Hypothermia and Cardiac Arrest Scientific Questions

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Hypothermia and Cardiac ArrestScientific
Questions

• Clifton W. Callaway, MD,PhD
• University of Pittsburgh
• Safar Center for Resuscitation Research
• Department of Emergency Medicine

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Induced Mild Hypothermia

• Works - but how?
• Sterz (HACA) and Bernard
• Insight into mechanism needed
• To better titrate timing and duration of cooling
• To design adjunctive therapy to augment the
  effects of cooling
• To generate ideas for other effective therapies
• To tease apart role of different mechanisms in
  brain injury

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Multiple Processes Contribute to Brain Injury
Cell Death - Proteases
Protein Synthesis Inhibition
New Gene Expression
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Cerebral Hypoperfusion
Oxidative Stress
Excitatory Amino Acid Release
Energy Failure / Acidosis
24 Hours
48 Hours
2 Hours
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How deep?

• (Weinrauch 1992 Leonov 1990)
• Neurological benefit was evident with mild
  hypothermia (32ºC)
• Complications increase with moderate (30ºC) and
  deep (15ºC) hypothermia.

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38C
Brain Injury
37C
36C
35C
Positive Inotropy, Increased SV, Decreased
HR, Heart Protection
34C
33C
32C
Brain Protection
31C
30C
Dysrhythmia / Irritability
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How quickly?

• (Leonov 1990a Leonov 1990b Sterz 991 Weinrauch
  1992 Kuboyama 1993 Safar 1996)
• Brief, mild hypothermia must be initiated as soon
  as possible.
• Delays of 15-30 minutes after reperfusion may
  negate beneficial effects.

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Hypothermia
Cell Death
Collapse
Oxidative Stress
Excitatory Amino Acid Release
Energy Failure / Acidosis
24 Hours
48 Hours
2 Hours
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How Long?

• (Hicks 2000 Hickey 2000 Hickey 2003)
• Prolonged, mild hypothermia is beneficial even if
  initiated hours after reperfusion.

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Arterial Blood Pressure Tracing 8 minutes of
asphyxia produces 5 minutes of circulatory
arrest.
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Hypothermia reduces mortality and improves
recovery
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The therapeutic window for hypothermia in this
and related studies provides clues to the
biochemical mechanisms
Decreased Temperature Helpful
1
24
48
12
0
6
Hours
Neurons Begin to Die
Asphyxial Cardiac Arrest
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Prolonged Hypothermia
Cell Death - Proteases
Protein Synthesis Inhibition
New Gene Expression
Collapse
Cerebral Hypoperfusion
Oxidative Stress
Excitatory Amino Acid Release
Energy Failure / Acidosis
24 Hours
48 Hours
2 Hours
13
Hypothemia and Intracellular Signaling -
extracellular-signal regulated kinase (ERK)
Hypothermia increases ERK activation and
phosphorylation of ERK substrates, such as p90Rsk.
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Hypothemia and Neurotrophic Factors - brain
derived neurotrophic factor (BDNF)
Hypothermia after resuscitation increases levels
of BDNF, activation of the BDNF receptor (TrkB)
and activation of ERK in hippocampus.
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Prolonged Hypothermia
Cell Death
New Gene Expression
Collapse
ERK Signaling
24 Hours
48 Hours
2 Hours
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Hypothermia after Reperfusion
Cell Survival
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How will you use this knowledge?

• Neurotrophic factors as drugs?
• Design selective activators of ERK?
• Screen genes affected by hypothermia for novel or
  unexplored pathways?