you know, and I'll add one thing to
  633. 00:22:31
    that. We had two safeguards, you know,
  634. 00:22:33
    so you have to build in safeguards for
  635. 00:22:34
    trials, not just for patient protection
  636. 00:22:37
    here, it's not patient protection, but
  637. 00:22:38
    we still felt there's an important
  638. 00:22:40
    Safety, both donor protection and
  639. 00:22:41
    recipient protection. So we had a DSMB,
  640. 00:22:44
    and we had the option, as maybe we'll
  641. 00:22:46
    briefly discuss, to have open-label
  642. 00:22:48
    rescue therapy with T4. And that was,
  643. 00:22:50
    again, based on your question, as we
  644. 00:22:52
    needed a way to convince Opio as well,
  645. 00:22:53
    yeah, this all goes down south, and
  646. 00:22:55
    the donor's unstable. And after 12
  647. 00:22:57
    hours, you can still give them thyroid
  648. 00:22:58
    hormone. So actually, that might have
  649. 00:23:00
    been the other part that we had to,
  650. 00:23:05
    you know, what's the word, accommodate
  651. 00:23:06
    or be flexible, you know, obviously to
  652. 00:23:08
    me, I would have preferred having a
  653. 00:23:09
    totally closed study and no open label
  654. 00:23:11
    and no blinded, we can talk about blind
  655. 00:23:13
    and that was very difficult, you know,
  656. 00:23:15
    so there was things we had to
  657. 00:23:16
    accommodate. I think hopefully they
  658. 00:23:18
    didn't really weaken the study too much,
  659. 00:23:20
    in my opinion, but they were things
  660. 00:23:22
    that were kind of compromises, I guess,
  661. 00:23:24
    to make the study feasible. Yeah. I
  662. 00:23:27
    think that's so smart and this iterative
  663. 00:23:29
    process you've gone through, I think,
  664. 00:23:32
    as an outsider looking in, it's just
  665. 00:23:34
    really impressive and I think culminates
  666. 00:23:36
    with, you know, a manuscript that
  667. 00:23:38
    really grabs attention. One thing that,
  668. 00:23:42
    again, as a neuro-intensityist who
  669. 00:23:44
    probably doesn't consider management of
  670. 00:23:47
    brain dead donors enough. One thing
  671. 00:23:49
    that I thought was interesting here is
  672. 00:23:52
    as you sort of build this case for
  673. 00:23:53
    equipoise is that there may actually be
  674. 00:23:56
    harms right from administering
  675. 00:23:59
    levothyroxine as opposed to just benefit
  676. 00:24:02
    or no benefit. And I think you'd shown
  677. 00:24:04
    that in one of your previous studies.
  678. 00:24:06
    So can you talk a little bit about those
  679. 00:24:09
    harms might be and why someone maybe
  680. 00:24:11
    doesn't even tolerate levothyroxine?
  681. 00:24:13
    Right, yeah, we definitely, and
  682. 00:24:14
    that's another benefit of the pilot
  683. 00:24:15
    studies. We really learned and modified
  684. 00:24:17
    our protocols to allow weaning of the
  685. 00:24:20
    drug, as I'll mention, and also just
  686. 00:24:21
    continuation and monitoring for adverse
  687. 00:24:24
    events because it became clear to us
  688. 00:24:26
    that, especially as you come off
  689. 00:24:28
    pressers, obviously when you're on
  690. 00:24:29
    pressers, hypertension is not so much
  691. 00:24:31
    of a problem. But as you stabilize the
  692. 00:24:32
    donor, which happens inevitably, to be
  693. 00:24:34
    honest without levothyroxine as we
  694. 00:24:36
    showed,
  695. 00:24:38
    then the risk of continuing the
  696. 00:24:39
    levothyroxine is just the blood pressure
  697. 00:24:41
    keeps going up. and the heart rate goes
  698. 00:24:42
    up. And in our pilot study, we, there
  699. 00:24:46
    was two pilot studies. One was the T3
  700. 00:24:47
    versus T4. One was just T4 versus
  701. 00:24:49
    placebo. The difference in the T4
  702. 00:24:51
    placebo, which was again, the more
  703. 00:24:53
    true comparison to this trial, was they
  704. 00:24:57
    didn't have to be unstable. They just
  705. 00:24:58
    had to have low EF. So those donors
  706. 00:25:01
    weren't hypotensive and we really found
  707. 00:25:02
    all of them became hypertensive. So
  708. 00:25:04
    that was really eye-opening that we
  709. 00:25:06
    needed to be careful. One, which we
  710. 00:25:08
    did, allow a protocol that allows you
  711. 00:25:10
    to titrate the drug, which, I mean,
  712. 00:25:12
    I'd make sense, but it wasn't like
  713. 00:25:14
    everyone has to run into this dose for
  714. 00:25:15
    all hours, regardless of blood pressure.
  715. 00:25:18
    And we can come back to that, actually
  716. 00:25:20
    did help, I think reduce serious
  717. 00:25:21
    adverse events. But we definitely saw a
  718. 00:25:23
    high incidence of hypertension,
  719. 00:25:24
    tethicardia. We were worried even about
  720. 00:25:26
    cardiac arrests. That's the last thing
  721. 00:25:28
    you want to obviously not donor. And so,
  722. 00:25:30
    yeah, no, there definitely can be harm
  723. 00:25:33
    from any treatment. And that's
  724. 00:25:34
    ultimately why we did it, is even if it
  725. 00:25:35
    doesn't work, some people may say,
  726. 00:25:38
    well, but maybe it helps a little bit,
  727. 00:25:39
    we can do it, but no, there's also a
  728. 00:25:40
    downside. things. And so that was
  729. 00:25:43
    definitely something we mounted with a
  730. 00:25:44
    DSMB, like I said, which is all, you
  731. 00:25:47
    know, all part of the learning for all
  732. 00:25:48
    of us interested in clinical research is
  733. 00:25:50
    like going through a study like this.
  734. 00:25:52
    It's just, you know, there's so many
  735. 00:25:53
    things you learn that are valuable
  736. 00:25:55
    regardless of the intervention. It
  737. 00:25:57
    could be Narcan, it could be
  738. 00:25:58
    Leviotharoxan, it could be steroids.
  739. 00:26:00
    But DSMB the, yeah was fascinating,
  740. 00:26:02
    putting that together,
  741. 00:26:03
    multi-disciplinary, you know, with an
  742. 00:26:05
    ethicist and a thoracic surgeon. But it
  743. 00:26:09
    was interesting, it was fun to be
  744. 00:26:10
    honest, to get their input, we also
  745. 00:26:12
    made changes based on what the thoracic
  746. 00:26:13
    surgeon said, what the ethicist said,
  747. 00:26:15
    you know, made sure you inform the
  748. 00:26:17
    transplant team. That's why it can be
  749. 00:26:19
    blinded, actually, because the
  750. 00:26:20
    transplant team turned out, wanted to
  751. 00:26:23
    know if the donor had received Levioth,
  752. 00:26:25
    we thought would want to know, in case
  753. 00:26:26
    they were not taking this heart because
  754. 00:26:28
    they didn't get Leviotharoxan, and then
  755. 00:26:29
    a heart could not be transformed. We
  756. 00:26:30
    wouldn't want to be responsible for that.
  757. 00:26:32
    So that was one of the reasons not only
  758. 00:26:34
    was it not blinded, but we actually
  759. 00:26:35
    posted in the transplant, there's a
  760. 00:26:38
    website, a registry that they look at,
  761. 00:26:41
    called DonorNet that all OPOs use. And
  762. 00:26:44
    we actually posted in the comments
  763. 00:26:45
    section, this donor is randomized to
  764. 00:26:46
    the study. They are receiving saline,
  765. 00:26:50
    et cetera. So that was all part of this
  766. 00:26:51
    ethics feedback that we went through.
  767. 00:26:53
    So yeah, there was a lot of learning
  768. 00:26:54
    that definitely I had to do to go
  769. 00:26:56
    through the study. Yeah, and I think
  770. 00:26:59
    these lessons really can generalize
  771. 00:27:01
    across neurocritical care. I don't
  772. 00:27:02
    think it might seem to listeners like
  773. 00:27:02
    we're
  774. 00:27:05
    piling on OPOs, but this is actually,
  775. 00:27:07
    we're all guilty of this is
  776. 00:27:08
    neuro-intensivist, right? We're very
  777. 00:27:09
    kind of wed to certain treatments that
  778. 00:27:11
    we've done historically with very little
  779. 00:27:13
    data supporting them. And I think we
  780. 00:27:16
    can learn lessons that from your
  781. 00:27:19
    experience with this, and hopefully
  782. 00:27:20
    maybe we can use those lessons to study
  783. 00:27:24
    things like, you know, management of
  784. 00:27:26
    DCI and sub-rocking and image, right,
  785. 00:27:28
    where we run into all these same biases.
  786. 00:27:32
    Maybe we can transition a little bit to
  787. 00:27:33
    getting to sort of the meat of this
  788. 00:27:35
    paper. So can you take us through,
  789. 00:27:39
    What patients are you actually
  790. 00:27:40
    interested in studying here? Or what
  791. 00:27:43
    donors, I guess he's a proper
  792. 00:27:45
    terminology, were you studying? So you
  793. 00:27:47
    mentioned previously, you had one paper,
  794. 00:27:49
    you looked at hypotensive patients,
  795. 00:27:51
    another one where you looked at patients
  796. 00:27:52
    low EF. What were the inclusion,
  797. 00:27:54
    exclusion criteria for this maintenance
  798. 00:27:56
    group? Sure, yeah, and we chose in
  799. 00:27:58
    this study, obviously brain dead donors,
  800. 00:28:01
    we weren't looking at, you know, DCD
  801. 00:28:02
    or anything like that. And we wanted it
  802. 00:28:04
    to be relatively close to brain death
  803. 00:28:05
    'cause that's another, you know,
  804. 00:28:07
    caveat 'cause they've obviously been
  805. 00:28:09
    doing treatment, you know, three days
  806. 00:28:10
    later, it might not really help the
  807. 00:28:11
    heart that's already going through the
  808. 00:28:13
    brain death process. So it had to be
  809. 00:28:15
    within 24 hours, although the median
  810. 00:28:16
    time was eight hours from declaration.
  811. 00:28:18
    So pretty quick, but yeah, importantly,
  812. 00:28:21
    they had to be heart eligible. So
  813. 00:28:22
    obviously if our outcome was
  814. 00:28:24
    transplantation of the heart, if you're,
  815. 00:28:26
    you know, 80 years old or you have
  816. 00:28:27
    heart disease, so that was a major
  817. 00:28:29
    exclusion. But we also, to your point,
  818. 00:28:32
    wanted to focus on the use case for T4,
  819. 00:28:35
    which predominantly, when we surveyed
  820. 00:28:37
    medical directors and opios
  821. 00:28:39
    as you said, human dynamic instability
  822. 00:28:41
    or low EF. And so that was really
  823. 00:28:43
    rather than going at every donor, like
  824. 00:28:45
    when we talked about this, obviously
  825. 00:28:47
    for many meetings, do we want to
  826. 00:28:48
    include an 80 year old donor who's
  827. 00:28:49
    unstable? Well, it might help with our
  828. 00:28:51
    instability question. It doesn't help
  829. 00:28:52
    with the heart question. We don't
  830. 00:28:53
    include, and we've decided
  831. 00:28:55
    pragmatically we didn't for the reasons
  832. 00:28:57
    I said, but also that we didn't want to
  833. 00:28:59
    just do it based on echo. Mainly for
  834. 00:29:01
    the reason that I mentioned earlier that
  835. 00:29:02
    we don't get echoes early enough. So it
  836. 00:29:04
    just wasn't pragmatic. You don't know.
  837. 00:29:06
    And thankfully from our prior study,
  838. 00:29:08
    like I mentioned, when we looked at
  839. 00:29:10
    human dynamic instability, that that is
  840. 00:29:12
    a pretty good surrogate for cardiac
  841. 00:29:16
    dysfunction or instability that we don't
  842. 00:29:19
    know what the average EF is in our study
  843. 00:29:21
    because we didn't have a baseline echo.
  844. 00:29:22
    That's certainly a fact. But based on
  845. 00:29:24
    our parallel data, we presume that it's
  846. 00:29:26
    a good surrogate, especially high dose
  847. 00:29:28
    pressers. And so we use that both based
  848. 00:29:31
    on the pragmatic equipoise question of
  849. 00:29:33
    when do people want to use T4 and also
  850. 00:29:36
    to kind of. enrich the population. I
  851. 00:29:37
    mean, and we did lose some people,
  852. 00:29:39
    obviously, who were stable, although I
  853. 00:29:40
    think it was maybe 25. I forget the
  854. 00:29:43
    numbers in the flowchart. But you know,
  855. 00:29:46
    there were some donors who are stable.
  856. 00:29:47
    And so we're like, well, maybe there's
  857. 00:29:49
    no active voice. No one would maybe use
  858. 00:29:51
    T4 in those donors. So why would we
  859. 00:29:52
    randomize them? So yeah, we focused on
  860. 00:29:54
    the unstable donors based on presser
  861. 00:29:56
    usage. And can you walk listeners
  862. 00:29:59
    through with what the actual
  863. 00:30:00
    intervention was? Yeah, so we chose,
  864. 00:30:04
    as I said, T4, Levotharots and
  865. 00:30:05
    intravenous. It's pretty accessible.
  866. 00:30:07
    Most OPOs have that. And most of them
  867. 00:30:10
    are using that, in fact. And we kind
  868. 00:30:11
    of surveyed the OPOs in the dose. And
  869. 00:30:13
    we decided on this dose of 30 micrograms
  870. 00:30:15
    an hour. OPOs use between 10 to 30
  871. 00:30:18
    micrograms as a bolus. They run an
  872. 00:30:20
    infusion, 10 to 30. And so we actually
  873. 00:30:22
    chose on a higher end. Again, with a
  874. 00:30:24
    slight caveat that we might see
  875. 00:30:26
    hypertension and tetrachartia, but we
  876. 00:30:27
    had a mechanism to adjust for that. But
  877. 00:30:30
    we didn't want to have it that we'd use
  878. 00:30:31
    a low dose. And then again, someone
  879. 00:30:33
    said, well, you just didn't give
  880. 00:30:34
    enough T4. So I think that was another
  881. 00:30:36
    discussion. And we ended up on this
  882. 00:30:38
    higher end of the spectrum of 30. And
  883. 00:30:42
    then we ran that for a minimum of 12
  884. 00:30:43
    hours. In our pilot study, it was
  885. 00:30:45
    eight hours. We kind of settled on 12
  886. 00:30:47
    hours with the option that certainly the
  887. 00:30:51
    OPOs did extended and half of them did
  888. 00:30:53
    all the way to ordering recovery,
  889. 00:30:55
    ordering procurement. But at the very
  890. 00:30:57
    minimum, it had to be 12 hours. And
  891. 00:30:58
    for those 12 hours, importantly, the
  892. 00:31:00
    sailing group could not cross over
  893. 00:31:04
    to T4 So that was the one caveat that
  894. 00:31:07
    even though we allowed that open label,
  895. 00:31:08
    later, as I mentioned, that was only
  896. 00:31:10
    after those 12 hours. And so we could
  897. 00:31:11
    at least do some endpoints at 12 hours,
  898. 00:31:13
    like press or reading, echo,
  899. 00:31:16
    without the kind of crossover issue.
  900. 00:31:20
    And so there were some patients then
  901. 00:31:22
    that, through the open label, we're
  902. 00:31:24
    allowed to cross over in the opposite
  903. 00:31:26
    direction from placebo, I guess, to
  904. 00:31:29
    levotharox, is that right? Right, for
  905. 00:31:31
    the reasons that we mentioned, mainly
  906. 00:31:32
    on the transplant side. we allowed that.
  907. 00:31:37
    And what we did was we discharged it,
  908. 00:31:39
    meaning we definitely didn't want it to
  909. 00:31:41
    be like your protocol should just be
  910. 00:31:42
    always to start it if even if the donor
  911. 00:31:44
    is unstable. And we collected and we
  912. 00:31:46
    forced collection of data on the reason
  913. 00:31:48
    you continued our crossover. And we
  914. 00:31:51
    thought it could be, you know,
  915. 00:31:52
    transplant requests, it could be, you
  916. 00:31:55
    know, whatever. But in fact, it was,
  917. 00:31:57
    and it's in the supplement somewhere,
  918. 00:31:58
    out of like, only 50, I think it was
  919. 00:32:01
    50, about 10 of the 400 and something
  920. 00:32:04
    donors who got placebo, crossed over.
  921. 00:32:06
    So a pretty small crossover rate. And
  922. 00:32:09
    out of those 50 donors, only three were
  923. 00:32:11
    due to transplant center request, which
  924. 00:32:12
    was super surprising. Like, we thought
  925. 00:32:14
    out the OPOs would say, no, no, the
  926. 00:32:16
    transplant center will force us to use
  927. 00:32:17
    T4. That wasn't the case. It actually
  928. 00:32:19
    was mainly the OPOs saying, well, they
  929. 00:32:22
    still got a low F. They still are on
  930. 00:32:23
    pressers. Yeah. So you're right.
  931. 00:32:25
    There was this crossover. And obviously
  932. 00:32:26
    we did, you know, sensitivity analysis
  933. 00:32:29
    and pro protocol analysis, all that
  934. 00:32:30
    kind of stuff. And I will say the
  935. 00:32:32
    statistics where. for our listeners. I
  936. 00:32:35
    mean, I went into the study thinking,
  937. 00:32:37
    you know, well, you know, I've done
  938. 00:32:38
    studies before. I might, you know,
  939. 00:32:40
    start with the statistics here, but
  940. 00:32:42
    definitely a lesson learned. If you're
  941. 00:32:44
    going to try to submit something to a
  942. 00:32:46
    high-level journal, do not try to do
  943. 00:32:47
    the statistics yourself. It got way too
  944. 00:32:50
    complicated very quickly, and I was
  945. 00:32:51
    very glad that WashU by statistics was
  946. 00:32:53
    able to help because they got really
  947. 00:32:56
    complicated. I mean, you know, not
  948. 00:32:57
    just this part, but other parts like
  949. 00:32:59
    imputation of missing values and all
  950. 00:33:01
    kinds of sensitivity analysis and
  951. 00:33:03
    subgroups. So that was sort of
  952. 00:33:05
    interesting to me. I was like, you
  953. 00:33:06
    know, I'm glad and I learned a lot of
  954. 00:33:07
    statistics in doing the study. So I'm
  955. 00:33:10
    glad I didn't do it myself. That's
  956. 00:33:12
    that's great advice. How did you choose
  957. 00:33:14
    your primary outcome? Yeah, I think
  958. 00:33:17
    based on those prior studies, you know,
  959. 00:33:19
    whether it's animal studies looking at
  960. 00:33:20
    the heart, that's just where the most
  961. 00:33:22
    rationale was. And when we talked to
  962. 00:33:23
    people, why do you do this? It could
  963. 00:33:26
    be the heart. It could be all thoracic
  964. 00:33:27
    organs, but really it was the heart
  965. 00:33:28
    that people cared about. Of course,
  966. 00:33:31
    there is the potential to improve all
  967. 00:33:32
    organs. just through improving the
  968. 00:33:34
    heart, honestly. And so we had a
  969. 00:33:35
    secondary outcome of thoracic organs and
  970. 00:33:38
    all organs, but we felt that, you know,
  971. 00:33:40
    the studies, the, you know,
  972. 00:33:41
    retrospective, the prospective had
  973. 00:33:43
    looked at vasopressors, which, you
  974. 00:33:45
    know, we looked at EF, which we looked
  975. 00:33:47
    at and heart. So really when we kind of
  976. 00:33:49
    surveyed, you know, it's not exactly
  977. 00:33:52
    like PCORI, it's not like patient
  978. 00:33:54
    outcomes, but it was sort of like OPO
  979. 00:33:55
    centered, you know, like what you guys
  980. 00:33:57
    really care about. And so we did a
  981. 00:33:59
    survey in a similar way you might deal
  982. 00:34:00
    with a patient centered outcome Okay.
  983. 00:34:04
    And maybe you can take us, what was
  984. 00:34:05
    your proposed effect size and maybe that
  985. 00:34:08
    can kind of segue into us, you know,
  986. 00:34:10
    how many patients actually did you end
  987. 00:34:11
    up enrolling in the trial? Sure. Yeah.
  988. 00:34:14
    And we based on our pilot studies,
  989. 00:34:15
    based on those other retrospective, we
  990. 00:34:17
    were like, well, what are people
  991. 00:34:19
    proposing? And it was as high as 20
  992. 00:34:20
    difference in the two groups, but I
  993. 00:34:23
    think, you know, we realized that's
  994. 00:34:24
    probably optimistic and we didn't want
  995. 00:34:25
    to, you know, power it so much because
  996. 00:34:27
    that would be a much smaller sample size.
  997. 00:34:29
    So we went with a 10 difference.
  998. 00:34:33
    of it that was sort of statistically
  999. 00:34:35
    interesting or from a trial methodology
  1000. 00:34:37
    was we proposed a superiority trial,
  1001. 00:34:40
    meaning in the end it didn't make a
  1002. 00:34:42
    massive difference to be honest, but it
  1003. 00:34:43
    was sort of you have to make your
  1004. 00:34:45
    hypothesis and I think that's the power
  1005. 00:34:48
    wise it wasn't a bit difference I guess,
  1006. 00:34:49
    but we said all we care about from the
  1007. 00:34:53
    parts transplant is does T4 result in
  1008. 00:34:55
    more hearts? We're not looking at like
  1009. 00:34:56
    less or more, you know, two-sided
  1010. 00:34:58
    hypothesis purely. So that was
  1011. 00:35:00
    interesting that we just looked at a
  1012. 00:35:01
    superiority of T4 and attempts and
  1013. 00:35:03
    effect size. And that gave us our
  1014. 00:35:05
    sample size of about 800 donors. And so
  1015. 00:35:08
    that was kind of what we started saying,
  1016. 00:35:09
    how many OPLs do we need? How many
  1017. 00:35:12
    years is this going to take? You know,
  1018. 00:35:13
    if it's going to take 15 years, like,
  1019. 00:35:15
    you know, like a carted dissection
  1020. 00:35:16
    trial and you're like, well, we
  1021. 00:35:17
    probably can't do this. So, you know,
  1022. 00:35:19
    so at least it was sort of feasible,
  1023. 00:35:20
    but we needed, you know, maybe 20 OPLs,
  1024. 00:35:23
    10 to 20. And that's eventually what we
  1025. 00:35:25
    got Great. Can you take us through your
  1026. 00:35:28
    main findings? Sure. So. because the
  1027. 00:35:31
    primary outcome was really heart's
  1028. 00:35:33
    transplanted, which again, the good
  1029. 00:35:34
    side from an methodology point of view
  1030. 00:35:36
    is you don't lose any primary outcome.
  1031. 00:35:38
    So even though I mentioned imputation
  1032. 00:35:39
    earlier, that was really for things
  1033. 00:35:41
    like echo finding that someone didn't
  1034. 00:35:42
    have an echo, which did happen. But
  1035. 00:35:44
    our primary outcome was really clean
  1036. 00:35:46
    that we obviously knew if the heart was
  1037. 00:35:47
    transplanted. And one thing we didn't
  1038. 00:35:49
    also mention so far is our second, our
  1039. 00:35:51
    co-primary outcome was did the heart
  1040. 00:35:53
    work in the recipient. And as a whole
  1041. 00:35:55
    discussion on that, that we may not
  1042. 00:35:56
    even go into, but it's sort of
  1043. 00:35:58
    interesting, if you're interested in
  1044. 00:35:59
    recipient outcomes, that we included
  1045. 00:36:02
    that for various reasons. And we also
  1046. 00:36:03
    made it a safety outcome. And there's
  1047. 00:36:05
    actually studies suggesting that if you
  1048. 00:36:08
    get thyroid hormone and it stopped,
  1049. 00:36:11
    because inevitably the donor goes
  1050. 00:36:13
    through recovery and then there's no
  1051. 00:36:14
    more thyroid hormone. And then the
  1052. 00:36:15
    recipient doesn't have that the heart
  1053. 00:36:17
    won't work as well. And so actually
  1054. 00:36:18
    there was a hypothesis that the outcome
  1055. 00:36:21
    could be inferior in the thyroid hormone
  1056. 00:36:23
    group. So there's sort of a whole line
  1057. 00:36:24
    of reasoning there. So we had these two
  1058. 00:36:26
    outcomes of recipient non-inferiority
  1059. 00:36:28
    and superiority of the heart.
  1060. 00:36:31
    But we had no missing data, and then
  1061. 00:36:33
    interestingly, we got our recipient
  1062. 00:36:35
    outcome data, which is a whole story
  1063. 00:36:36
    about how we got that, and we did that
  1064. 00:36:38
    through IRB, 'cause those are human
  1065. 00:36:39
    subjects, and we got it through a
  1066. 00:36:42
    request to a registry that collects all
  1067. 00:36:44
    recipient data called SRTR. But we were
  1068. 00:36:47
    like missing one data point. We had,
  1069. 00:36:49
    what was it? 443, no, 443 hearts
  1070. 00:36:52
    transplanted out of 838 donors in both
  1071. 00:36:56
    groups. So we said here, we wanna know
  1072. 00:36:57
    if these hearts worked, and we sent it
  1073. 00:36:59
    to SRTR, and they sent it back, and
  1074. 00:37:00
    they said, yeah, 30 days, this many
  1075. 00:37:01
    hearts worked. But we're missing one,
  1076. 00:37:03
    and we're like, what happened to this
  1077. 00:37:04
    one heart? It was sort of an
  1078. 00:37:06
    interesting, and I was like, okay, we
  1079. 00:37:07
    don't have one missing data point. And
  1080. 00:37:09
    then I was like, which OPO does this
  1081. 00:37:10
    come from? I came from Life Center
  1082. 00:37:12
    Northwest, which is in Seattle, and we
  1083. 00:37:14
    said, well, what happened to this
  1084. 00:37:15
    heart? Like how come, like, oh yeah,
  1085. 00:37:17
    that heart went to Canada. And so
  1086. 00:37:19
    obviously SRTR doesn't track that, but
  1087. 00:37:21
    they - International borders, huh?
  1088. 00:37:22
    Yeah, they called the hospital in
  1089. 00:37:25
    Canada and found out how the heart did.
  1090. 00:37:27
    So that was really neat that we actually
  1091. 00:37:29
    had no missing data for our heart
  1092. 00:37:30
    outcome. and for
  1093. 00:37:34
    the recipient outcome. So that rarely
  1094. 00:37:35
    happens in studies, I feel like, that
  1095. 00:37:35
    you have no missing data, but our
  1096. 00:37:37
    primary outcome was the hearts, and
  1097. 00:37:38
    that was equal in those groups, or was
  1098. 00:37:41
    not different in the two groups. Yeah.
  1099. 00:37:43
    And you all did some subgroup analysis
  1100. 00:37:45
    too, right? Where you looked at
  1101. 00:37:48
    patients specifically with low EF or
  1102. 00:37:49
    normally if they did have an echo, and
  1103. 00:37:52
    did you find any signals within those
  1104. 00:37:53
    subgroup analyses that maybe some
  1105. 00:37:56
    subpopulation benefited from the
  1106. 00:37:57
    intervention? Right, and yeah, we had
  1107. 00:38:00
    these two pre-specified, and we did
  1108. 00:38:01
    extra ones later based on the reviewers,
  1109. 00:38:03
    but definitely the most important one
  1110. 00:38:05
    was the low EF, 'cause we thought,
  1111. 00:38:06
    well, maybe it doesn't work in all
  1112. 00:38:08
    unstable, but it'll work in, and so
  1113. 00:38:11
    forget exactly what the percentages were,
  1114. 00:38:12
    but there was a significant percentage
  1115. 00:38:14
    that had low EF, and yeah, there was
  1116. 00:38:16
    no difference even in that subgroup
  1117. 00:38:18
    based on the echo findings of having low
  1118. 00:38:22
    EF. We also looked at early treatment
  1119. 00:38:23
    versus late treatment and other things
  1120. 00:38:26
    that we can discuss, but
  1121. 00:38:29
    yeah, Actually, that was, yeah,
  1122. 00:38:30
    actually now I remember. It actually
  1123. 00:38:32
    was sort of interesting, again,
  1124. 00:38:33
    because it was delayed at least 12 hours
  1125. 00:38:35
    of average. So again, it's not a super
  1126. 00:38:37
    early echo, but the frequency of a very
  1127. 00:38:40
    low EF, less than 50, was
  1128. 00:38:42
    actually lower than we anticipated. We
  1129. 00:38:44
    might have anticipated 20 to 40. It was
  1130. 00:38:46
    actually more like 10 to 20. So
  1131. 00:38:48
    actually one was not as common by that
  1132. 00:38:50
    time once you've given time. The art to
  1133. 00:38:52
    recover. So it's not as big a subgroup
  1134. 00:38:55
    as we thought, but even in that
  1135. 00:38:56
    subgroup, there was absolutely no. It
  1136. 00:38:58
    was like actually higher percentage of
  1137. 00:38:59
    hearts were transplanted in the normal
  1138. 00:39:01
    saline group than that T4 group. So we
  1139. 00:39:03
    really felt strongly that there was no
  1140. 00:39:05
    signal that even those hearts needed
  1141. 00:39:08
    levothyropsin. And you all measured
  1142. 00:39:11
    thyroid hormone levels in these donors,
  1143. 00:39:13
    right? And did the patients who were
  1144. 00:39:15
    deficient, did they seem to benefit
  1145. 00:39:16
    more? Right. And that we definitely
  1146. 00:39:19
    measured it and we had it for most, not
  1147. 00:39:20
    all. And as I said earlier, it was
  1148. 00:39:22
    interesting that only a minority, still
  1149. 00:39:25
    like 38 I think total were deficient.
  1150. 00:39:27
    So less than half were deficient, And
  1151. 00:39:30
    they were not that deficient. It was
  1152. 00:39:31
    just under the 08, 09 level of normal
  1153. 00:39:34
    for free T4 level. But even in that
  1154. 00:39:37
    subgroup, which was actually a
  1155. 00:39:38
    post-talk analysis, we didn't, for
  1156. 00:39:40
    whatever reason, pre-specified.
  1157. 00:39:41
    Another lesson learned is, you know,
  1158. 00:39:44
    you make your protocol and you have to
  1159. 00:39:45
    stick to it, obviously, when you
  1160. 00:39:46
    publish in a good journal. And so that
  1161. 00:39:48
    wasn't pre-specified. So that, we try
  1162. 00:39:50
    to sneak that into the main paper and
  1163. 00:39:52
    they said, no, it has to be in the
  1164. 00:39:52
    supplement. So if you go to supplement,
  1165. 00:39:54
    you'll see the low free T4. More high
  1166. 00:39:57
    free T4. But yes, there was no
  1167. 00:39:57
    difference in that And we also looked at
  1168. 00:39:59
    the vasopressor dose that we might talk
  1169. 00:40:01
    about. And even in, 'cause one of the
  1170. 00:40:03
    reviewers said, well, what about
  1171. 00:40:04
    donors who are really unstable? You
  1172. 00:40:06
    know, maybe they were unstable, right?
  1173. 00:40:08
    Really unstable. Exactly. And so we
  1174. 00:40:09
    looked at like higher vasopressor usage,
  1175. 00:40:12
    basically over 01 of Levo on average of
  1176. 00:40:16
    Norapie and we didn't find a benefit
  1177. 00:40:18
    even those very unstable donors. So
  1178. 00:40:20
    essentially we didn't find any subgroup,
  1179. 00:40:22
    obviously with all the caveats of
  1180. 00:40:24
    subgroup analysis that Levo Tharatson
  1181. 00:40:25
    had to benefit in Yeah, and we're
  1182. 00:40:29
    learning. improvement in intermediate
  1183. 00:40:31
    outcomes, like the vasopressor dose.
  1184. 00:40:33
    Yeah, and that was, you know, the
  1185. 00:40:35
    other funny thing was our primary
  1186. 00:40:38
    outcome for many reasons was the heart
  1187. 00:40:39
    transplanted for the reasons that it's
  1188. 00:40:41
    more recipient centered or whatever,
  1189. 00:40:43
    you know, it's more meaningful. But
  1190. 00:40:46
    people said, well, you know, we may
  1191. 00:40:47
    or may not show a difference, but we
  1192. 00:40:49
    definitely want to look at vasopressors
  1193. 00:40:50
    because, you know, there's a strong
  1194. 00:40:53
    rationale. And even if we don't show
  1195. 00:40:55
    this, maybe we'll show that secondary
  1196. 00:40:57
    outcome and maybe we'll still use T4 And
  1197. 00:41:00
    every single person who felt that was
  1198. 00:41:02
    100 committed to that being the benefit.
  1199. 00:41:03
    Even if the arts weren't better than we
  1200. 00:41:05
    actually showed, which was, you know,
  1201. 00:41:07
    I honestly didn't know where I stood. I
  1202. 00:41:08
    was pretty much an equipoise on that one.
  1203. 00:41:10
    I, you know, people tell me they start
  1204. 00:41:12
    T4 and the pressor's dose comes down.
  1205. 00:41:14
    And so it just goes to the fact that yes,
  1206. 00:41:17
    these practices that we all do, you
  1207. 00:41:19
    know, that we're like, yeah, it
  1208. 00:41:20
    definitely works when we do whatever for,
  1209. 00:41:22
    you know, you know, cerebral edema or
  1210. 00:41:24
    something, it had no difference. I
  1211. 00:41:27
    mean, the pressor's impressively came
  1212. 00:41:28
    down by half in 12 hours in both groups.
  1213. 00:41:30
    And the other group was getting placebo.
  1214. 00:41:32
    I mean, they got saline. So it was my,
  1215. 00:41:34
    they were getting some other treatment.
  1216. 00:41:37
    So yeah, there was actually no
  1217. 00:41:38
    improvement in vasopressor weaning. And
  1218. 00:41:40
    then of those that got echoes, which
  1219. 00:41:42
    was a majority, not everyone, I think
  1220. 00:41:44
    it was like 90 or 85. There was
  1221. 00:41:47
    absolutely no difference in the EF of
  1222. 00:41:49
    those echoes. So those were the two
  1223. 00:41:51
    main secondary outcomes. And really we
  1224. 00:41:53
    had no, and there was just no signal.
  1225. 00:41:56
    I mean, it was a little surprising like
  1226. 00:41:57
    how maybe we'd see no primary outcome,
  1227. 00:42:00
    but yeah, but it might be the echo
  1228. 00:42:01
    slightly better, but it really wasn't.
  1229. 00:42:04
    No, I think it's almost, we poured
  1230. 00:42:05
    through the supplement data, looking
  1231. 00:42:06
    for this signal, and it's just not
  1232. 00:42:08
    there in your data at all. And I think
  1233. 00:42:09
    it's fascinating. And I think for the
  1234. 00:42:12
    first time, it helped me understand
  1235. 00:42:15
    what is the natural history of the brain
  1236. 00:42:17
    dead donor, right? And we don't know
  1237. 00:42:19
    that through all of our anecdotal
  1238. 00:42:23
    experience So this is, I think, for me,
  1239. 00:42:25
    a really impactful study.
  1240. 00:42:28
    Again, I'm just so appreciative that
  1241. 00:42:30
    it's out there. Kind of wrapping it up,
  1242. 00:42:34
    you know, what effect has this study
  1243. 00:42:35
    had on maybe your own practice or the
  1244. 00:42:39
    OPLs in your region? Right, yeah, no,
  1245. 00:42:42
    that was the first step, was like,
  1246. 00:42:44
    okay, now we've done this and kind of
  1247. 00:42:45
    take a deep breath, present it to the
  1248. 00:42:47
    OPLs that participated and many were
  1249. 00:42:49
    surprised. I mean, you know, that we
  1250. 00:42:52
    expected, we weren't so surprised
  1251. 00:42:54
    because actually our OPL would stop
  1252. 00:42:55
    using T4, it was one of the three that
  1253. 00:42:56
    wasn't using it for a few years prior.
  1254. 00:42:59
    And so, you know, that's sort of a
  1255. 00:43:00
    retrospective study, like, oh, we
  1256. 00:43:02
    stopped using them, our donors are
  1257. 00:43:03
    doing fine. But so we continued to
  1258. 00:43:06
    change our practice and not use it. And
  1259. 00:43:08
    then a few other OPLs immediately
  1260. 00:43:09
    changed. A few other OPLs,
  1261. 00:43:11
    interestingly said, let's wait for the
  1262. 00:43:13
    publication. You know, we see the data,
  1263. 00:43:15
    but we want it to be published. I mean,
  1264. 00:43:16
    it's the same data, but I guess it's a
  1265. 00:43:18
    foreign article, but it's on paper, I
  1266. 00:43:19
    guess. And then they changed. Some
  1267. 00:43:22
    said we got to go through our medical
  1268. 00:43:23
    advisory board, which is fine And so,
  1269. 00:43:25
    yeah, so generally - I would say the
  1270. 00:43:27
    participating OPOs have been very
  1271. 00:43:29
    receptive and we present them
  1272. 00:43:30
    individually to their groups, to the,
  1273. 00:43:30
    I presented at
  1274. 00:43:34
    the OPO national meeting last summer,
  1275. 00:43:36
    before the publication even. I
  1276. 00:43:38
    presented to the transplant community at
  1277. 00:43:39
    their national meeting, both in
  1278. 00:43:43
    platform sessions and got good feedback,
  1279. 00:43:45
    especially from the OPOs actually. The
  1280. 00:43:46
    transplant community was like, okay,
  1281. 00:43:48
    that's fine, whatever the
  1282. 00:43:51
    OPOs wanna do. Even though the OPOs say
  1283. 00:43:52
    it's whatever the transplant centers
  1284. 00:43:53
    wanna do, the transplant centers were
  1285. 00:43:55
    kind of like, we don't mind, like if
  1286. 00:43:56
    you show us it doesn't work, we won't
  1287. 00:43:58
    force it, which was good. And the OPOs
  1288. 00:44:01
    were really impressed in the fact that
  1289. 00:44:04
    we could do this kind of science, I
  1290. 00:44:05
    would say. And I think they'll also
  1291. 00:44:07
    feed into future studies, I hope, that
  1292. 00:44:08
    they'll be like, okay, this is, can
  1293. 00:44:11
    be in factful to our community. And so,
  1294. 00:44:13
    finally, yeah, I don't know if all
  1295. 00:44:15
    have changed yet, I would say, and
  1296. 00:44:16
    that's something we actually plan to do
  1297. 00:44:18
    a follow up survey, you know, to see
  1298. 00:44:20
    like, like one thing I'm not an expert
  1299. 00:44:22
    in, but I'd certainly love to hear
  1300. 00:44:23
    people's feedback like the Semination
  1301. 00:44:25
    Science implementation. Uh, that's a
  1302. 00:44:28
    whole challenge in changing a four
  1303. 00:44:30
    decade old practice. I really think
  1304. 00:44:32
    this is very interesting. How does a
  1305. 00:44:34
    definitive study, you know, that any
  1306. 00:44:36
    one can look at in public, in
  1307. 00:44:37
    publication, does it change your
  1308. 00:44:39
    practice? And I'm very interested in
  1309. 00:44:40
    the year's time when we survey these
  1310. 00:44:42
    OPOs. So my, my anecdotal sense is
  1311. 00:44:44
    many have changed, but not all. And
  1312. 00:44:46
    I'd love to see how we can implement it
  1313. 00:44:48
    better, you know, disseminate the
  1314. 00:44:50
    paper, disseminate, you know, talks,
  1315. 00:44:51
    I don't know. But yeah, I think it'll
  1316. 00:44:54
    be really interesting to see how OPO
  1317. 00:44:56
    practice changes as a kind of a case
  1318. 00:44:57
    study in that. Great. Well, I think
  1319. 00:45:00
    you really provided sort of definitive
  1320. 00:45:01
    evidence in this area. You mentioned
  1321. 00:45:03
    that this wasn't the first
  1322. 00:45:06
    kind of area of neural hormonal
  1323. 00:45:09
    physiology you looked at in brain dead
  1324. 00:45:10
    donors.
  1325. 00:45:13
    Where do we stand with corticosteroids?
  1326. 00:45:15
    Where do we stand with other treatments
  1327. 00:45:17
    and is that something that you're
  1328. 00:45:18
    interested in looking into? Yeah. Yeah,
  1329. 00:45:21
    I mean, I think right now it's sort of
  1330. 00:45:22
    a hodgepodge based on the kind of
  1331. 00:45:23
    retrospective studies. We have the low
  1332. 00:45:25
    dose, OPOs.
  1333. 00:45:27
    that were maybe half, I forget, in our
  1334. 00:45:29
    15. And then high dose is still out
  1335. 00:45:31
    there. And so, yeah, we're actively
  1336. 00:45:34
    thinking and thinking of actually some
  1337. 00:45:35
    new methodologies. There's a lot of
  1338. 00:45:37
    clinical trial methodologies out there,
  1339. 00:45:39
    like cluster randomized studies, et
  1340. 00:45:40
    cetera, that you can do to really
  1341. 00:45:42
    answer the steroid question more
  1342. 00:45:43
    definitively. So that is something
  1343. 00:45:45
    we're thinking about. And then, I
  1344. 00:45:47
    think other questions are like, can we
  1345. 00:45:49
    improve the heart with vasopressus
  1346. 00:45:51
    bearing approaches? Like, we always
  1347. 00:45:53
    think in our tachosubo patients, or at
  1348. 00:45:56
    least some do, or at times, our
  1349. 00:45:58
    presser's actually hurting the patient,
  1350. 00:45:59
    since it's catacolumimmediate damage to
  1351. 00:46:01
    the heart. So that's another question
  1352. 00:46:03
    we're interested in, is like, can we
  1353. 00:46:04
    actually do things that promote the
  1354. 00:46:06
    heart to get better if thyroid hormone
  1355. 00:46:08
    is not doing it, what can do it? So,
  1356. 00:46:10
    yeah, I think there's definitely future
  1357. 00:46:11
    studies that the OPOs are open to now.
  1358. 00:46:14
    And I think, for my point of view,
  1359. 00:46:15
    selfish, I don't wanna lose that
  1360. 00:46:16
    momentum, I guess. I mean, I'm taking
  1361. 00:46:18
    a year off at least. I was like, once
  1362. 00:46:20
    it got published, I'm like, I'm taking
  1363. 00:46:21
    a year sabbatical from any research,
  1364. 00:46:23
    clinical research.
  1365. 00:46:26
    I mean, happy, but tired after putting
  1366. 00:46:27
    all this together for like two, three
  1367. 00:46:29
    years. So it was a two year trial, one
  1368. 00:46:30
    year publication. So those three years
  1369. 00:46:33
    were very busy. And that's fair. I
  1370. 00:46:35
    think I interesting to get your thoughts
  1371. 00:46:37
    on this. So some of my friends and
  1372. 00:46:40
    colleagues around the country and
  1373. 00:46:42
    looking at these data have said, well,
  1374. 00:46:44
    you mentioned this issue of timing,
  1375. 00:46:46
    right? And
  1376. 00:46:48
    I think clearly brain death doesn't
  1377. 00:46:51
    happen at the moment of declaration And
  1378. 00:46:53
    perhaps sometimes there's a long delay
  1379. 00:46:56
    between when we suspect maybe cerebral
  1380. 00:46:59
    herniation to occur in brain death and
  1381. 00:47:01
    then when the declaration occurs. And
  1382. 00:47:03
    for that reason, some of my colleagues
  1383. 00:47:06
    will start some of these therapies
  1384. 00:47:07
    before declaration, which they think
  1385. 00:47:10
    might be good for stabilizing the
  1386. 00:47:11
    patient through apnea testing, et
  1387. 00:47:13
    cetera. And what do you think about
  1388. 00:47:15
    that practice? And do you see that as a
  1389. 00:47:18
    limitation to your data? Or do you
  1390. 00:47:22
    think differently about it? I do get
  1391. 00:47:24
    that and I think that's sort of the
  1392. 00:47:26
    limitation of donor research as it has
  1393. 00:47:28
    to be by definition in the donor once
  1394. 00:47:29
    they've declared. I think as a
  1395. 00:47:31
    neurointensivist, yeah, I agree that
  1396. 00:47:33
    there's questions about her nation
  1397. 00:47:36
    management that this study doesn't
  1398. 00:47:38
    answer, I guess. I would say I don't
  1399. 00:47:40
    know whether these interventions would
  1400. 00:47:42
    help. I sort of doubt it, but I
  1401. 00:47:44
    certainly, that's just my own
  1402. 00:47:45
    speculation, like anyone else's
  1403. 00:47:46
    speculation. I don't have good data on
  1404. 00:47:50
    that I think what I would say, though,
  1405. 00:47:52
    is this study was challenging but
  1406. 00:47:54
    feasible. Those kind of studies are way
  1407. 00:47:56
    harder to do in a hernium patient with
  1408. 00:47:58
    consent and with these kind of issues.
  1409. 00:48:00
    We got authorization for research from
  1410. 00:48:02
    families, but not consent. And there
  1411. 00:48:04
    was less IRB issues, I would say,
  1412. 00:48:07
    there's still IRB issues. So I think
  1413. 00:48:09
    that would be fascinating to do and
  1414. 00:48:11
    think about, I don't think there's, I
  1415. 00:48:13
    wouldn't do it myself, but I do see the
  1416. 00:48:16
    rationale or the, you know, Yeah, I
  1417. 00:48:20
    don't think our study answers that
  1418. 00:48:21
    question. I don't know if that word
  1419. 00:48:22
    home is the answer. Maybe it's, you
  1420. 00:48:24
    know, change in pressers. Personally,
  1421. 00:48:27
    I think the idea based on some very
  1422. 00:48:29
    small studies, but it's just my own
  1423. 00:48:30
    feeling is beta blockade and herniation
  1424. 00:48:31
    makes a lot of sense. Like we've talked,
  1425. 00:48:33
    you know, I'm sure you're aware in the
  1426. 00:48:34
    early type of subo studies having stuff
  1427. 00:48:37
    out there a little bit. If we could do
  1428. 00:48:38
    that study, I've been thinking about
  1429. 00:48:39
    for years, but realistically to this
  1430. 00:48:41
    audience, like, could we do that study?
  1431. 00:48:43
    Like, I'd love to do that. But how
  1432. 00:48:45
    would you randomize people who are
  1433. 00:48:47
    herniating to a aggressive IV
  1434. 00:48:48
    intervention? You know, if we could do
  1435. 00:48:51
    it, I mean, I'd be all forward. Let's
  1436. 00:48:52
    get the community together, and that
  1437. 00:48:55
    would be the intervention I would be
  1438. 00:48:56
    interested in personally. Yeah, and
  1439. 00:48:58
    there's huge ethical considerations
  1440. 00:49:00
    before declaration, which I don't know
  1441. 00:49:02
    how you would possibly work around
  1442. 00:49:04
    during getting through an ARB. So this
  1443. 00:49:06
    kind of approach with some limitations
  1444. 00:49:09
    is just so much more feasible. And the
  1445. 00:49:11
    Opio community, like I said, there are
  1446. 00:49:13
    issues that everyone in the near ICU
  1447. 00:49:15
    probably is aware of, But it's getting
  1448. 00:49:17
    better at number one and two. This has
  1449. 00:49:19
    really opened the door, I think, to
  1450. 00:49:20
    research. So if there's more people
  1451. 00:49:21
    interested out there, the community, I
  1452. 00:49:24
    think, is open to that. And let me
  1453. 00:49:25
    know, or let your OPO know.
  1454. 00:49:29
    And they're open to collaboration. So
  1455. 00:49:30
    it's not a closed door, maybe, like it
  1456. 00:49:32
    once was. Yeah. Well, Raj, thanks so
  1457. 00:49:36
    much for joining us. This is such a
  1458. 00:49:38
    cool story that unfolded over a decade,
  1459. 00:49:43
    it sounds like, or longer.
  1460. 00:49:46
    What are some lessons that you can share
  1461. 00:49:48
    with listeners who maybe they're not
  1462. 00:49:50
    interested in bringing up donors, but
  1463. 00:49:51
    there's something that they're seeing in
  1464. 00:49:53
    practice that interests them or
  1465. 00:49:56
    frustrates them and they want to solve a
  1466. 00:49:58
    clinical problem. How do they get it
  1467. 00:50:00
    from that kind of something I see on
  1468. 00:50:03
    rounds type of thing to what you've done
  1469. 00:50:05
    and putting out really what I consider
  1470. 00:50:07
    sort of a definitive trial in the New
  1471. 00:50:09
    England Journal? Yeah, no, I think
  1472. 00:50:11
    we've outlined some of the journey and I
  1473. 00:50:13
    think that's certainly taking those
  1474. 00:50:14
    steps and having the persistence and
  1475. 00:50:16
    making connections. of other interested
  1476. 00:50:19
    parties in that area, whether it be
  1477. 00:50:21
    through a sub-wracking hemorrhage
  1478. 00:50:22
    conference or a focused brain death
  1479. 00:50:25
    thing or whatever area it might be. And
  1480. 00:50:27
    I'm sure people are doing that where you
  1481. 00:50:28
    meet people and you talk and you, but
  1482. 00:50:30
    take that to the next level and say,
  1483. 00:50:31
    hey, could we do a study one day? What
  1484. 00:50:33
    does that take? And then the planning
  1485. 00:50:35
    of the study is we've also alluded to,
  1486. 00:50:37
    definitely be very deliberative about
  1487. 00:50:40
    doing the, personally, and I think the
  1488. 00:50:43
    study's a perfect example, I'm maybe
  1489. 00:50:44
    biased, is that what we need to do in
  1490. 00:50:46
    neurofritical care I know it's not easy
  1491. 00:50:48
    and that will be my plug to take away,
  1492. 00:50:50
    if we have junior people and even
  1493. 00:50:52
    mid-career and senior people, I think
  1494. 00:50:54
    we need to do more of this in our field
  1495. 00:50:55
    and we're not doing enough of it. I
  1496. 00:50:56
    know it's challenging, but I think it
  1497. 00:51:00
    takes commitment and we've had an OPO
  1498. 00:51:01
    commitment here, which made a big
  1499. 00:51:02
    difference. Also, one thing we didn't
  1500. 00:51:03
    mention is the study was not funded,
  1501. 00:51:05
    which I'll say as an aside, the New
  1502. 00:51:07
    England Journal reviewers could not
  1503. 00:51:09
    believe, 'cause if you look at every
  1504. 00:51:10
    paper there, it's like funded by Novar
  1505. 00:51:11
    Nord, it's funded by this, and I'm
  1506. 00:51:13
    like, Who wrote the paper for you? Who
  1507. 00:51:15
    did this? And I was like, No, no one
  1508. 00:51:16
    did this just like us and two other
  1509. 00:51:17
    people. You know, so that's an
  1510. 00:51:18
    interesting aside for the journal. But
  1511. 00:51:21
    obviously if you can get funding,
  1512. 00:51:22
    that's a helpful thing. But definitely
  1513. 00:51:24
    the planning and taking it through. But
  1514. 00:51:26
    I do think we need to do these kind of
  1515. 00:51:27
    trials. So it's like having young
  1516. 00:51:28
    people who can get together, I think,
  1517. 00:51:31
    and join whether it's an NCS community
  1518. 00:51:33
    of sites or you make your own community
  1519. 00:51:35
    of sites, I don't know. But yes, plan,
  1520. 00:51:39
    I mean, I learned a lot, like I've
  1521. 00:51:40
    said in this thing about getting the
  1522. 00:51:42
    sites together, training them, getting
  1523. 00:51:44
    the data forms together, you know,
  1524. 00:51:46
    putting the IRB together You know,
  1525. 00:51:47
    there's so many steps, but I think
  1526. 00:51:49
    there's senior people who can help you
  1527. 00:51:50
    with that. You know, I'm obviously
  1528. 00:51:52
    happy to help there's others who have
  1529. 00:51:53
    done clinical trials. But yes, taking
  1530. 00:51:55
    an idea to a trial is I think so
  1531. 00:51:58
    important in our field and we don't do
  1532. 00:51:59
    it enough. So I would definitely
  1533. 00:52:00
    encourage people to just be persistent,
  1534. 00:52:03
    it might take a long time. You get the
  1535. 00:52:05
    buying of the community, leaders in the
  1536. 00:52:07
    community, like in my case, I was able
  1537. 00:52:09
    to do, and you know, whatever stage
  1538. 00:52:12
    you're at, if you show interest, like
  1539. 00:52:13
    I did, and some kind of leadership
  1540. 00:52:16
    almost, I'll do this, I'll do the work.
  1541. 00:52:18
    you know, people will follow you, I
  1542. 00:52:19
    guess. I mean, it wasn't through
  1543. 00:52:21
    expertise that I did this. It was just
  1544. 00:52:23
    honestly through hard work. And so I
  1545. 00:52:26
    think a lot of people out there have
  1546. 00:52:27
    that. And I think that's the future of
  1547. 00:52:29
    our field. If we can do more of this in
  1548. 00:52:31
    our field and have papers like this come
  1549. 00:52:33
    out and all these areas that I'm sure
  1550. 00:52:35
    you're aware of and the readers, but
  1551. 00:52:37
    it's a challenge. And we need to maybe
  1552. 00:52:38
    at the NCS level make ways to facilitate
  1553. 00:52:40
    that. And I know think there are ways
  1554. 00:52:42
    that they're working on. And so I'm
  1555. 00:52:45
    happy to help from my experience But I
  1556. 00:52:47
    learned a lot in this. And so
  1557. 00:52:49
    definitely it's a wonderful learning
  1558. 00:52:51
    experience, regardless of the specific
  1559. 00:52:52
    study you're doing. I think it's been
  1560. 00:52:54
    an amazing
  1561. 00:52:57
    side job. It's really, I have my
  1562. 00:52:58
    separate primary research in living
  1563. 00:53:00
    patients. So this was actually just
  1564. 00:53:02
    like, again, a volunteer position.
  1565. 00:53:04
    But it's not the worst volunteer thing
  1566. 00:53:06
    to do if you have a nice product at the
  1567. 00:53:08
    end that makes a difference for whatever
  1568. 00:53:10
    aspect of clinical medicine. I think
  1569. 00:53:11
    that is really satisfying. So I would
  1570. 00:53:13
    encourage people to do that Well, I
  1571. 00:53:16
    think that you've. clearly sort of
  1572. 00:53:18
    paved the way for others to see how to
  1573. 00:53:21
    do this type of work. And time and time
  1574. 00:53:23
    again, we sort of think of these pipe
  1575. 00:53:26
    dream research ideas that, oh, if only
  1576. 00:53:28
    we could get people together and solve
  1577. 00:53:29
    this really pragmatic question that
  1578. 00:53:31
    we've all been wondering about, but we
  1579. 00:53:33
    lack the collaboration to get done. And
  1580. 00:53:36
    you've done that in one important area.
  1581. 00:53:36
    I would ask you
  1582. 00:53:41
    maybe one day to think about putting on
  1583. 00:53:43
    a workshop at NCS on sort of the skills
  1584. 00:53:46
    needed to do this, because it strikes
  1585. 00:53:47
    me that a lot of them might be sort of
  1586. 00:53:50
    technical skills, but it's a lot of
  1587. 00:53:51
    non-technical skills. It's a lot of
  1588. 00:53:53
    consensus building and collaboration.
  1589. 00:53:55
    And I'm sure you had a pretty nice
  1590. 00:53:58
    elevator pitch for these OPOs just to
  1591. 00:54:01
    get your head in their office and get
  1592. 00:54:04
    them to respond to your emails. And I
  1593. 00:54:06
    think those things are so important.
  1594. 00:54:07
    And we don't really teach that very well.
  1595. 00:54:10
    And I think a lot of us fail at that
  1596. 00:54:11
    step So, from an educator, I would.
  1597. 00:54:16
    ask you maybe if you could share those
  1598. 00:54:17
    lessons with us at NCS one day. Yeah,
  1599. 00:54:20
    and I appreciate your interest and
  1600. 00:54:22
    hopefully the audience too. This area
  1601. 00:54:24
    is not, we don't always think about it,
  1602. 00:54:25
    but I appreciate you reaching out and
  1603. 00:54:27
    kind of talking through this with me.
  1604. 00:54:30
    All right, well, congratulations again
  1605. 00:54:31
    on a really wonderful paper. And we're
  1606. 00:54:35
    so lucky to have you talk through it
  1607. 00:54:36
    here on the podcast. This is the
  1608. 00:54:38
    Neurocrular Care Society podcast. We
  1609. 00:54:40
    are available anywhere you get your
  1610. 00:54:42
    podcasts and continuing medical
  1611. 00:54:44
    education credits are available for
  1612. 00:54:46
    select episodes. Dr. Raj Darr, thanks
  1613. 00:54:49
    so much for joining us and can't wait to
  1614. 00:54:52
    see what comes next in your search to
  1615. 00:54:56
    stabilize the brain dead donor.