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Hypothermia and Cardiac Arrest Scientific Questions

Hypothermia and Cardiac Arrest Scientific Questions. Clifton W. Callaway, MD,PhD University of Pittsburgh Safar Center for Resuscitation Research Department of Emergency Medicine. Induced Mild Hypothermia. Works - but how? Sterz (HACA) and Bernard Insight into mechanism needed:

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Hypothermia and Cardiac Arrest Scientific Questions

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  1. Hypothermia and Cardiac ArrestScientific Questions Clifton W. Callaway, MD,PhD University of Pittsburgh Safar Center for Resuscitation Research Department of Emergency Medicine

  2. 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

  3. Multiple Processes Contribute to Brain Injury 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

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

  5. 38°C Brain Injury 37°C 36°C 35°C Positive Inotropy, Increased SV, Decreased HR, Heart Protection 34°C 33°C 32°C Brain Protection 31°C 30°C Dysrhythmia / Irritability

  6. 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.

  7. Hypothermia Cell Death Collapse Oxidative Stress Excitatory Amino Acid Release Energy Failure / Acidosis 24 Hours 48 Hours 2 Hours

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

  9. 250 ROSC Asphyxia 200 150 Cardiac Arrest CPR 100 Arterial Blood Pressure (mmHg) 50 0 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (minutes) Arterial Blood Pressure Tracing: 8 minutes of asphyxia produces ~5 minutes of circulatory arrest.

  10. Hypothermia reduces mortality and improves recovery

  11. Hicks et al. Hickey et al. Hickey et al. Increased Temperature Harmful The therapeutic window for hypothermia in this and related studies provides clues to the biochemical mechanisms Decreased Temperature Helpful 0 1 6 12 24 48 Hours Neurons Begin to Die Asphyxial Cardiac Arrest

  12. Intracellular signaling 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.

  14. 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.

  15. Prolonged Hypothermia Cell Death New Gene Expression Collapse ERK Signaling 24 Hours 48 Hours 2 Hours

  16. BDNF TrkB SEK Raf JNK mRNA MEK pJun ERK pATF p90Rsk pCREB Hypothermia after Reperfusion Cell Survival

  17. 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?

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