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Ischemic Preconditioning (IPC)

Presented Apr 2003. 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. Objectives. Introduction to the topic of IP

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Ischemic Preconditioning (IPC)

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  1. Presented Apr 2003 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

  2. Objectives • Introduction to the topic of IP • Risk factors for CAD • Cardiac anatomy and ischemia • Ischemic preconditioning (IPC) and anesthetic agents • Summary

  3. 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.

  4. What is cardiac ischemia? • Cardiac ischemia is a situation in which the bloodflow 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.

  5. Coronary artery distribution • LV - Anterior - LAD Anterolateral - OM branch CxA Inferior - PDA branch of RCA, CxA Apex - Distal LAD Posterior / Posterolateral - CxA Septum - 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%)

  6. Methods to Detect Ischemia • 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

  7. J-point Isoelectric point Intraoperative ECG monitoring • Computerized ST segment monitoring • ST depression > 1 mm 60 msec after J-point • Slope of the depression • horizontal • downsloping

  8. Anatomic location of ischemia on ECG V1-V4 I, aVL, V5-V6 II, aVF LAD CxA RCA

  9. Sensitivity of ECG lead combinations Two lead system II / V5 - 80 % II / V4 - 82 % V4 / V5 - 90 % London, Anesthesiology, 1998; Vol 69, 232

  10. Sensitivity of ECG lead combinations Three lead system V3/V4/V5 - 94 % II/V4/V5 - 96 % London, Anesthesiology, 1998; Vol 69, 232

  11. Intraoperative Monitoring • 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

  12. Treatment of ischemia • 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 Miller 5th edition; page 1763

  13. Anti-ischemic Rx. on myocardial O2 Demand Supply Miller 5th edition; page 1762

  14. 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

  15. Ischemic preconditioning (IPC)?  IPC describes the adaptation(1) of the myocardium to ischemicstress (2) preceded by short periods of ischemia(3) andreperfusion (4).

  16. Effects of inhalational anesthetics on IPC(I) • Volatile anesthetics produce direct coronary artery relaxation by affecting intracellular Ca2+ regulation at several locations in the vascular smooth muscle cell.

  17. Effects of inhalational anesthetics on IPC(II) • Volatile agentsinhibit Ca2+ influx through voltage - and receptoroperated Ca2+ channels in coronary vascular smooth muscle

  18. Effects of inhalational anesthetics on IPC(III) • 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.

  19. Inhalational anesthetics (1)The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002; *Halothane; ** Isoflurane; *** Desflurane; **** Sevoflurane; ¶ Electrophysiologic effects

  20. Inhalational anesthetics (2)The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002;

  21. Ischemic preconditioning (1) • Study from Torino, Italy • Firstperiod 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: 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.

  22. Ischemic preconditioning (2) • From Aachen, Germany, clinical studies  ischemia was demonstrated with administration of • adenosine • adenosine-receptor-agonists • dipyridamole-a nucleoside-transport inhibitor • Therapeutic applications of ischemicpreconditioning 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. 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.

  23. Ischemic preconditioning (3I) • 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 ICK-MB • IP induced by occluding the LAD 2x for a 2-min, followed by3-min LAD reperfusion before grafting of the first coronary vessel 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

  24. Results IP Non-IP SVI  HR   Troponin   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

  25. Ischemic preconditioning (3III) • 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 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

  26. Ischemic preconditioning (4I) • UK prospective double-blind study of 30 CABG patients (one surgeon) divided into 3 groups: • intermittent cross-clamp fibrillation (control) • pharmacologicalpreconditioning (adenosine A1 agonist) • ischemic preconditioning (two 3-min periods of ischemia, each followed by 2 min of reperfusion). 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.

  27. Troponin Control Adenosine IP group levels (mcg/l) 1.32 1.22 0.58 Ischemic preconditioning (4II) • 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. • CONCLUSION of UK study: Ischemic preconditioning was superior to the other techniques at limiting myocardial necrosis during CABG. 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.

  28. Sevoflurane Effects on IPC (5II) Measurements: 1. Ca++ release in the coronary muscle cells 2. LVP 3. Contractility and relaxation (lusitropy) 4. Infarct size 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

  29. The lowest Ca++ release was in Sevo gp Sevoflurane Effects on IPC (5III) 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

  30. Sevoflurane Effects on IPC (5IV) • 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: 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

  31. Ketamine inhibits IPC(6) • 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 • Infarct size reduced from 45 %  24% in IPC group/controls • Infarct size not reduced in Ketamine/IPC group • Conclusion: Ketamine abolished IPC (K+ ATP channels) 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.

  32. 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 opener 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.

  33.    R-Ketamine Thiopental Pentobarbital S-Ketamine Propofol Midazolam Etomidate No effect No effect No effect No effect IV Anesthetic Effects on IPC (7II) The effects on mitoK(ATP) channel opening: 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.

  34. IV Anesthetic Effects on IP (7III) CONCLUSIONS: These results suggest that R-Ketamine, Thiopental, Pentobarbital may abolish IPC via effects on mitoK(ATP) channels 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.

  35. 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.

  36. Summary(2) • Ischemia might be protective for the heart if it is mild and reversible • Inhalational anesthetics may precondition the heart and reduce postoperative ischemia • Choice of anesthetic may decrease: • AMI • duration of hospitalization • costs of total medical care

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