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Live at Annual Episode 2: Clinical Trials - INTREPID with Dr David Greer

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Description

Multiple studies demonstrate that fever/elevated temperature is associated with poor outcomes in patients with vascular brain injury; however, there are no conclusive studies that demonstrate that fever prevention/controlled normothermia is associated with better outcomes. The primary objective of the INTREPID (Impact of Fever Prevention in Brain-Injured Patients) trial was to test the hypothesis that fever prevention is superior to standard temperature management in patients with acute vascular brain injury. Dr David Greer, Professor and Chair of the Department of Neurology at Boston University School of Medicine, joins Dr Nick Morris to discuss the results from the study, which have just been released.

Contributors

  • David Greer, MD, MA FCCM, FAHA, FNCS, FAAN, FANA


    Dr. David Greer is Professor and Chair of the Department of Neurology at Boston University School of Medicine and the Richard B. Slifka Chief of Neurology at Boston Medical Center.

    Dr. Greer is the editor-in-chief of Seminars in Neurology, and the past editor-in-chief for Neurocritical Care on Call. He has authored more than 350 peer-reviewed manuscripts, reviews, chapters, guidelines and books.

    He was the 2022 recipient of the American Academy of Neurology’s A.B. Baker Award for Lifetime Achievement in Neurology Education, and has been a devoted mentor and teacher to many students, residents, fellows and faculty.

    His research interests include predicting recovery from coma after cardiac arrest, brain death, and multiple stroke-related topics, including acute stroke treatment, temperature modulation and stroke prevention.

  • 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. 00:00:20
    Hi, this is Nick Morris for the NCS
  2. 00:00:21
    podcast and this is our live at annual
  3. 00:00:24
    series where we are taking hopefully the
  4. 00:00:26
    best and brightest from the sessions at
  5. 00:00:29
    the annual meeting and with me after the
  6. 00:00:31
    clinical trial session, I have Dr.
  7. 00:00:32
    David Greer, Dr. Greer, thanks for
  8. 00:00:34
    joining us. Thanks for having me, Nick.
  9. 00:00:36
    And Dr. Greer just released for the
  10. 00:00:38
    first time the results of the Intrepid
  11. 00:00:39
    study. This is a study that we at
  12. 00:00:42
    University of Maryland enrolled in and
  13. 00:00:44
    maybe you could just give us a quick
  14. 00:00:46
    summary of the study and why you did it
  15. 00:00:49
    and what you found. Sure. So, thanks.
  16. 00:00:52
    So, we looked at patients with acute
  17. 00:00:54
    vascular brain injury and that means a
  18. 00:00:56
    scheme of stroke, intracellular
  19. 00:00:57
    hemorrhage and subarachone hemorrhage.
  20. 00:01:00
    And the question was, we knew that
  21. 00:01:03
    fever occurred in these patients. We
  22. 00:01:05
    knew that fever was associated with
  23. 00:01:06
    worse outcome, but we didn't know was
  24. 00:01:09
    preventing fever. Does that actually
  25. 00:01:11
    benefit people or not? And so, that
  26. 00:01:13
    was the premise of the study We use
  27. 00:01:14
    fever prevention versus standard care to
  28. 00:01:17
    impact outcomes.
  29. 00:01:20
    Great, and what did you find? Well,
  30. 00:01:23
    we found that we A, could control
  31. 00:01:25
    temperature, which is a really
  32. 00:01:27
    important question, and B, we looked
  33. 00:01:29
    at secondary outcomes also to see, did
  34. 00:01:31
    it actually make a difference? So the
  35. 00:01:33
    first question was, were we able to
  36. 00:01:35
    control in this population, an ICU
  37. 00:01:37
    population, even keeping people at
  38. 00:01:40
    normal thermia? And the answer was
  39. 00:01:42
    there was a statistical difference
  40. 00:01:44
    between the patients who were kept
  41. 00:01:46
    normal thermic or the fever prevention
  42. 00:01:47
    arm and the standard of care arm So that
  43. 00:01:50
    was great to show that we could at least
  44. 00:01:51
    do that. The more important question is,
  45. 00:01:55
    did it impact outcomes? And we looked
  46. 00:01:56
    at the 90-day modified Rankin Scale
  47. 00:01:59
    score of 0 to 3 as the proof of benefit.
  48. 00:02:03
    And we did not find that there was a
  49. 00:02:05
    benefit by preventing the fever up from.
  50. 00:02:07
    We looked at a number of secondary
  51. 00:02:08
    outcomes, including the Glasgow outcome
  52. 00:02:10
    scale, extended the
  53. 00:02:14
    Barthel index, mocha scores. And
  54. 00:02:17
    across the board, we didn't find any
  55. 00:02:20
    benefit for the the functional outcomes.
  56. 00:02:23
    Now interestingly, there were a bunch
  57. 00:02:26
    of patients about 30 in the standard of
  58. 00:02:29
    care arm who never got a fever. So
  59. 00:02:32
    maybe that diluted the trial to a
  60. 00:02:33
    certain degree, we're not sure. The
  61. 00:02:37
    shivering control in the fever
  62. 00:02:38
    prevention arm was challenging. A lot
  63. 00:02:40
    of centers struggled with that. So
  64. 00:02:42
    could that have worked against that arm?
  65. 00:02:44
    It's unclear. We did not find that
  66. 00:02:46
    there was an increase in mortality or
  67. 00:02:47
    any lengthening of ICU stay or overall
  68. 00:02:52
    hospital stay. So those things were all
  69. 00:02:55
    good and no difference in the
  70. 00:02:56
    significant adverse events either
  71. 00:02:58
    including pneumonia, sepsis, mortality.
  72. 00:03:01
    They were all equal between their groups.
  73. 00:03:04
    I think as someone who participated in
  74. 00:03:06
    the study, we all would have hoped to
  75. 00:03:08
    have seen a greater effect that would
  76. 00:03:09
    have shown benefit to patients of
  77. 00:03:12
    treating fever, which is something we
  78. 00:03:13
    all were doing very aggressively for a
  79. 00:03:15
    long time. What's been your clinical
  80. 00:03:18
    takeaway? What are you doing fever
  81. 00:03:20
    control and has that changed based on
  82. 00:03:21
    the results of the study? Yeah, I
  83. 00:03:23
    think we're kind of back to the drawing
  84. 00:03:24
    board a little bit with that. So I tend
  85. 00:03:26
    to jump on fever pretty aggressively
  86. 00:03:28
    still. I still in my heart of hearts
  87. 00:03:30
    think that it's bad or at least
  88. 00:03:32
    associated with bad. And so I don't let
  89. 00:03:34
    people be febrile for very long, but am
  90. 00:03:38
    I convinced that it works? No, am I
  91. 00:03:40
    willing to let patients be febrile for a
  92. 00:03:42
    longer period of time to find out? No,
  93. 00:03:46
    not at the present time I'm still
  94. 00:03:48
    treating people pretty aggressively. I
  95. 00:03:49
    don't put them immediately on the Arctic
  96. 00:03:51
    Sun or another device to do febrile
  97. 00:03:54
    prevention upfront, but I'm still
  98. 00:03:57
    treating febrile pretty aggressively.
  99. 00:03:59
    And where do we need to go next in this
  100. 00:04:02
    science? Is it about different methods
  101. 00:04:04
    of controlling fever? Is it
  102. 00:04:05
    understanding them basic molecular
  103. 00:04:08
    underpinnings of what's going on here?
  104. 00:04:10
    Where do we need to go in order to
  105. 00:04:11
    better understand the relationship
  106. 00:04:13
    between fever and poor outcomes and
  107. 00:04:15
    whether this is purely association or
  108. 00:04:17
    there's some
  109. 00:04:19
    I think that the central question is,
  110. 00:04:22
    who gets a fever and why do they get a
  111. 00:04:24
    fever? And if we can figure out, and I
  112. 00:04:25
    think we can, from our data, what are
  113. 00:04:28
    the phenotypes of the patients? Are
  114. 00:04:29
    they younger patients, older patients?
  115. 00:04:30
    Is it people with blood in the head or
  116. 00:04:32
    not blood in the head? These are the
  117. 00:04:34
    really the central questions. We, I
  118. 00:04:37
    will admit, we didn't do a great job
  119. 00:04:39
    with the shiver control early in the
  120. 00:04:40
    study. We got better and better at it
  121. 00:04:42
    over time, but as we were adding on
  122. 00:04:44
    more sites, every site had to learn how
  123. 00:04:46
    to jump on shivering better So could we
  124. 00:04:48
    do better, especially in the early
  125. 00:04:50
    going, to treat the shivering and keep
  126. 00:04:53
    patients comfortable and keep them on
  127. 00:04:55
    therapy for longer or more comfortably?
  128. 00:04:58
    I think that that's a central question
  129. 00:05:00
    also. And then, thinking about what
  130. 00:05:02
    are the right severities of patients,
  131. 00:05:05
    are they, or maybe the patients that
  132. 00:05:07
    should be in this are ones who are
  133. 00:05:08
    requiring intubation and can get into
  134. 00:05:11
    esophageal thermistor instead. And
  135. 00:05:14
    they're still salvageable, but they're
  136. 00:05:16
    more severe strokes rather than the
  137. 00:05:18
    person with a. Subarachimin hemorrhage
  138. 00:05:20
    is a hunt test one but has a lot of
  139. 00:05:22
    blood in their head But they're gonna
  140. 00:05:23
    sail through perhaps with no problem But
  141. 00:05:25
    they may not tolerate the therapy very
  142. 00:05:27
    well at all These are all the remaining
  143. 00:05:29
    questions that we need to dissect the
  144. 00:05:30
    data to figure out great. Well, lots
  145. 00:05:33
    to be done But thank you dr. Greer for
  146. 00:05:34
    a wonderful presentation and we I think
  147. 00:05:37
    all will learn a lot from the study And
  148. 00:05:40
    congratulations not just to you But for
  149. 00:05:42
    BD to pulling this off and getting all
  150. 00:05:44
    of our centers to act as you said go
  151. 00:05:47
    through a it was a pretty difficult
  152. 00:05:48
    protocol But we did it and I think it
  153. 00:05:51
    shows what we can do in neuro critical
  154. 00:05:52
    care when we all work together. So
  155. 00:05:54
    congrats again. Great. Thank you,
  156. 00:05:55
    Nick.