Göran Olivecrona, MD, PhdDepartment of CardiologyLund UniversitySkåne University Hospital, Sweden

Hypothermia in awake STEMI patients:Hypothermia in awake STEMI patients:Results from the RAPID MI-ICE trial Results from the RAPID MI-ICE trial and insights to the CHILL MI trial:and insights to the CHILL MI trial:

Why Hypothermia is Why Hypothermia is CoolCool again again

20112011

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

Potential conflicts of interest

Jolife AB, Medtronic,Abbott VascularCordis,Physio ControlTerumoEdwards Lifesciences

Treatment of Myocardial infarction:Revascularisation

• Thrombolysis • Primary-PCI

Background hypothermia for the heart

• Hypothermia protects the heart during:

Cardiac surgery Heart transplantations

Hypothermia in the prevention of MI Animal studies

Control

xxx

Open surgery ligation of LAD in pigs. 34 C during 40 out of 60 min ischemia (Radiant).

Hypothermia

Ischemia 60 minHypothermia 55 min

Start after 20 min ischemia

End 15 minafter

reperfusionSlow 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

Reperfusion 3 h.

Dae MW, et al. 2002, Am J Physiol Heart Circ Physiol

Reperfusion injury

Reperfusion

Infarctionsize

Time

Ischemia

Mechanism of Cardioprotection

• Cyclosporin: Mitocondria• C5a inhib: Complement• Adenosine: Inflammation• Postcond: Myocyte(?)• PKCdelta-: Myocyte apoptosis• ?: Metabolism• ?: Reactive hyperemia• ?: Endothelium• ?: Systemic effects

Hypothermia

Hypothermia for MI

• Two failed larger clinical studies COOL MI COOL MI ICE ITICE IT

• Failed because only 1/3 randomized to Hypothermia reached <35°C at time of Reperfusion ?

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

Hypothermia protocol for rapid cooling

Celsius Control System™Endovascular cooling catheter (14 F)Initiation and maintaining hypothermia

1000 ml cold saline (4ºC)Quick initiation of hypothermia

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.

Infarct size/area at risk(Porcine model)

Gotberg et al., BMC Cardiovascular Disorders, 2008

~ 5 min to reach < 35ºC with cold saline and endovascular cooling

Pre-reperfusion cooling reduce infarct size.Post-reperfusion cooling has no effect

39% reduction

Speckled infarction in pigWavefront 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

RAPID MI-ICEThe 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 FeasibilitySecondary outcome: Reduction in infarct size Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

Feasibility

Arrival at cath lab

0 10 20 30 40 50 60 7033

34

35

36

37

HypothermiaControl

Time (min)

Tem

pera

ture

(C)

ECG Patient Info

Randomization

Time ofreperfusion

Initiation of cold saline

infusion

Initiation ofendovascular

cooling

Patient prep, catheterization Angiography, PCI

End of PCI

14 ± 5 min 14 ± 6 min 15 ± 3 min40 ± 6 min

HypothermiaControl

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. 2010 Oct;3(5):400-7.

Clinical and Angiographic Data Variable Hypothermia (n=9) Control (n=9)Age 62 ± 10 58 ± 7 NS Women 2 2 NSHypertension 3 2 NSDiabetes 1 2 NSInfarct related artery  LAD 6 7 NS

RCA 3 2 NSInitial TIMI flow  0/1 7 8 NS

2/3 2 1 NSOnset of symptoms 174 ± 51 174 ± 62 NSto reperfusion (min)Door-to-balloon time (min) 43 ± 7 40 ± 6 NS

Successful revascularization 9 9 NSTIMI 3 flow post PCI 9 9 NSThrombectomy 8 7 NSAbciximab 6 6 NSBivalirudin 3 3 NS

2/20 patients, One from each group was excluded for technical reasonsGotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

Variable Hypothermia Control (n=9) (n=9)

30 day mortality 0 0Re-infarction 0 0 CABG 0 030 day MACE 0 0 Heart failure 0 3 VT/VF 0 2 Stroke 0 0 Infection 3 0 Major bleeding 0 0 Bradycardia 0 0

Safety

NT-proBNP day 1

Hypothermia Control0

500

1000

1500

2000

NT-

proB

NP

(ng/

l)

Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

Reduction of infarct size Final Infarct Size/ Myocardium at Risk

Reduction in Troponin (Peak value)

Efficacy

p = 0·04

Hypothermia Control0

1020304050607080

Δ = 38%

Infa

rct s

ize

/ Myo

card

ium

at r

isk

Hypothermia Control012345678

Trop

onin

T (u

g/l)

p = 0·01Δ = 43%

Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

Speckled infarction in man

Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

CHILL-MIRapid Endovascular Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the

Treatment of Acute Myocardial InfarctionA 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 InvestigatorsDavid Erlinge and Göran Olivcecrona

http://clinicaltrials.gov/ct2/show/NCT01379261?term=olivecrona&rank=1

ProtocolPatients 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

Endpoint

Primary Efficacy Endpoint:

Cardiac MRI infarct size as a percentage of area at risk at 4±2 days. (MRI)

Conclusions

• Troponin T release was significantly reduced.

• 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.

• A larger trial to verify findings from animal research and RAPID MI-ICE is needed: CHILL-MI (Start June 2011)