815-20 mins following normothermic ischemia: Total diastolic arrest from cell membrane depolarisationMyocardial contracture … ‘stone heart’Vacuolization of SR, mitochondriaRelease of lysosomal enzymesUncoupling of oxidation and respirationSequester calcium/expel hydrogen
9Depletion of ATP < 50% of Normal Level- irreversible lethal cell injuryglycolysis is blockedincreasing cellular acidityprotein denaturationstructural, enzymatic, nuclear changes
10Hibernating 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)
11Stunned myocardium Severe reduction in myocardial blood flow Function of the myocardium remains impaired (stunned) for a certain period despite reestablishment of flowBut full recovery is expectedProcess occurs over a period of 1-2 weeksContractile proteins recover if the myocyte is reperfused before irreversible damage
12Myocardial injury..factors IschemiaVentricular distensionTachycardiaHypertension / hypotensionFall in DPTI:TTI ratioVentricular hypertrophyReperfusion
14Hypothermia 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.
17INTERMITTENT AoXCl + VF + MODERATE HYPOTHERMIC PERFUSION (30°C TO 32°C) Quiet field (during ventricular fibrillation)Avoids the profound metabolic changes that occur with more prolonged periods of ischemia.Duration of fibrillation till completion of distalsHeart defib, proximals using an aortic partial clamp
18In 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.
19In 2002, Raco et al-800 pts CABGMortality- 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.
20SYSTEMIC HYPOTHERMIA AND ELECTIVE FIBRILLATORY ARREST Systemic hypothermia (25-28°C)Elective fibrillatory arrestMaintenance of perf pres bet mmHgSurgical field may be obscured by blood during revascularization
21In 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.
22CONTINOUS CORONARY PERFUSION Continous blood perfusion of empty beating heartAortic root/ ostial infusionUsed in OPCABUnsafe for open heartContinous retro + AoXCl- open heart
26Cardioplegic delivery Antegrade routeAdvantage: immediate cardioplegiaProblems:Impaired perfusion beyond obstructionAVI..also in mitral surgery as aortic root distorted on atrial retractionHypertrophied heart
30Hypothermia Decreased metabolic rate Ischemia: intracellular pH ….. nonionised : ionised substrate ratio… NI substrate escapeout of cell.Hypothermia NI:I ratioSemiliquid to semisolid memebrane.. calcium influx.glutamate release in brain… ca sequest.
31Hypothermia Total extracorporeal circulation Surface cooling Surface cooling with partial CPBDeep hypothermic total circulatory arrestLow-flow, profoundly hypothermic perfusionAll cooling for 30mins before starting CPBsurface: <2.5 kg; small ascending aorta . Temp drops to 20c
32Problems of hypothermia DHCA can cause seizures, stroke, change in mental status and muscle tone, post pump choreoathetosis.Neocortex, hippocampus, striatumLoss of cerebral autoregulation<15°CCoagulopathy,acidosis,enzyme dysfunctionAlong with alkalosis, shift Bohr’s oxy-dissociation curve to left.
33 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).
34Rewarming<10-12°C gradient between venous blood and water temperature….also between arterial blood entering and core temperature.CPB withdrawn when bladder temp is 37°CPrevent hyperthermiaEsophageal/PAC temp not reliableAlpha stat method to correct pH……. probably better neuro. outcome in profound hypothermiaMediastinum flushed with cold saline
35Reperfusion Cell damage following ischaemia is biphasic; injury being initiated during ischaemiaexacerbated during reperfusion
36Components: Intracell Ca2+ overload during isch & reper Oxidative stress induced by reactive oxygen species (ROS)Ischemia ↓ endogenous antioxidant defenseLoss of cell memb integrity
37conjugated dienes are “chemical signatures” of oxygen free-radical lipid peroxidation Romaschin AD, Rebeyka I, Wilson GJ, et al.J Mol Cell Cardiol 1987;19:free radicals are generated within 10 seconds of reperfusion after ischaemiaZweier JL, Flaherty JT, Weisfeldt ML.Proc Natl Acad Sci USA 1987;84:
38Reduce reperfusion injury Reduce ionic calcium conc. in reperfusate1.0 meq/L…chelate with CPDpH ofReperfusate pressure 50 mm Hg & osmolality of 350 mOsm..reduce edemaMaintaining potassium arrestInfusing at 37°C
39Calcium regulation Hallmark of reperfusion is Ca uptake Post ischemic failure of normal sequestration by SR / contractile app.Calcium phosphate crystal deposition in mitochondrial matrixDamage to respiratory chain and failure of ATP production
40Other measures: Antioxidants- Vit E, glutathione OFR scavengers-SOD, catalase, peroxidase, allopurinol, mannitol, CoQ10, deferoxamine mesylateWBC filters
41BLOOD CP LEUCOCYTE FILTRATION Myocardial ischemia and reperfusion- activation of neutrophilsBenefit of filtration in:patients undergoing emergency CABGprolonged crossclamping,depressed ejection fraction,heart transplantation.
42At least 90% of leucocytes must be removed to attenuate reperfusion injury markedly. Leucocyte depletion should be maintained for 5–10 min after the start of initial reperfusion prior to aortic clamp release.Filters remove more than 90% of WBCs
43CONTROLLED 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%.
44Complications of protective strategies RV dysfunction..rewarming / poor distribution…topical coolingCoronary ostial stenosis..soft tipped cannula/leakage around cannulaEndothelial damage to vein graft from hyperkalemic crystalloid cardioplegicCoronary sinus injuryInfusion pressure <50mmHg through sinus
45Energy depleted heart Cardiogenic shock/ unstable angina Preop stabilisation with IABP / pharmacological support / MechVentPrompt amino acid enriched warm blood cardioplegiaFollowed by cold cardioplegiaBoth antegrade + retrograde flow
47Ischemic 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.
48Brief 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.
49Enzyme 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 CAD…net production of urate increased in ischemia.
50A 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 deathineff if sustained ischemic insult > 3 hrsPreconditioning failed to protect the mid and subepicardial myocardium
51Second 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
52IP involves a complex cascade of intracellular events ischemic stimulusadenosine subtype 1 (A1) receptoramplifiedG protein and protein kinase C (PKC).effectorATP–regulated potassium channel (KATP).?protective effect
53Anesthetic preconditioning A safer and simpler alternative to IP is pharmacologic intervention by inhalation anestheticsAPC shares the same mechanism of action as IPThe 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.
54Anesthetic preconditioning Isoflurane was administered in the pre–cardiopulmonary bypass (CPB) periodThe 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
55Dogs 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
56Sevoflurane decreases the inflammatory response after CPB, as measured by the release of IL-6, CD11b/CD18, and TNF-α.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
571. 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.
60Sodium/Hydrogen Exchange Inhibition Amiloride, cariporide, eniporide, zoniporideEjection 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.
61opioidsHibernating animals use only '10% of their normal, active energy expenditure.Hibernation is a process mediated by cyclical variation in endogenous opiate compounds.δ-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 δ -opiate activity confer myocardial protection, which is additive to cardioplegia.
62MYOCARD PROTECTION- OPCAB Short-acting beta blocker esmololCariporide and aprotinin- associated with a marked attenuation of stunning.
63Conclusion:Ideal solution, technique, or delivery method has yet to be identifiedComplexity of ischemia/reperfusion injury,Ideal protection is no longer limited to OTNeed to develop new therapeutic strategies to protect the heart
66Pediatric CPB Immature handling of calcium Immature myocardium can use carbo/ aa/ketones/MCFA/LCFA.Hypoglycemia / hemodilutionResistant to ischemia :increased gycolytic cababilitydecreased 5’nucleotidase..increased ATP
67SUPPLY…. DEMAND 100 Ao DPTI: diastolic pressure time index AoDPTI: diastolic pressure time indexTTI: tension time indexDPTI……………………………………………….LA or PA wedgeTTIBuckberg 1972
68Protection strategies Design of cardioplegic solutionTemperatureElectromechanical work statepHMetabolic substrates/additives
69Protection techniques Systemic hypothermia with VFIschemic arrest with hypothermiaContinuous coronary perfusionChemical cardioplegia
70Coming off bypass Problems: Systemic rewarming and aortic unclamping…tachy/fever/ increased SVR / rise in circulating catecholaminesMore compliant heart..greater LVEDAcute withdrawal of CCB/BBCoronary vasospasmElevated O2 req. of recovering myocardium
71Solutions:Reinstitute bypass in ventricular distensionOptimise hemodynamic parametersHigh dose ionotropes better avoidedAdequate preloadAfterload reduction or IABPBleeding correctedFailure to achieve separation….IABP/LVAD
72Cessation of Myocardial Blood Flow mitochondriacellular pO2 < 5mmHg within secondsoxidative phosporilation stopscytosolanaerobic glycolysisglycogenglucose-6-phosphatepyruvatelactatecellular acidosisdepletion of ATP