göran olivecrona, md, phd department of cardiology lund university skåne university hospital,...
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Göran Olivecrona, MD, PhdDepartment of Cardiology
Lund University
Skåne 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 min
Hypothermia 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)Wavefront phenomenon
(Jennings)HypothermiaHypothermia NormothermiaNormothermia
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
per
atu
re (
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 min
40 ± 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 NS
Hypertension 3 2 NS
Diabetes 1 2 NS
Infarct related artery LAD 6 7 NS
RCA 3 2 NSInitial TIMI flow 0/1 7 8 NS
2/3 2 1 NS
Onset of symptoms 174 ± 51 174 ± 62 NSto reperfusion (min)
Door-to-balloon time (min) 43 ± 7 40 ± 6 NS
Successful revascularization 9 9 NS
TIMI 3 flow post PCI 9 9 NS
Thrombectomy 8 7 NS
Abciximab 6 6 NS
Bivalirudin 3 3 NS2/20 patients, One from each group was excluded for technical reasons
Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.
Variable Hypothermia Control (n=9) (n=9)
30 day mortality 0 0
Re-infarction 0 0
CABG 0 0
30 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
-pro
BN
P (
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
10
20
30
40
50
60
70
80
Δ = 38%
Infa
rct
size
/ M
yoca
rdiu
m a
t ri
sk
Hypothermia Control0
1
2
3
4
5
6
7
8
Tro
po
nin
T (
ug
/l)
p = 0·01
Δ = 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 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 InvestigatorsDavid Erlinge and Göran Olivcecrona
http://clinicaltrials.gov/ct2/show/NCT01379261?term=olivecrona&rank=1
CHILL-MIRapid 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 InvestigatorsDavid Erlinge and Göran Olivcecrona
http://clinicaltrials.gov/ct2/show/NCT01379261?term=olivecrona&rank=1
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
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
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)