ischemic preconditioning (ipc) darko j. vodopich md resident @ mhmc-cwru department of...
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Ischemic Preconditioning
(IPC)Darko J. Vodopich MD
Resident @ MHMC-CWRU Department of Anesthesiology
Charles E. Smith MD, FRCPC
Director of Cardiothoracic Anesthesia @ MHMC-CWRU Department of Anesthesiology
Presented Apr 2003
Objectives
Introduction to the topic of IP Risk factors for CAD Cardiac anatomy and ischemia Ischemic preconditioning
(IPC) and anesthetic agents Summary
Epidemiology
CAD is the leading cause of death Direct cost of cardiovascular care > 260 billion ~ 1,000,000 deaths form CAD per year Every 29 seconds one American dies of AMI Cost of CABG > 12 billion (2% of all heath care costs)
In US (1996) ~ 300,000 CABG; 400,000 PTCA Waiting time for CABG (UK, Sweden, Canada) > 9 mo.
What is cardiac ischemia? Cardiac ischemia is a situation in
which the blood flow within a coronary artery is limited to the point where the oxygen demands of the heart muscle cannot be met (hypoxia).
* Impaired oxygen supply/demand ratio.
Coronary artery distribution
LV - Anterior - LAD
Anterolateral - OM branch CxA Inferior - PDA branch of RCA, CxA
Apex - Distal LADPosterior / Posterolateral - CxASeptum - septal branches of LAD
RV - RCA, and branches of LAD and CxA
Sinus node - proximal RCA (55%), CxA (45%)
A-V node - distal RCA (90%), CxA (10%)
Chest pain if patient is awake ECG changes Hypotension Tachycardia Elevated pulmonary artery occlusion pressure (PAOP)
Large v-waves on PAOP tracing Fall in cardiac output/index Detection with TTE/TEE
Methods to Detect Ischemia
Intraoperative ECG monitoring
Computerized ST segment monitoring
ST depression > 1 mm 60 msec after J-point Slope of the depression
horizontal downsloping
J-point
Isoelectric point
Sensitivity of ECG lead combinations
II / V5 - 80 %
II / V4 - 82 %
V4 / V5 - 90 %
Two lead system
London, Anesthesiology, 1998; Vol 69, 232
Sensitivity of ECG lead combinations
V3/V4/V5 - 94 %
II/V4/V5 - 96 %
Three lead system
London, Anesthesiology, 1998; Vol 69, 232
Five standard ASA monitors: POX BP EtCO2
ECG Temperature
Intraarterial catheter Pulmonary artery catheter (PAC)
CO/CI (not truly continuous) CVP PCWP LVSWI SVR,PVR
TTE/TEE (currently not routinely available @ MHMC) LidCO/Pulse CO*
Continuous SV, MAP, SVR, CO, SPV**
* integration of arterial pressure wave form** systolic peak velocity
Intraoperative Monitoring
Treatment of ischemia
Miller 5th edition; page 1763
Correction of H/D abnormalities I.v. NTG ß Adrenergic receptor blockers Oxygen Morphine Heparin (TPA) Ca++ channel blockers CPB Intra aortic balloon pump Other
Anti-ischemic Rx. on myocardial O2
Demand Heart Rate Contractility Preload Afterload Nitrates No , No ,
-blockers No , No DHP* No No
V / D** No , No , No ,
Supply Regional CBF Diastolic filling time Nitrates +/ -
-blockers DHP*
V / D**
Miller 5th edition; page 1762
*Dihydropyridines (nifedipine, nicardipine, nitrendipine); ** Verapamil, Diltiazem
Demand
Supply
Choice of Anesthesia
No good or bad anesthesia so far defined BUT...
With the theory of Ischemic Preconditioning
It may become important to choose
appropriate anesthesia
Ischemic preconditioning (IPC)?
IPC describes the adaptation(1) of the myocardium to ischemic stress (2) preceded by short periods of
ischemia(3) and reperfusion (4).
Volatile anesthetics produce direct coronary artery relaxation by affecting intracellular Ca2+ regulation
at several locations in the vascular smooth muscle cell.
Effects of inhalational anesthetics on IPC(I)
Volatile agents inhibit Ca2+ influx through voltage - and receptor operated Ca2+ channels in coronary vascular smooth muscle
Effects of inhalational anesthetics on IPC(II)
Volatile anesthetics also reduce Ca2+ accumulation in and release by the coronary vascular smooth muscle sarcoplasmic reticulum (SR), inhibit G proteins linked to phospholipase C, and decrease formation of the second messenger inositol triphosphate.
Effects of inhalational anesthetics on IPC(III)
Inhalational anesthetics (1)The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002;
EP¶ EFF HALO* ISO** DES*** SEVO****
Atrial conductiontime
No No
Atrial refractoryperiod No No
Nodal conduction No
Predisposes toPVC’s Yes No No No
Action onarrhythmias No , Suppress Suppress Suppress
Action on QTinterval
*Halothane; ** Isoflurane; *** Desflurane; **** Sevoflurane;
¶ Electrophysiologic effects
CVS EFFECT HALO ISO DES SEVOCardiac Output
MVO2
LVDF depress protective protective protectiveLusitropic
Compliance*
Coronary steal No Minimally Minimally
Transient myocardialischemia
+ +++ ++ +++
Ischemicpreconditioning
*Lusitropic (myocardial relaxation)
Inhalational anesthetics (2)The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002;
Study from Torino, Italy First period or window of protection can lasts up to 3 hours Second window of protection (SWOP) which begins about 24 hours after the brief coronary occlusions and lasts about 72 hours. Release of endogenous agents such as adenosine and nitric oxide (NO) may activate protein-kinase C (PKC) and ATP sensitive potassium (K+(ATP) channels. Free oxygen radicals released during preconditioning are likely to take part in the delayed protection through the production of peroxynitrite which activates PKC and antioxidant
enzymes such as Manganese superoxide-dismutase.
Ischemic preconditioning (1)
Ischemic preconditioning: from the first to the second window of protection. Pagliaro P - Life Sci - 25-May-2001; 69(1): 1-15. Dipartimento di Scienze Cliniche e Biologiche dell'Università di Torino, Orbassano, Italy.
From Aachen, Germany, clinical studies ischemia was demonstrated with administration of
adenosine adenosine-receptor-agonists dipyridamole-a nucleoside-transport inhibitor
Therapeutic applications of ischemic preconditioning have been developed for:
brief periods of ischemia "pharmacologic preconditioning" prior to coronary angioplasty prior to cardiac surgery protection of donor heart for cardiac transplantation.
Ischemic preconditioning (2)
Ischemic preconditioning. Does this animal experiment phenomenon have clinical elevance?; Reffelmann T - Med Klin - 15-Oct-2000; 95(10): 559-67 ; Medizinische Klinik I, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen.
Controlled, randomized, prospective study - Finland 32 patients with LAD or two-vessel heart disease (including LAD), off-pump CABG randomized into an IP (16) and control group (16). M/M: hemodynamic data and measurement of cardiac troponin I CK-MB IP induced by occluding the LAD 2x for a 2-min, followed by 3-min LAD reperfusion before grafting of the first coronary vessel
Ischemic preconditioning (3I)
Regional ischemic preconditioning enhances myocardial performance in off-pump coronary artery bypass grafting.; Chest 2002 Apr;121(4):1183-9 ; Laurikka J et al; Department of Surgery, Tampere University Hospital, Tampere, Finland
Ischemic preconditioning (3II)
Regional ischemic preconditioning enhances myocardial performance in off-pump coronary artery bypass grafting.; Chest 2002 Apr;121(4):1183-9 ; Laurikka J et al; Department of Surgery, Tampere University Hospital, Tampere, Finland
Results IP Non-IP
SVI
HR
Troponin
Conclusion of Finland study: Two cycles of regional 2-min IPC in the LAD followed by 3 min of reperfusion is applicable and safe in patients undergoing off-pump myocardial revascularization Tended to decrease immediate myocardial enzyme release Prohibited postoperative increase in HR Enhanced recovery of SVI
Ischemic preconditioning (3III)
Regional ischemic preconditioning enhances myocardial performance in off-pump coronary artery bypass grafting.; Chest 2002 Apr;121(4):1183-9 ; Laurikka J et al; Department of Surgery, Tampere University Hospital, Tampere, Finland
UK prospective double-blind study of 30 CABG patients (one surgeon) divided into 3 groups:
intermittent cross-clamp fibrillation (control) pharmacological preconditioning (adenosine A1 agonist) ischemic preconditioning (two 3-min periods of ischemia, each followed by 2 min of reperfusion).
Ischemic preconditioning (4I)
The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery. Cardiovasc Res 2002 Jan;53(1):175-80 Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. The Hatter Institute for Cardiovascular Studies, Department of Cardiology, UCL Hospitals, Grafton Way, London WC1E 6DB, UK.
CONCLUSION of UK study:
Ischemic preconditioning was superior to the other techniques at limiting myocardial necrosis during CABG.
Ischemic preconditioning (4II)
The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery. Cardiovasc Res 2002 Jan;53(1):175-80 Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM. The Hatter Institute for Cardiovascular Studies, Department of Cardiology, UCL Hospitals, Grafton Way, London WC1E 6DB, UK.
Mean CPB time was 91+/-11.6 (S.D.) min. Mean ischemic time was 33+/-5.5 (S.D.) min with no inter- group difference.
Troponin Control Adenosine IP grouplevels (mcg/l) 1.32 1.22 0.58
Sevoflurane Effects on IPC (5II)
Measurements:
1. Ca++ release in the coronary muscle cells
2. LVP
3. Contractility and relaxation (lusitropy)
4. Infarct sizeAnesthetic Preconditioning Attenuates Mitochondrial Ca2++ Overload During Ischemia in Guinea Pig Intact Hearts: Reversal by 5-Hydroxydecanoic Acid; Matthias L. Riess, MD et al.; Anesth Analg 2002;95:1540-1546
Sevoflurane Effects on IPC (5III)
The lowest Ca++ release was in Sevo gp
Anesthetic Preconditioning Attenuates Mitochondrial Ca2++ Overload During Ischemia in Guinea Pig Intact Hearts: Reversal by 5-Hydroxydecanoic Acid; Matthias L. Riess, MD et al.; Anesth Analg 2002;95:1540-1546
Sevoflurane Effects on IPC (5IV)
Anesthetic Preconditioning Attenuates Mitochondrial Ca2++ Overload During Ischemia in Guinea Pig Intact Hearts: Reversal by 5-Hydroxydecanoic Acid; Matthias L. Riess, MD et al.; Anesth Analg 2002;95:1540-1546
Results continued:
Sevo IPC hearts exhibited better recovery of systolic LVP Lusitropy was better in Sevo IPC hearts Coronary flow after reperfusion was significantly higher in Sevo ICP groups compare to the others The size of AMI:
Control APC APC+5-HD 5-HD
AMI size 55% 31% 53% 54%
46 alpha-chloralose-anesthetized rabbits LVEDP (tip manometer), CO (ultrasonic flow probe), and AMI size (triphenyltetrazolium staining) were measured Ketamine - 10 mg/kg given to 1/2 of the rabbits Control group - no Ketamine IPC - 5 min of occlusion of a LAD + 10 min of reperfusion LAD occlusion 30 min, then measured AMI size
Ketamine inhibits IPC(6)
Infarct size reduced from 45 % 24% in IPC group/controls
Ketamine, but not S(+)-ketamine, blocks ischemic preconditioning in rabbit hearts in vivo. Müllenheim J - Anesthesiology - 01-Apr-2001; 94(4): 630-, Müllenheim J; Frässdorf J; Preckel B; Thämer V; Schlack W; Institut für Klinische Anaesthesiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Conclusion: Ketamine abolished IPC (K+ ATP channels)
Infarct size not reduced in Ketamine/IPC group
IV Anesthetic Effects on IPC (7I)
Institute of Anesthesiology, University Hospital Zurich, Switzerland. MitoK(ATP) channels mediate cardiac preconditioning Microscope used to detecte mitoK(ATP) channel activity in response to diazoxide* Various anesthetics tested Hypoosmolar trypan blue staining proved the effects of the anesthetics on mitoK(ATP) channels+myocyte viability
* direct and highly selective mitoK(ATP) channel openerDifferential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection. Anesthesiology 2002 Jul;97(1):15-23 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Garcia C, Schaub MC. Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
IV Anesthetic Effects on IPC (7II)
Differential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection. Anesthesiology 2002 Jul;97(1):15-23 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Garcia C, Schaub MC. Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
R-KetamineThiopentalPentobarbitalS-KetaminePropofolMidazolamEtomidate
No effectNo effectNo effectNo effect
The effects on mitoK(ATP) channel opening:
IV Anesthetic Effects on IP (7III)
Differential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection. Anesthesiology 2002 Jul;97(1):15-23 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Garcia C, Schaub MC. Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
CONCLUSIONS: These results suggest that R-
Ketamine, Thiopental, Pentobarbital may abolish IPC via effects on mitoK(ATP) channels
Summary(1)
Anesthetic agents have distinctive actions on IPC.
Choice of background anesthesia may play a major role in cardiac protection in clinical and
experimental medicine.
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