RESUSCITATIVE HYPOTHERMIA ACADEMIC INDUSTRY ROUNDTABLE Hypothermia: future directions

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RESUSCITATIVE HYPOTHERMIA ACADEMIC INDUSTRY
ROUNDTABLEHypothermia future directions

• Midori A. Yenari, MD
• Depts. of Neurosurgery Neurology
• Stanford Stroke Center Stanford University
• Stanford, CA

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Introduction

• Hypothermia is a robust neuroprotectant.
• Compelling pre-clinical data to justify clinical
  trials
• Questions at preclinical level duration/delay,
  permanent occlusion, combination with
  thrombolysis, combination with other treatments?

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Summary Hypothermia in Experimental Stroke

• Depth 34.5C or lower results in comparable
  neuroprotection, but lower temperatures are
  associated with compromised hemodynamics most
  consistent results with 30-33C
• Duration At least one hour, provided cooling
  begins soon after ischemia onset. Several hours
  (6-12 h) if cooling is delayed by more than
  several hours
• Delay consistent protection with 2-3 h delay
  with at least 2 h cooling can delay up to 6 h
  provided cooling is maintained for 1-2d
• Long term protection observed out to 2 mos with
  2 h intraischemic cooling, or 1 h delay with
  prolonged cooling (2d) 70 protection in global
  model out to 6 mos, but extent of protection
  decreases over time
• Permanent vs. Temporary mixed results

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Protect against permanent ischemia?

• Less consistent data compared to temporary
  ischemia
• Protects
• Intraischemic hypothermia for 6 h ?infarct size _at_
  6 h(Baker et al, Exp Neurol 1991)
• Intraischemic hypothermia for 24 h ?infarct size
  _at_ 48 h (Yamamoto et al, Stroke 2001)
• ? infarct size _at_ 24 h when cooling (30-34.5C)
  delayed up to 1 h maintained for 1 h (Kader et
  al, Neurosurgery 1992)
• Doesnt protect
• No difference in infarct size when cooling (33C)
  was instituted during ischemia, and maintained
  for 1 h (Ridenour et al, Stroke 1992)
• No protection when cooling to 30-36C was
  instituted shortly after occlusion and maintained
  for 2 h (Morikawa et al, JCBFM 1992)

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Optimize duration/delay

• Brief intraischemic hypothermia (1-2 h) protects,
  but also protects when cooling begins 2-3 h after
  ischemia onset
• Prolonging the duration of cooling to several
  hours seems to lengthen the temporal therapeutic
  window
• What are the limits in rodents? In humans?

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Combination hypothermia rt-PA

• Embolic model in rats
• Hypothermia (32C), normothermia (37C) or
  hyperthermia (39C) for 2 h pre/post embolization
• rt-PA 2 h after embolization
• Angiographic recanalization best _at_ 39C
• rt-PA Rx itself ? inf. Size 50
• _at_ 48h largest infarcts (39C), smallest (32C),
  hypothermia ?inf. size by 70
• No further improvement with rt-PA/hypothermiais
  lack of difference due to robust protection by
  hypothermia?
• Interaction of rt-PA and temperature?
• Can hypothermia prolong the window for rt-PA Rx?
  Reduce hemorrhage?

(Meden et al, Br Res, 1994)
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Effect of temperature on clot lysis

• rt-PA is the only approved treatment for acute
  stroke
• combination rt-PA and mild hypothermia?
• how does temperature influence clot lysis?

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Effect of temperature on clot lysis

• Thrombin stabilized, 24 h aged clots from whole
  blood of donor rabbits.
• Incubate in sterile PBS at 24, 30, 33, 35, 37
  40C.
• Incubate with rt-PA (concentrations corresponding
  to serum levels in rabbits given doses of 1, 3
  and 6 mg/kg)
• Measure pre- and post-incubation weights

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Clot lysis is dose dependent

• clot lysis is dose dependent
• each 1 ug/ml increase in rt-PA increases clot
  lysis by 4

(Yenari et al, Thrombosis research, 1995)
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Clot lysis temperature

• rt-PA 0.5 decreased clot lysis/1C drop
• control 0.5 increased in clot lysis/1C drop

(Yenari et al, Thrombosis research, 1995)
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Combination RX with hypothermia gene therapy
(Zhao et al.)

• HSV viral vectors
• Overexpress potentially neuroprotective genes
• Bcl-2 as a prototypical anti-apoptosis,
  anti-necrosis gene

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(No Transcript)
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Bcl-2, an anti-apoptotic protein, to treat stroke
-6-15 h 0 1h 1.5h
5h 48h
Inject vector occlude reperfuse end
experiment
Delay vector delivery
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Striatal Bcl-2 overexpression protects neurons
from tMCAO (Lawrence et al, JCBFM, 1995)
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Combination Bcl-2 gene therapy hypothermia
0 1h 2h 5h 48h
Inject vectors
Occlude reperfuse
end experiment
Groups 33C-control 33C-Bcl-2 37C-control 37C-Bcl-
2
Cool to 33C
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Hypothermia prolongs the temporal therapeutic
for Bcl-2 gene therapy
vs 37ºC-Bcl-2, plt0.01 vs. 33C-control, plt0.01
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Conclusions

• Permanent occlusion?
• Optimal duration/delay?
• Combination Rx with thrombolytics?
• Combination Rx with neuroprotectants?