Transcript Remote ischaemic preconditioning: kidney and heart

Cardiac preconditioning:
myths and mysteries
Enjarn Lin
May 2011
Introduction
 Perioperative myocardial infarction is
associated with prolonged hospital stay &
increased mortality
 Identify at risk patients
 Institute therapeutic strategies
 coronary revascularisation
 β-blockade
 α2-adrenoceptor agonists
 aspirin & statins
 prayer
 US Multicentre RCT
 1802 patients undergoing CABG
 Randomised to 3 groups:
 Uncertain but received prayer
 Uncertain & did not receive prayer
 Certain & received prayer
Intercessory prayer
 No effect on complication-free recovery
from CABG
 Intercessory prayer had a higher incidence
of complications.
Ischaemia-reperfusion injury
 ATP depletion
 Accumulation of H+
 Na+ & Ca2+ influx
Ischaemia-reperfusion injury
 Rapid normalisation of
pH
 Ca2+/ROS
 Opening of
mitochondrial
permeabilitytransition
pore (mPTP)
 Uncoupling of oxidative
phosphorylation
Goals of myocardial
protection
1. Limit the duration and extent of ischaemia
2. Ensure the adequacy of timely reperfusion
3. Modify the cellular responses to ischaemia-
reperfusion injury
4. Cardiac conditioning
Ischaemic Preconditioning
 4 cycles of 5 minute
ischaemia with
intermittent reperfusion
prior to coronary
occlusion
 Subsequent infarct size
75% smaller than controls
 22 RCT’s 933 patients
 On pump patients received cardioplegia or ICCF
 Variable IPC protocols
 Pooled analysis:
 No difference in mortality or perioperative MI
 Significant reductions in ventricular arrhythmias,
inotrope use & ICU length of stay
Ischaemic PostConditioning
 Conditioning stimulus applied after onset of
myocardial ischaemia during reperfusion
period
 Similar ability to attenuate the detrimental
effects of IRI as IPC.
 Strategy to improve outcome from evolving
myocardial infarction
Ischaemic postconditioning in
cardiac surgery
Study
Patient group
Stimulus
Outcomes
Number
Luo 2007 Repair Tetralogy of Fallot
Aortic clamping (2
cycles of 5 min)
Less troponin I release
24
Luo 2008 Valve surgery(cold-blood
cardioplegia)
Aortic clamping (3
cycles of 5 min)
Reduced CK-MB
No change to troponin I
Less inotropic support
50
Luo 2008 Congenital heart
disease(cold-blood
cardioplegia)
Aortic clamping (2
cycles of 5 min)
Less troponin I release
Less inotropic support
40
 6 RCTs, 244 patients
presenting with STEMI
undergoing primary PCI
 Significant reduction in
peak CK & improved LV
performance
 Intervention benefit over
standard care
Clinical Applicability
 Clinical benefits limited :
 Cardiology & cardiothoracic surgery
 Transplantation
 Inducing ischaemia in an already
diseased target organ
‘Preconditioning at a distance’
 Brief episodes of ischaemia & reperfusion in LCx territory
reduced size of a subsequent infarct due to occlusion
of LAD coronary artery
 Magnitude of ischaemic protection similar to direct
ischaemic preconditioning
 Extended to non cardiac organs: kidney, small intestine,
brain & skeletal muscle
 Remote ischaemic preconditioning or ischaemic
preconditioning at a distance
Conditioning the myocardium
Brief ischaemia remotely or locally
Ischaemia
Reperfusion
PreCon
Ischaemia
Reperfusion
PerCon
Reperfusion
PostCon
Remote ischaemia
Ischaemia
Mitogen-activated
protein kinases
Activation via G-protein
couple receptor
Pro-survival
protein kinases
Mitochondrial KATP
channel
Mitochondrial permeability
Transition pore (mPTP)
The end effectors?
mitochondrial KATP
channel:
mitochondrial
permeability transition
pore:
 Implicated as
 Non-specific high
 Sulphonylureas
 Opening uncouples
critical mediator
abolish IPC
 Maintains Ca2+
homeostasis
 Interaction with
mPTP unclear
conductance
channel
oxidative
phosphorylation &
ATP depletion
 Prevention of
opening underpins
IPC/RIPC
Clinical trials in RIC
Study
Journal
Patient group
Stimulus
Outcomes
Number
Cheung (2006)
JACC
Paediatric cardiac
surgery
Upper-limb ischaemia (4
cycles of 5 min)
Reduced troponin; reduced inotrope
score; reduced airway resistance
37
Hausenloy
(2007)
Lancet
CABG
Upper-limb ischaemia (3
cycles of 5 min)
Reduced troponin
57
Ali (2007)
Circulation
AAA surgery
Lower-limb ischaemia (2
cycles of 10 min)
Reduced troponin; reduced
perioperative MI; preserved renal
function
82
Hoole (2009)
Circulation
Elective coronary
angioplasty
Upper-limb ischaemia (3
cycles of 5 min)
Reduced troponinI ;
reduced MACCE
242
Venugopal
(2009)
Heart
CABG (cold-blood
cardioplegia)
Upper-limb ischaemia (3
cycles of 5 min)
Reduced troponin
45
Botker (2009)
Lancet
Primary coronary
angioplasty
(STEMI)
Upper-limb ischaemia (3
cycles of 5 min)
Increased myocardial salvage;
decreased infarct size at 1 month
333
Pharmacological preconditioning
Study
Patient group
Drug
Outcomes
Number
Mangano 2006
CABG
Acadesine (adenosine
modulator)
No difference in MI
2698
Kitakaze 2007
STEMI
Atrial Natriuretic Peptide
and Nicorandil
ANP: decreased infarct
size & improved LV
function
Nicorandil: No difference
1216
Mentzer 2008
CABG
Cariporide (Na+/H+
exchange inhibitor)
Decreased MI
Increased CVA
5761
Opioid preconditioning
 Opioids (via δ&κ receptors) can trigger cardiac
preconditioning; naloxone blocks
preconditioning
 Cardiomyocytes sites of endogenous opioid
synthesis, storage and release
 Opioids act as autocoids, released during times
of stress & ischaemia
 Open the KATP channel & close the mPTP.
 46 patients undergoing CABG randomised to morphine
or fentanyl before CPB
 No difference in BNP or troponin
 Morphine improved LV function
 40 patients randomised to receive remifentanil bolus &
infusion prior to sternotomy
 Primary outcome troponin I reduced
 Shorter mechanical ventilation time
Volatile anaesthetic
preconditioning
 Volatile anaesthetics can protect the myocardium
 Volatile anaesthetics can similarly
precondition/postcondition the myocardium
 Similar mechanistic pathways as ischaemic conditioning
 Evidence of volatile anaesthetic late preconditioning
Clinical trials with volatile
anaesthetics
 Randomized 200 patients undergoing CABG to 4
anaesthetic protocols
1.
2.
3.
4.

Propofol TIVA
Sevoflurane from sternotomy to CPB
Sevoflurane after coronary anastomosis
Sevoflurane from sternotomy
Compared to TIVA, continuous Sevoflurane
significantly reduced troponin I leakage for the first
48 hours
 22 RCTs identified, 1922 patients undergoing
cardiac surgery, all too small to report on
mortality
 Predominantly undergoing on-pump CABG, 6
RCTs of OPCAB, 1 of mitral surgery
 Majority had volatile throughout; 6 had volatile
only before or during expected period of
ischaemia
 Dosage: Desflurane 0.15-2.0 MAC & Sevoflurane
0.25-4.0 MAC
Landoni et al. 2007
 enzyme leak
 hospital length of stay
 inotrope requirement
  MI
 mechanical ventilation
 all cause mortality
time
 ICU length of stay
PostConditioning
 58 patients with STEMI
 IV cyclosporine (non
specific mPTP blocker)
prior to PCI
 Reduction in enzyme
leakage
 Significant reduction in
infarct size assessed by
cardiac MRI
RCTs in conditioning for IRI
 >50 ischaemic conditioning
 Predominately RIC
 >40 pharmacological preconditioning
 Predominately volatile anaesthesia
Conclusions
 Brief ischaemia is good/prolonged
ischaemia is bad
 Anaesthesia is good for you!
 Larger trials are required
 Praying for our patients doesn’t appear
to improve outcomes