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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

Hypothermia and Cardiac ArrestScientific Questions

Clifton W. Callaway, MD,PhD

University of Pittsburgh

Safar Center for Resuscitation Research

Department of Emergency Medicine

induced mild hypothermia
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
slide3

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

how deep
How deep?

(Weinrauch 1992; Leonov 1990)

  • Neurological benefit was evident with mild hypothermia (32ºC)
  • Complications increase with moderate (30ºC) and deep (15ºC) hypothermia.
slide5

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

how quickly
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.
slide7

Hypothermia

Cell Death

Collapse

Oxidative Stress

Excitatory Amino Acid Release

Energy Failure / Acidosis

24 Hours

48 Hours

2 Hours

how long
How Long?

(Hicks 2000; Hickey 2000; Hickey 2003)

  • Prolonged, mild hypothermia is beneficial even if initiated hours after reperfusion.
arterial blood pressure tracing 8 minutes of asphyxia produces 5 minutes of circulatory arrest

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.
slide11

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

slide12

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

slide13

Hypothemia and Intracellular Signaling

- extracellular-signal regulated kinase (ERK)

Hypothermia increases ERK activation and phosphorylation of ERK substrates, such as p90Rsk.

slide14

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.

slide15

Prolonged Hypothermia

Cell Death

New Gene Expression

Collapse

ERK Signaling

24 Hours

48 Hours

2 Hours

slide16

BDNF

TrkB

SEK

Raf

JNK

mRNA

MEK

pJun

ERK

pATF

p90Rsk

pCREB

Hypothermia after Reperfusion

Cell Survival

how will you use this knowledge
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?