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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

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Presentation Transcript
introduction
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
slide3

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
Intercessory prayer
  • No effect on complication-free recovery from CABG
  • Intercessory prayer had a higher incidence of complications.
ischaemia reperfusion injury
Ischaemia-reperfusion injury
  • ATP depletion
  • Accumulation of H+
  • Na+ & Ca2+ influx
ischaemia reperfusion injury1
Ischaemia-reperfusion injury
  • Rapid normalisation of pH
  • Ca2+/ROS
  • Opening of mitochondrial permeabilitytransition pore (mPTP)
  • Uncoupling of oxidative phosphorylation
goals of myocardial protection
Goals of myocardial protection
  • Limit the duration and extent of ischaemia
  • Ensure the adequacy of timely reperfusion
  • Modify the cellular responses to ischaemia-reperfusion injury

4. Cardiac conditioning

ischaemic preconditioning
Ischaemic Preconditioning
  • 4 cycles of 5 minute ischaemia with intermittent reperfusion prior to coronary occlusion
  • Subsequent infarct size 75% smaller than controls
slide9

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
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
slide12

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 Applicability
  • Clinical benefits limited :
    • Cardiology & cardiothoracic surgery
    • Transplantation
  • Inducing ischaemia in an already diseased target organ
preconditioning at a distance
‘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
Conditioning the myocardium

Brief ischaemia remotely or locally

PreCon

Ischaemia

Reperfusion

Remote ischaemia

Ischaemia

Reperfusion

PerCon

Ischaemia

Reperfusion

PostCon

slide16

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
The end effectors?

mitochondrial permeability transition pore:

Non-specific high conductance channel

Opening uncouples oxidative phosphorylation & ATP depletion

Prevention of opening underpins IPC/RIPC

mitochondrial KATP channel:

  • Implicated as critical mediator
  • Sulphonylureas abolish IPC
  • Maintains Ca2+ homeostasis
  • Interaction with mPTP unclear
opioid preconditioning
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.
slide21

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 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
Clinical trials with volatile anaesthetics
  • Randomized 200 patients undergoing CABG to 4 anaesthetic protocols
    • 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
slide24

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
Landoni et al. 2007
  • enzyme leak
  • inotrope requirement
  • mechanical ventilation time
  • ICU length of stay
  • hospital length of stay
  •  MI
  • all cause mortality
postconditioning
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
RCTs in conditioning for IRI
  • >50 ischaemic conditioning
    • Predominately RIC
  • >40 pharmacological preconditioning
    • Predominately volatile anaesthesia
conclusions
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