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Ischemic preconditioning

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					                                                 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
 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 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%)
 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
Intraoperative ECG monitoring
  Computerized ST segment
     monitoring
  ST depression > 1 mm 60 msec
                                         J-point
     after J-point
  Slope of the depression
            horizontal
            downsloping Isoelectric point
Anatomic location of ischemia on
             ECG

        LAD V1-V4

        CxA I, aVL, V5-V6

        RCA II, aVF
         Sensitivity of ECG lead
              combinations
     Two lead system
               II / V5 - 80 %

               II / V4 - 82 %

               V4 / V5 - 90 %
London, Anesthesiology, 1998; Vol 69, 232
         Sensitivity of ECG lead
              combinations
     Three lead system

                   V3/V4/V5 - 94 %

                   II/V4/V5 - 96 %

London, Anesthesiology, 1998; Vol 69, 232
 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
                        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
         Anti-ischemic Rx. on myocardial O2
Demand




Supply




Miller 5th edition; page 1762
       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).
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.
Effects of inhalational anesthetics on IPC(II)

 Volatile agents inhibit Ca2+ influx
    through voltage - and receptor
    operated Ca2+ channels in coronary
    vascular smooth muscle
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.
                    Inhalational anesthetics (1)
           The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002;




*Halothane; ** Isoflurane; *** Desflurane; **** Sevoflurane;
¶   Electrophysiologic effects
         Inhalational anesthetics (2)
The pharmacology of Inhalational Anesthetics Eger, Weiskopf, Eisenkraft, 2002;
          Ischemic preconditioning (1)
 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: 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.
             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 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. 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.
       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 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



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)

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



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 (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
       Ischemic preconditioning (4I)
 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).
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.
       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.

  Troponin               Control                  Adenosine                             IP group
levels (mcg/l)            1.32                       1.22                                  0.58

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

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.
       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.
            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.
                  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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