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Live at Annual Episode 3: Clinical Trials - Early Drain with Dr Stefan Wolf

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Description

Aneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage had not been evaluated prospectively in a randomized controlled trial until Dr Stefan Wolf and his colleagues at Charité – Universitätsmedizin in Berlin conducted their study. Dr Wolf joins Dr Nick Morris to discuss the study's results.

Contributors

  • Stefan Wolf, MD

    Neurosurgery, Charité Universitätsmedizin Berlin

  • 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. 00:00:19
    Hi, this is Nick Morris for Live at
  2. 00:00:21
    Annual, our neuro critical care podcast.
  3. 00:00:23
    We're exploring the latest sessions from
  4. 00:00:25
    the annual neuro critical care meeting.
  5. 00:00:27
    We've just finished the clinical trial
  6. 00:00:29
    session. I'm here with Dr. Stefan Wolf
  7. 00:00:31
    from Cherry Today Hospital in Berlin.
  8. 00:00:34
    He is a neurosurgeon and neuro
  9. 00:00:35
    intensivist and PI on the early drain
  10. 00:00:38
    trial, which he just described for all
  11. 00:00:40
    of us. And Stefan, welcome to the
  12. 00:00:42
    podcast and please for the listeners who
  13. 00:00:44
    couldn't make it to the session today
  14. 00:00:46
    Would you give a summary of why you did
  15. 00:00:47
    the trial and what you found? Yes.
  16. 00:00:51
    Hello, everybody. This is Stefan from
  17. 00:00:54
    Schoritie University in Berlin speaking.
  18. 00:00:57
    Well, I just presented results of our
  19. 00:01:00
    early drain trial. This was actually
  20. 00:01:03
    stipulated by work from a US physician
  21. 00:01:06
    Paul Klimo from Salt Lake City who
  22. 00:01:09
    presented on lumber drains in separate
  23. 00:01:12
    hemorrhage patients in 2004 in the
  24. 00:01:14
    Journal of new surgery and showing that
  25. 00:01:16
    these patients were. grown to have a
  26. 00:01:18
    way better outcome looking
  27. 00:01:20
    retrospectively. And so there was
  28. 00:01:22
    lacking evidence for prospective trials
  29. 00:01:24
    for the reason why we conceived the
  30. 00:01:26
    early-trained thing.
  31. 00:01:29
    Basically, what we did is taking
  32. 00:01:31
    separate energy patients of all severity
  33. 00:01:33
    crates and randomizing after aneurysine
  34. 00:01:37
    treatment,
  35. 00:01:39
    randomizing whether they should receive
  36. 00:01:40
    a lumber train for lumber, so we
  37. 00:01:43
    respond with fluid drainage of 5
  38. 00:01:44
    milliliters per hour for the first week
  39. 00:01:46
    or not. The idea would be that the
  40. 00:01:49
    blood gets better out from a lumber
  41. 00:01:51
    drain than the EVD, because, well,
  42. 00:01:54
    you know, blood
  43. 00:01:56
    is - berythrocytes have some weight.
  44. 00:01:58
    They tend to sediment by weight. They
  45. 00:01:59
    get down in the basal systems, but the
  46. 00:02:01
    load is located in the separate image
  47. 00:02:04
    patients, and the lumber road seems to
  48. 00:02:06
    be more better to get this out. This
  49. 00:02:08
    was a physiology behind that, and we
  50. 00:02:10
    were able to show that this was to be
  51. 00:02:13
    done safely It didn't have a high
  52. 00:02:15
    complication rate, it was actually
  53. 00:02:17
    lower. in standard of care having an
  54. 00:02:20
    EVD as required or no EVDF, not
  55. 00:02:23
    required. And yeah, we were able to
  56. 00:02:27
    show that it was safe and we succeeded
  57. 00:02:30
    in having a better outcome for the
  58. 00:02:31
    patients measured by the modified
  59. 00:02:33
    rankings score at six months. We were
  60. 00:02:36
    also able to show that this
  61. 00:02:39
    early-lumbered drainage of cerebrospine
  62. 00:02:41
    fluid leads to less infarctions,
  63. 00:02:44
    secondary infarctions at discharge,
  64. 00:02:46
    which are mostly triggered by vasospasm.
  65. 00:02:49
    The vasospasm rate itself, however,
  66. 00:02:51
    was not affected by the lumbar drain.
  67. 00:02:53
    These are basically our findings. You
  68. 00:02:55
    can read this if you want to have in
  69. 00:02:59
    germinorology this month's issue,
  70. 00:03:00
    August 23. Great. Well, I think all
  71. 00:03:04
    of us were very excited when this study
  72. 00:03:07
    was first released online and we got to
  73. 00:03:08
    read it. And at this point, we've
  74. 00:03:10
    already had journal clubs and discussed
  75. 00:03:11
    at length because it's honestly, it's
  76. 00:03:14
    the first major positive trial we've had
  77. 00:03:16
    in suburban hemorrhage management. in
  78. 00:03:18
    decades, and it's very, very exciting
  79. 00:03:20
    for all of us. We have employed at
  80. 00:03:23
    University of Maryland where I'm a
  81. 00:03:25
    physician, lumbar drains for sabbatical
  82. 00:03:28
    and hemorrhage in the last year,
  83. 00:03:30
    actually even starting before the trial
  84. 00:03:31
    was released. And we learned some
  85. 00:03:33
    lessons along the way, and we learned
  86. 00:03:34
    more lessons from your paper, and one
  87. 00:03:36
    of which was this idea of actually
  88. 00:03:39
    measuring the pressure gradient between
  89. 00:03:41
    an EVD and a lumbar drain. And I
  90. 00:03:43
    mentioned that because we had a pause in
  91. 00:03:46
    our practice after we had a patient
  92. 00:03:47
    herniate through the brain sag, and
  93. 00:03:50
    probably from over drainage from the
  94. 00:03:52
    lumbar drain. And we were not measuring
  95. 00:03:54
    ICPs at that time, and we didn't have a
  96. 00:03:56
    good solution until we read your paper,
  97. 00:03:58
    and we decided to use this protocol.
  98. 00:04:00
    Can you talk about how you came up with
  99. 00:04:02
    this protocol and why it may be
  100. 00:04:04
    important for safety? Well, the safety
  101. 00:04:07
    issue was the main consideration in the
  102. 00:04:10
    beginning. And in fact, some of our
  103. 00:04:12
    centers participating wanted to end,
  104. 00:04:14
    include only good weight patients being
  105. 00:04:17
    awake. easy to be monitored because at
  106. 00:04:19
    one they thought it would be more safe
  107. 00:04:21
    to use the lumburgrenes in these
  108. 00:04:23
    patients. Other of us were more prone
  109. 00:04:26
    to use it in the high-grade WFNS
  110. 00:04:29
    patients because they seem to be benefit
  111. 00:04:31
    more and this was actually the
  112. 00:04:32
    population which was introduced in the
  113. 00:04:35
    premature trial by proclymal. So there
  114. 00:04:38
    was a clinic like because which patient
  115. 00:04:40
    to include and we really did not know.
  116. 00:04:43
    To overcome the safety issue we took a
  117. 00:04:45
    proposal from a colleague of ours from
  118. 00:04:47
    Germany, Dimitry Steik, from Erlangen,
  119. 00:04:49
    who measured actually pressure gradient
  120. 00:04:49
    on both a lumbar drain and an EVD
  121. 00:04:54
    inserted simultaneously in a patient,
  122. 00:04:57
    the sub-word hemorrhage. This was done
  123. 00:04:59
    before, shortly before early drain was
  124. 00:05:01
    about to start and we decided to include
  125. 00:05:04
    this idea as additional safety measure
  126. 00:05:07
    and the idea is simple. If both are
  127. 00:05:10
    zeroed on the external acoustic channel,
  128. 00:05:11
    they should measure the same pressure
  129. 00:05:12
    level if the CSF
  130. 00:05:16
    paper. is a patent. If there's a
  131. 00:05:19
    difference like cloudy and blockage in
  132. 00:05:21
    the, let's say, aqueduct or even the
  133. 00:05:25
    ventricular blood, there should be a
  134. 00:05:26
    difference in pressure with the lumbar
  135. 00:05:28
    drain being lower reading than the EBD.
  136. 00:05:30
    And this gradient gives you additional
  137. 00:05:32
    safety. This was nightly shown in the
  138. 00:05:34
    paper by Dimitra Spike of references in
  139. 00:05:37
    the final early-drained paper as well as
  140. 00:05:39
    in the protocol. And this really gave
  141. 00:05:43
    us confidence to do the safety. Having
  142. 00:05:47
    said that, I remember the numbers from
  143. 00:05:50
    actual early-drained lumbar drain. The
  144. 00:05:52
    difference between both pressures was 1
  145. 00:05:54
    in 144 patients randomized to lumbar
  146. 00:05:58
    drain. So the occurrence rate is low of
  147. 00:06:00
    this brain zagging.
  148. 00:06:03
    I don't know the particular features of
  149. 00:06:05
    your case. This may be interesting to
  150. 00:06:08
    learn.
  151. 00:06:10
    Sounds a little bit unusual because they
  152. 00:06:12
    usually do not get this in awake
  153. 00:06:16
    patients. is only the utmost severe
  154. 00:06:18
    patients. And then I question whether
  155. 00:06:21
    that would be really the longer drain or
  156. 00:06:23
    just initial hemorrhage severity. The
  157. 00:06:25
    patients would be too worse anyways,
  158. 00:06:28
    but need to learn more about their face.
  159. 00:06:31
    Sure, sure. And so since we changed
  160. 00:06:34
    our protocol, one thing we've noticed
  161. 00:06:36
    in the lower grade patients is we are
  162. 00:06:39
    big believers in trying to let them have
  163. 00:06:41
    some sleep during their ICU stay,
  164. 00:06:43
    especially if they otherwise are doing
  165. 00:06:44
    well But when we're measuring this
  166. 00:06:46
    pressure gradient every hour, of course,
  167. 00:06:48
    it becomes harder and harder to get
  168. 00:06:50
    sleep in the ICU. And so I'm wondering
  169. 00:06:53
    maybe if, as you see looking forward,
  170. 00:06:56
    if the pressure gradient should be
  171. 00:06:58
    measured in high grade patients, but
  172. 00:06:59
    perhaps we may not need to in low grade
  173. 00:07:02
    patients. What are your thoughts on
  174. 00:07:03
    that? Well, this was not specified in
  175. 00:07:06
    the protocol. It was up to the
  176. 00:07:07
    discretion of each local investigator.
  177. 00:07:09
    And I can only tell you my experience
  178. 00:07:11
    and trial this running from
  179. 00:07:14
    to your. continued use of lumbar drains,
  180. 00:07:18
    it seems to be that the good-grade
  181. 00:07:20
    patients do not need both an EVT and a
  182. 00:07:23
    lumbar drain because you can perfectly
  183. 00:07:26
    monitor them at clinical places. I
  184. 00:07:28
    would, however, recommend to do this
  185. 00:07:30
    in high-grade patients being on the
  186. 00:07:33
    ventilator or even more invasive
  187. 00:07:36
    monitoring like oxygen probes or
  188. 00:07:37
    something like that. If you think you
  189. 00:07:39
    need that, you probably want to have
  190. 00:07:41
    both an EVT and the lumbar drain for
  191. 00:07:42
    safety And it seems to be rare, but
  192. 00:07:46
    still, if you capture this, you're
  193. 00:07:48
    upfront, it may be better. And second
  194. 00:07:52
    thing is, to my current understanding,
  195. 00:07:55
    lumbar over drainage from brain-zagging
  196. 00:07:57
    is completely different from classic
  197. 00:08:00
    herniation by pressure forcing the brain
  198. 00:08:07
    down in the cisterna market. And this
  199. 00:08:11
    is a completely different
  200. 00:08:13
    one as high ICP. and the other is low
  201. 00:08:16
    ICP. So this may be interesting to know
  202. 00:08:18
    the features of your patients. Yeah,
  203. 00:08:21
    it was quite interesting that ICPs were
  204. 00:08:22
    not high at all. They're actually quite
  205. 00:08:23
    low. And to treat the patient, we
  206. 00:08:25
    actually instilled sterile saline into
  207. 00:08:28
    the lumbar chain with immediate
  208. 00:08:30
    improvement. Yes, we do that in case
  209. 00:08:33
    of accidental drainage, over drainage,
  210. 00:08:35
    we do that as well. And seems to work
  211. 00:08:37
    safely and feasible. I've never seen
  212. 00:08:39
    any problem with that. One thing I
  213. 00:08:42
    noted in the paper was, as you said,
  214. 00:08:44
    the EVD management was up to the
  215. 00:08:47
    institution. Yes. Do you have a sense
  216. 00:08:49
    of what the common practices were for
  217. 00:08:51
    EVD management with lumbar drains where
  218. 00:08:53
    most institutions keeping it open,
  219. 00:08:55
    keeping it closed?
  220. 00:08:57
    No, we did not unfortunately record
  221. 00:09:00
    this data in our case report form.
  222. 00:09:03
    There's one of the few of the lots of
  223. 00:09:06
    shortcomings. Looking more detailed to
  224. 00:09:08
    find more shortcomings all the way, but
  225. 00:09:11
    this is with every trial you do probably.
  226. 00:09:14
    I would assume that I visited each
  227. 00:09:17
    center in person to ensure compliance to
  228. 00:09:20
    the protocol and issued the safety issue
  229. 00:09:23
    with the both with the gradient
  230. 00:09:25
    measurement in each center. So at least
  231. 00:09:28
    in the high-grade patients, pressure
  232. 00:09:30
    was regularly monitored. In Berlin, we
  233. 00:09:33
    stick with this work just to keep the
  234. 00:09:35
    EVT closed and open it up on demand.
  235. 00:09:37
    This is backed up by, I think, work
  236. 00:09:41
    from Duke University, which are, by
  237. 00:09:42
    all said, that showing that closed EVTs
  238. 00:09:46
    have less infections, less cluttered
  239. 00:09:50
    and less prone of complications like
  240. 00:09:53
    dislocation and any other problems. And
  241. 00:09:56
    it seems to be natural. Having,
  242. 00:09:58
    looking at the statistics, I think 70
  243. 00:10:00
    of centers do have an open EVT protocol
  244. 00:10:03
    and only 30 have this closed-point
  245. 00:10:06
    open-demand protocol.
  246. 00:10:09
    I've said that on the podium before we
  247. 00:10:10
    are doing a passionate analysis now to
  248. 00:10:12
    see whether the drainage rates are.
  249. 00:10:14
    EVDs correlate to outcome, and it seems
  250. 00:10:17
    to be that draining the blood out of the
  251. 00:10:21
    base assistance via EVD is not a
  252. 00:10:23
    fortunate idea. But this is preliminary.
  253. 00:10:26
    This is not in the paper for good reason
  254. 00:10:28
    because we did not randomize for that
  255. 00:10:30
    and did not investigate that otherwise
  256. 00:10:32
    it would be completely understood,
  257. 00:10:35
    not difficult to understand.
  258. 00:10:37
    Interesting. And you mentioned this
  259. 00:10:39
    outcome of looking at secondary infarct,
  260. 00:10:42
    and some of us have noted that in the
  261. 00:10:43
    control group the rate of secondary
  262. 00:10:45
    infarct, which was mostly by CT scan if
  263. 00:10:47
    I'm correct, was quite high, it was
  264. 00:10:49
    nearly 40 and in some of our own
  265. 00:10:54
    institutional data we looked at our
  266. 00:10:56
    rates seem to be much lower and so I'm
  267. 00:10:58
    wondering what your thoughts are on this
  268. 00:11:01
    rate and how if you looked into that.
  269. 00:11:03
    This is one indicator for quality of
  270. 00:11:06
    care and you may argue that this rate is
  271. 00:11:10
    too high or whatever. Keep in mind.
  272. 00:11:14
    that most of our subnet hemorrhage
  273. 00:11:16
    knowledge comes from previous trials,
  274. 00:11:19
    like the Klatsus Anton trials,
  275. 00:11:22
    conscious one, conscious two, or the
  276. 00:11:24
    NIMODP in Newton edge trial. And these
  277. 00:11:28
    were trials having an enriched
  278. 00:11:30
    population prohibiting the most severe
  279. 00:11:32
    patients entering the trial. So this is
  280. 00:11:36
    usually WFNS grade one, two, three,
  281. 00:11:39
    and four, maybe not even grade one So
  282. 00:11:42
    this is patients having a lower
  283. 00:11:43
    infarction rate. And in early train,
  284. 00:11:47
    about half of the infarct rate was in
  285. 00:11:49
    the high grade WFNS five patients. This
  286. 00:11:52
    is data presented more on the supplement
  287. 00:11:56
    side. I think it's supplement too, but
  288. 00:11:57
    I don't know the correct figure number.
  289. 00:12:00
    Have a look at that. These high grade
  290. 00:12:02
    patients contributed to half about half
  291. 00:12:04
    of the infarction rate. So it may
  292. 00:12:06
    depend on your local policy, which
  293. 00:12:08
    patient to treat, which patient to
  294. 00:12:10
    include in for the longer train.
  295. 00:12:14
    which patients you're looking at. And
  296. 00:12:17
    this is just a perception bias, to my
  297. 00:12:19
    understanding. And this is also backed
  298. 00:12:22
    up by one paper from Alejandro Arenstein
  299. 00:12:24
    from Mayo Clinic, who is probably one
  300. 00:12:26
    of the most best clinics in the world to
  301. 00:12:30
    treat sub-right hemorrhage. If I want
  302. 00:12:31
    to have a sub-right hemorrhage, I
  303. 00:12:33
    probably want to have it there for the
  304. 00:12:35
    expertise. And they did have an
  305. 00:12:37
    extraction rate for 39. The paper of
  306. 00:12:41
    2004-2005 in stroke, which was
  307. 00:12:44
    reassuring to me, we are just on par
  308. 00:12:46
    with this level, having a mixed
  309. 00:12:48
    sub-right hemorrhage-grade population.
  310. 00:12:51
    And then lastly, any thoughts about why
  311. 00:12:53
    the secondary infarction rate was so
  312. 00:12:54
    different with no change in vasoskeletal?
  313. 00:12:56
    This is the key question, and I have no
  314. 00:12:59
    good answer on that, because this trial
  315. 00:13:02
    was designed to show the evidence that
  316. 00:13:05
    it may be appropriate and advantage is
  317. 00:13:10
    to use a lambda train. It was not for
  318. 00:13:11
    physiology studies. there's some work
  319. 00:13:14
    coming out of Boston ICU on spreading
  320. 00:13:18
    depolarizations, which is a precursor
  321. 00:13:20
    of infarctions. And these three
  322. 00:13:22
    manipulizations may be triggered by ICP
  323. 00:13:25
    spikes, which are there in the control
  324. 00:13:28
    group. And they may also be triggered
  325. 00:13:30
    by a higher ICP level, which was also
  326. 00:13:33
    higher in the control group in early
  327. 00:13:34
    train. So I could only speculate on
  328. 00:13:39
    this, but the lumber drain seems to be
  329. 00:13:42
    promoting the natural CSF flow
  330. 00:13:47
    better than an EVD just to prohibit
  331. 00:13:50
    stasis of the blood and debate
  332. 00:13:52
    assistance. So if you have more regular
  333. 00:13:56
    CSF circulation, as always happens,
  334. 00:13:57
    regardless how much you are training,
  335. 00:14:00
    this may be better for the patient.
  336. 00:14:03
    Well, let that be the last word. Thank
  337. 00:14:04
    you so much, Dr. Wolf.
  338. 00:14:05
    Congratulations on the early drain trial
  339. 00:14:08
    This has been really a game changer in
  340. 00:14:10
    neurocritical care and we're all very
  341. 00:14:11
    excited by it. and we look forward to
  342. 00:14:14
    more research from you and your group.