Myocardial Protection

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Myocardial Protection
www.anaesthesia.co.in anaesthesia.co.in_at_gmail.co
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• "MYOCARDIAL PROTECTION"
• Refers to strategies and methodologies used
  either to attenuate or to prevent postischemic
  myocardial dysfunction that occurs during and
  after heart surgery.

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Multiple factors

• Pre-CPB hemodynamic stability
• Cardioplegic techniques
• Success adequacy of surgical repair
• Separation from CPB
• Hemodynamic stability in early postop.
• Preexisting systemic myocardial disease

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• PREOPERATIVE FACTORS
• INTRAOPERATIVE FACTORS
• POSTOPERATIVE FACTORS

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Preoperative factors

• Adult Vs pediatric
• CAD Vs Valv HD
• Preop hemodyn stability
• Ischemia/ infarction
• Arrhythmias, hypotension

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Intraoperative factors

• Anaesthetic
• Hypovolemia
• LV dysfn
• Arrhythmias, tachy, HT
• Inadeq ventilation
• Direct manipulation
• MIDCAB, OPCAB

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Postoperative factors

• Adequate ventilation
• Avoid vent distension
• Avoid vasospasm
• Maintain hemodynamics
• Control bleeding
• Maintain CBF

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15-20 mins following normothermic ischemia

• Total diastolic arrest from cell membrane
  depolarisation
• Myocardial contracture stone heart
• Vacuolization of SR, mitochondria
• Release of lysosomal enzymes
• Uncoupling of oxidation and respiration
• Sequester calcium/expel hydrogen

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Depletion of ATP lt 50 of Normal Level-

• irreversible lethal cell injury
• glycolysis is blocked
• increasing cellular acidity
• protein denaturation
• structural, enzymatic, nuclear changes

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Hibernating myocardium

• Moderate and persistent reduction in myocardial
  blood flow cause diminished regional contraction
  (non-contractile)
• Metabolic processes remain intact (viable)
• Decrease in the magnitude of the pulse of calcium
  involved in the excitation-contraction process
• (inadequate calcium levels in the cytsol during
  each heart beat)

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Stunned myocardium

• Severe reduction in myocardial blood flow
• Function of the myocardium remains impaired
  (stunned) for a certain period despite
  reestablishment of flow
• But full recovery is expected
• Process occurs over a period of 1-2 weeks
• Contractile proteins recover if the myocyte is
  reperfused before irreversible damage

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Myocardial injury..factors

• Ischemia
• Ventricular distension
• Tachycardia
• Hypertension / hypotension
• Fall in DPTITTI ratio
• Ventricular hypertrophy
• Reperfusion

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Pharmacological measures
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• Hypothermia and potassium infusions the
  cornerstone of myocardial protection during
  on-pump heart surgery,
• Many other cardioprotective techniques and
  methodologies available.
• The ideal cardioprotective technique, solution,
  and/or method of administration has yet to be
  found.

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Myocardial O2 demand
75
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Non cardioplegic techniques
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INTERMITTENT AoXCl VF MODERATE HYPOTHERMIC
PERFUSION (30C TO 32C)

• Quiet field (during ventricular fibrillation)
• Avoids the profound metabolic changes that occur
  with more prolonged periods of ischemia.
• Duration of fibrillation till completion of
  distals
• Heart defib, proximals using an aortic partial
  clamp

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• In 1992, Bonchek et al- 3000 pts of CABG
• Elective operative mortality of rate 0.5, an
  urgent mortality rate of 1.7, and an emergency
  rate of 2.3.
• Inotropic support was needed in only 6.6
• 1 required IABP.

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• In 2002, Raco et al-
• 800 pts CABG
• Mortality- 0.6, 3.1, 5.6 in elective, urgent,
  emergent groups.
• Intermittent AoXCl is a safe technique both in
  elective and nonelective pts when performed by an
  exp surgeon.

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SYSTEMIC HYPOTHERMIA AND ELECTIVE FIBRILLATORY
ARREST

• Systemic hypothermia (25-28C)
• Elective fibrillatory arrest
• Maintenance of perf pres bet 80-100 mmHg
• Surgical field may be obscured by blood during
  revascularization

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• In 1984, Atkins et al reported a low incidence of
  perioperative infarction (1.8 ) and a low
  hospital mortality rate (0.4) in 500 consecutive
  patients using this technique.

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CONTINOUS CORONARY PERFUSION

• Continous blood perfusion of empty beating heart
• Aortic root/ ostial infusion
• Used in OPCAB
• Unsafe for open heart
• Continous retro AoXCl- open heart

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CARDIOPLEGIC TECHNIQUES
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Cardioplegic solutions

• Crystalloid cardioplegia
• Blood cardioplegia

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Cardioplegic principles

• Immediate arrest..rapid infusion for 2mins
• Hypothermia
• Substratesglucose/aa/adenosine
• Maintain pH..bicarb/ THAM/ blood
• Free radical damage mannitol/deferoxamine/LDBC/al
  lopurinol
• Edema ..mannitol/glucose/albumin

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Cardioplegic delivery

• Antegrade route
• Advantage immediate cardioplegia
• Problems
• Impaired perfusion beyond obstruction
• AVI..also in mitral surgery as aortic root
  distorted on atrial retraction
• Hypertrophied heart

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• Retrograde route
• Advantage
• Better septal cooling
• Cardioplegic solution perfuse beyond stenosis
• Problems
• RV not adequately protected
• Risk of coronary sinus perforation / myocardial
  hemorrage / edema
• Infusion pressure kept lt 50mmHg
• Antegrade retrograde
• More prompt arrest
• Better disribution of solution

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Hypothermia

• Basal metabolism
• in the absence of myocardial contraction, the
  myocyte still requires oxygen for basic house
  keeping functions
• This basal cost can be further reduced with
  hypothermia

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Hypothermia

• 
  Oxygen Demand reduction
• Normothermic Arrest (37oC) 1mL/100g/min
  90
• Hypothermic Arrest (22oC) 0.30
  mL/100g/min 97
• Hypothermic Arrest (10oC) 0.14 mL/100g/min
  97

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Hypothermia

• Decreased metabolic rate
• Ischemia intracellular pH .. nonionised
  ionised substrate ratio NI substrate escapeout
  of cell.
• Hypothermia NII ratio
• Semiliquid to semisolid memebrane.. calcium
  influx.
• glutamate release in brain ca sequest.

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Hypothermia

• Total extracorporeal circulation
• Surface cooling
• Surface cooling with partial CPB
• Deep hypothermic total circulatory arrest
• Low-flow, profoundly hypothermic perfusion
• All cooling for 30mins before starting CPB

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Problems of hypothermia

• DHCA can cause seizures, stroke, change in mental
  status and muscle tone, post pump
  choreoathetosis.
• Neocortex, hippocampus, striatum
• Loss of cerebral autoregulationlt15C
• Coagulopathy,acidosis,enzyme dysfunction
• Along with alkalosis, shift Bohrs
  oxy-dissociation curve to left.

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•  In a multicenter trial- continuous warm blood
  cardioplegia Vs intermittent cold blood
  cardioplegia.
• Similar myocardial preservation (mortality,
  postoperative incidence of myocardial infarction,
  need for intraaortic balloon counterpulsation).

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Rewarming

• lt10-12C gradient between venous blood and water
  temperature.also between arterial blood entering
  and core temperature.
• CPB withdrawn when bladder temp is 37C
• Prevent hyperthermia
• Esophageal/PAC temp not reliable
• Alpha stat method to correct pH. probably
  better neuro. outcome in profound hypothermia

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Reperfusion

• Cell damage following ischaemia is biphasic
• injury being initiated during ischaemia
• exacerbated during reperfusion

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Components

• Intracell Ca2 overload during isch reper
• Oxidative stress induced by reactive oxygen
  species (ROS)
• Ischemia ? endogenous antioxidant defense
• Loss of cell memb integrity

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• conjugated dienes are chemical signatures of
  oxygen free-radical lipid peroxidation
• Romaschin AD, Rebeyka I, Wilson GJ, et al.
• J Mol Cell Cardiol 198719289-293
• free radicals are generated within 10 seconds of
  reperfusion after ischaemia
• Zweier JL, Flaherty JT, Weisfeldt ML.
• Proc Natl Acad Sci USA 1987841404-1408

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Reduce reperfusion injury

• Reduce ionic calcium conc. in reperfusate
• 1.0 meq/Lchelate with CPD
• pH of 7.6-7.8
• Reperfusate pressure 50 mm Hg osmolality of 350
  mOsm..reduce edema
• Maintaining potassium arrest
• Infusing at 37C

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Calcium regulation

• Hallmark of reperfusion is Ca uptake
• Post ischemic failure of normal sequestration by
  SR / contractile app.
• Calcium phosphate crystal deposition in
  mitochondrial matrix
• Damage to respiratory chain and failure of ATP
  production

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Other measures

• Antioxidants- Vit E, glutathione
• OFR scavengers-SOD, catalase, peroxidase,
  allopurinol, mannitol, CoQ10, deferoxamine
  mesylate
• WBC filters

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BLOOD CP LEUCOCYTE FILTRATION

• Myocardial ischemia and reperfusion- activation
  of neutrophils
• Benefit of filtration in
• patients undergoing emergency CABG
• prolonged crossclamping,
• depressed ejection fraction,
• heart transplantation.

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• At least 90 of leucocytes must be removed to
  attenuate reperfusion injury markedly.
• Leucocyte depletion should be maintained for
  510 min after the start of initial reperfusion
  prior to aortic clamp release.
• Filters remove more than 90 of WBCs

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CONTROLLED REPERFUSION

• Reduce reperfusion inj after ac coro occlusion.
• AoXCl release- blood CP given at 50 ml/min per
  graft with a perfusion pressure 50 mmHg for
  20 min into the grafts only.
• Cannulation of a side branch of the vein graft.
• Multicenter trial, the results were evaluated in
  156 pts with acute coronary occlusion- reduced
  overall mortality from 8.7 to 3.9.

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Complications of protective strategies

• RV dysfunction..rewarming / poor
  distributiontopical cooling
• Coronary ostial stenosis..soft tipped
  cannula/leakage around cannula
• Endothelial damage to vein graft from
  hyperkalemic crystalloid cardioplegic
• Coronary sinus injury
• Infusion pressure lt50mmHg through sinus

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Energy depleted heart

• Cardiogenic shock/ unstable angina
• Preop stabilisation with IABP / pharmacological
  support / MechVent
• Prompt amino acid enriched warm blood
  cardioplegia
• Followed by cold cardioplegia
• Both antegrade retrograde flow

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PROTECTION STRATEGIES UNDER INVESTIGATION
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Ischemic preconditioning

• Brief episode of ischemia slows the rate of ATP
  depletion during subsequent ischemic episodes.
• (1) slowing of ATP depletion, or
• (2) limitation of catabolite accumulation during
  the terminal episode of ischemia.
• Depletion of ATP could be slowed by a reduction
  in energy demand during ischemia, or by an
  increase in the net availability of high-energy
  phosphates.

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• Brief periods of ischemia are known to cause
  prolonged contractile dysfunction, the so called
  "stunned myocardium."
• preconditioning could effectively stun the
  myocardium .reduce ATP utilization during the
  early phase of ischemia.
• Intermittent ischemia results in degradation of
  larger molecules breakdown products, lactate,
  H', NH3, inorganic phosphate, etc., are then
  washed out upon reperfusion.limit catabolite
  accumulation during the occlusion.
• Alternatively, a reduced energy demand might
  drive anaerobic glycolysis to a lesser extent.

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• Enzyme xanthine oxidase contributes to myocardial
  cell death by generating superoxide anions
• Preconditioning adenine nucleotide content of
  the myocardium. limit hypoxanthine accumulation
  and superoxide production.
• Myocardial lipid peroxidation, estimated as MDA
  formation, is common during intermittent
  ischemia-reperfusion.
• Huizer et al measured urate production by human
  hearts with CADnet production of urate increased
  in ischemia.

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• A reduction in catabolite accumulation could
  limit the osmotic load that occurs during
  ischemia.
• Another possibility is that preconditioning could
  limit accumulation of chemotactic factors that
  attract neutrophils to ischemic/reperfused
  tissue.
• Preconditioning can only delay cell death
• ineff if sustained ischemic insult gt 3 hrs
• Preconditioning failed to protect the mid and
  subepicardial myocardium

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• Second phase of protection req 24 hours to appear
  sustained for up to 72 hours.
• Second window of protection (SWOP), late phase
  preconditioning, or delayed precond.
• Unlike classical preconditioning, which protects
  only against infarction, the late phase protects
  against both infarction and myocardial stunning

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IP involves a complex cascade of intracellular
events
ischemic stimulus
adenosine subtype 1 (A1) receptor
amplified
G protein and protein kinase C (PKC).
effector
ATPregulated potassium channel (KATP).
?
protective effect
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Anesthetic preconditioning

• A safer and simpler alternative to IP is
  pharmacologic intervention by inhalation
  anesthetics
• APC shares the same mechanism of action as IP
• The effect of inhalation anesthetics was present
  30 minutes after discontinuation window of
  protection
• During this time, which can last for 1 to 2
  hours, there is an acute memory phase of
  preconditioning.

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Anesthetic preconditioning

• Isoflurane was administered in the
  precardiopulmonary bypass (CPB) period
• The higher cardiac index in the isoflurane group
  was associated with a lesser degree of ST segment
  changes than in the control group.
• There was no significant difference between the 2
  groups in the incidence of reperfusion
  arrhythmias

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Dogs were randomly assigned to receive 2 ml drug
vehicle (50 polyethylene glycol in ethyl
alcohol control experiments) or glyburide (0.05
mg/kg sup -1 administered intravenously) in the
presence or absence of 1 MAC (end-tidal)
isoflurane in four experimental groups
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• Sevoflurane decreases the inflammatory response
  after CPB, as measured by the release of IL-6,
  CD11b/CD18, and TNF-a.
• Total intravenous anesthesia was provided for
  both study and control groups by infusion of
  propofol,fentanyl, and midazolam. Sevoflurane 2
  was added to the cardioplegia solution in the
  experimental group.
• Myocardial function after CPB, as assessed by
  RWMA and LVSVI, was also improved

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• 1. Normothermic global ischemia lasting 15 min
  significantly augmented the adhesion of PMNs to
  the coronary endothelium.
• 2. This effect could be completely blocked by
  halothane, isoflurane, or sevoflurane
  continuously administered before and during
  ischemia and reperfusion at 1 and 2 MAC each.
• 3. Isoflurane given under control conditions
  without ischemia had no effect on basal PMN
  adhesion.
• 4. Administration of sevoflurane just at the
  onset of reperfusion was as effective as
  continuous application.
• 5. Suppression of the postischemic-enhanced PMN
  adhesion by the volatile anesthetics was
  independent of their vasodilating potency.
• 6. The volatile anesthetics did not influence the
  severity of ischemic challenge, as judged by
  myocardial lactate release.

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Adenosine

• Coronary vasodilatation
• Immediate arrest
• Ischemic preconditioning
• Retards ischemia-induced ATP deple, delays onset
  of ischemic contracture, atten myo stun, ?infarct
  size
• ? lipid peroxidation, ?SOD, catalase, glutathione
  peroxidase, glutath reductase.

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Sodium/Hydrogen Exchange Inhibition

• Amiloride, cariporide, eniporide, zoniporide
• Ejection fraction was greater, the resolution of
  regional left ventricular wall motion
  abnormalities tended to occur earlier, and the
  cumulative release of CK-MB was less.

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opioids

• Hibernating animals use only '10 of their
  normal, active energy expenditure.
• Hibernation is a process mediated by cyclical
  variation in endogenous opiate compounds.
• d-opiate receptor in particular is responsible.
• Hibernation reversed by opiate antagonists.
• Biological mechanism duplicated in humans,
  thereby inducing a profound state of energy
  conservation.
• Drugs with d -opiate activity confer myocardial
  protection, which is additive to cardioplegia.

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MYOCARD PROTECTION- OPCAB

• Short-acting beta blocker esmolol
• Cariporide and aprotinin- associated with a
  marked attenuation of stunning.

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Conclusion

• Ideal solution, technique, or delivery method has
  yet to be identified
• Complexity of ischemia/reperfusion injury,
• Ideal protection is no longer limited to OT
• Need to develop new therapeutic strategies to
  protect the heart

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Thank you
THANK YOU!
Dr. Narender to continue.
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Pediatric CPB

• Immature handling of calcium
• Immature myocardium can use carbo/
  aa/ketones/MCFA/LCFA.
• Hypoglycemia / hemodilution
• Resistant to ischemia
• increased gycolytic cabability
• decreased 5nucleotidase..increased ATP

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SUPPLY. DEMAND
100 0
Ao
DPTI diastolic pressure time index TTI tension
time index
DPTI
.. .LA or PA wedge
TTI
Buckberg 1972
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Protection strategies

• Design of cardioplegic solution
• Temperature
• Electromechanical work state
• pH
• Metabolic substrates/additives

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Protection techniques

• Systemic hypothermia with VF
• Ischemic arrest with hypothermia
• Continuous coronary perfusion
• Chemical cardioplegia

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Coming off bypass

• Problems
• Systemic rewarming and aortic unclampingtachy/fev
  er/ increased SVR / rise in circulating
  catecholamines
• More compliant heart..greater LVED
• Acute withdrawal of CCB/BB
• Coronary vasospasm
• Elevated O2 req. of recovering myocardium

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• Solutions
• Reinstitute bypass in ventricular distension
• Optimise hemodynamic parameters
• High dose ionotropes better avoided
• Adequate preload
• Afterload reduction or IABP
• Bleeding corrected
• Failure to achieve separation.IABP/LVAD

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Cessation of Myocardial Blood Flow
mitochondria cellular pO2 lt 5mmHg within
seconds oxidative phosporilation stops
cytosol anaerobic glycolysis glycogen glucose-6-
phosphate pyruvate lactate cellular
acidosis depletion of ATP
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