1. Hypothermia in awake STEMI patients:
Results from the RAPID MI-ICE trial and insights to the CHILL MI trial:
Why Hypothermia is Cool again
Göran Olivecrona, MD, Phd
Department of Cardiology
Lund University
Skåne University Hospital, Sweden
2011 1

2. Potential conflicts of interest
Speaker’s name: Göran Olivecrona
 I have the following potential conflicts of interest to report:
 Other(s)
 Unrestricted Grant, Innercool, Inc, San Diego, CA
 Minor Lectur honorariums
Jolife AB,
Medtronic,
Abbott Vascular
Cordis,
Physio Control
Terumo
Edwards Lifesciences

3. Treatment of Myocardial infarction: Revascularisation
Thrombolysis
Primary-PCI

4. Background hypothermia for the heart
Hypothermia protects the heart during:
 Cardiac surgery
 Heart transplantations

5. Hypothermia in the prevention of MI
Animal studies
Control
Hypothermia
Open surgery ligation of LAD in pigs.
34 C during 40 out of 60 min ischemia (Radiant).
Ischemia 60 min
Reperfusion 3 h.
Hypothermia 55 min
Start after 20 min ischemia
End 15 min after reperfusion Slow warm up 2 h
80% relative reduction in infarct size (P < 0.001)
Based on this study on 22 animals two major clinical trials were conducted
xxx
Dae MW, et al. 2002, Am J Physiol Heart Circ Physiol

6. Reperfusion injury
Infarction
size
Reperfusion
Ischemia
Time

7. Mechanism of Cardioprotection
Cyclosporin: Mitocondria
C5a inhib: Complement
Adenosine: Inflammation
Postcond: Myocyte(?)
PKCdelta-: Myocyte apoptosis
?: Metabolism
?: Reactive hyperemia
?: Endothelium
?: Systemic effects
Hypothermia

8. Hypothermia for MI Two failed larger clinical studies  COOL MI
 ICE IT
Failed because only 1/3 randomized to Hypothermia reached <35°C at time of Reperfusion ?

9. Hypothermia for MI Is target temp <35°C the key?
How can that be achieved?
How can we cool the awake patient?
More basic animal research needed 9

10. Hypothermia protocol for rapid cooling
Combination hypothermia: Cold saline (4ºC), 1000 ml iv infusion
in 5 min as a ”kick start” for quick initiation of hypothermia together with an endovascular cooling catheter.
Celsius Control System™
Endovascular cooling catheter (14 F)
Initiation and maintaining hypothermia
1000 ml cold saline (4ºC)
Quick initiation of hypothermia

11. Infarct size/area at risk
(Porcine model)
39% reduction
~ 5 min to reach < 35ºC with cold saline and endovascular cooling
Pre-reperfusion cooling reduce infarct size.
Post-reperfusion cooling has no effect
Gotberg et al., BMC Cardiovascular Disorders, 2008

12. Speckled infarction in pig
Wavefront phenomenon
(Jennings)
Hypothermia
Normothermia
Hypothermia causes disruption of the wavefront phenomenon.
Götberg M et al . BMC Cardiovasc Disord. 2008, 8:7
Also seen in hypothermia treatment by Dae et al., Am J Physiol, 2002, with SPECT

13. (Safety & Feasibility study in man)
RAPID MI-ICE
The Rapid Intravascular Cooling in Myocardial Infarction as Adjunctive to Percutaneous Coronary Intervention study
(Safety & Feasibility study in man)
20 Patients
Anterior or large Inferior STEMI
<6 hrs from onset of symtoms
Rapid infusion 1-2 liters 4°C Saline solution.
Endovascular cooling with Philips InnerCool endovascular system with Accutrol catheter starting before angiogram and continuing 3 h after PCI
Cardiac MRI day 4±2, infarct size/ myocardium at risk (T2 stir)
Primary outcome: Safety and Feasibility
Secondary outcome: Reduction in infarct size
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7.

14. Initiation of cold saline infusion
Feasibility
Arrival at
cath lab
ECG
Patient Info
Randomization
Time of
reperfusion
Initiation of cold saline infusion
Initiation of
endovascular
cooling
Patient prep,
catheterization
Angiography, PCI
End of PCI
14 ± 5 min
14 ± 6 min
15 ± 3 min
40 ± 6 min
Hypothermia
Control
3 min prolonged procedure before reperfusion
Temp: 34.7 ± 0.3°C at reperfusion
All patients reached target temp
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7.

15. Clinical and Angiographic Data
Variable Hypothermia (n=9) Control (n=9)
Age 62 ± ± 7 NS
Women NS
Hypertension NS
Diabetes NS
Infarct related artery
  LAD NS
RCA NS
Initial TIMI flow
  0/ NS
2/ NS
Onset of symptoms ± ± 62 NS
to reperfusion (min)
Door-to-balloon time (min) 43 ± ± 6 NS
Successful revascularization NS
TIMI 3 flow post PCI NS
Thrombectomy NS
Abciximab NS
Bivalirudin NS
2/20 patients, One from each group was excluded for technical reasons
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7.

16. Safety NT-proBNP day 1 Variable Hypothermia Control (n=9) (n=9)
30 day mortality 0 0
Re-infarction 0 0
CABG
30 day MACE 0 0
Heart failure 0 3
VT/VF
Stroke
Infection
Major bleeding 0 0
Bradycardia 0 0
NT-proBNP day 1
2000
1500
NT-proBNP (ng/l)
1000
500
Hypothermia
Control
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7.

17. Reduction of infarct size Final Infarct Size/ Myocardium at Risk
Efficacy
Reduction of infarct size
Final Infarct Size/ Myocardium at Risk
Reduction in Troponin
(Peak value)
Δ = 38%
Δ = 43%
p = 0·04
p = 0·01 80 8 70 7 60 6 50 5
Infarct size / Myocardium at risk 40
Troponin T (ug/l) 4 30 3 20 2 10 1
Hypothermia
Control
Hypothermia
Control
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7.

18. Speckled infarction in man
Gotberg et al. Circ Cardiovasc Interv Oct;3(5):400-7. 18

19. Principal Investigators David Erlinge and Göran Olivcecrona
CHILL-MI
Rapid Endovascular Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction
A Randomized, Controlled Study of the Use of Central Venous Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction
Principal Investigators
David Erlinge and Göran Olivcecrona

20. Protocol
Patients will receive 1-2 liters of cold (4° C) saline solution upon arrival to cath lab, together with buspirone and meperidine.
Endovascular cooling will begin prior to diagnostic angiography and PCI.
After first reperfusion, cooling will be maintained for 1 hour. Then the cooling catheter will be removed and the patient will spontaneously rewarm at CCU.
120 patients at 10 sites in Europe 20

21. Endpoint Primary Efficacy Endpoint:
Cardiac MRI infarct size as a percentage of area at risk at 4±2 days. (MRI) 21

22. Conclusions Rapid induction of hypothermia with iv cold saline and
endovascular catheter reduces Infarct size by 38% in animals
and 39% in humans (infarct size/ area at risk).
Hypothermia treated animals and humans exhibit a
morphologically “different” infarkt (Speckled infarct) as
opposed to the wave front Phenomenon.
All patients in RAPID MI-ICE reached target temperature,
<35°C, before reperfusion.
Troponin T release was significantly reduced.
A larger trial to verify findings from animal research and
RAPID MI-ICE is needed: CHILL-MI (Start June 2011)