15-20 mins following normothermic ischemia: Total diastolic arrest from cell membrane depolarisation Total diastolic arrest from cell membrane depolarisation Myocardial contracture … ‘stone heart’ Myocardial contracture … ‘stone heart’ Vacuolization of SR, mitochondria Vacuolization of SR, mitochondria Release of lysosomal enzymes Release of lysosomal enzymes Uncoupling of oxidation and respiration Uncoupling of oxidation and respiration Sequester calcium/expel hydrogen Sequester calcium/expel hydrogen
Depletion of ATP < 50% of Normal Level- irreversible lethal cell injury glycolysis is blocked glycolysis is blocked increasing cellular acidity increasing cellular acidity protein denaturation protein denaturation structural, enzymatic, nuclear changes structural, enzymatic, nuclear changes
Hibernating myocardium Moderate and persistent reduction in myocardial blood flow cause diminished regional contraction (non-contractile) Moderate and persistent reduction in myocardial blood flow cause diminished regional contraction (non-contractile) Metabolic processes remain intact (viable) Metabolic processes remain intact (viable) Decrease in the magnitude of the pulse of calcium involved in the excitation-contraction process 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)
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
Myocardial injury..factors Ischemia Ischemia Ventricular distension Ventricular distension Tachycardia Tachycardia Hypertension / hypotension Hypertension / hypotension Fall in DPTI:TTI ratio Fall in DPTI:TTI ratioratio Ventricular hypertrophy Ventricular hypertrophy Reperfusion Reperfusion
Hypothermia and potassium infusions the cornerstone of myocardial protection during on-pump heart surgery,Hypothermia and potassium infusions the cornerstone of myocardial protection during on-pump heart surgery, Many other cardioprotective techniques and methodologies available.Many other cardioprotective techniques and methodologies available. The ideal cardioprotective technique, solution, and/or method of administration has yet to be found.The ideal cardioprotective technique, solution, and/or method of administration has yet to be found.
Myocardial O 2 demand: 75% 50% 10%
Non cardioplegic techniques
INTERMITTENT 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 distals Heart defib, proximals using an aortic partial clamp
In 1992, Bonchek et al 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.
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.
SYSTEMIC HYPOTHERMIA AND ELECTIVE FIBRILLATORY ARREST Systemic hypothermia (25-28°C) Elective fibrillatory arrest Maintenance of perf pres bet mmHg Surgical field may be obscured by blood during revascularization
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.
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
Cardioplegic delivery Antegrade route Advantage: immediate cardioplegia Advantage: immediate cardioplegia Problems: Problems: Impaired perfusion beyond obstruction Impaired perfusion beyond obstruction AVI..also in mitral surgery as aortic root distorted on atrial retraction AVI..also in mitral surgery as aortic root distorted on atrial retraction Hypertrophied heart Hypertrophied heart
Retrograde route Advantage: Advantage: Better septal cooling Better septal cooling Cardioplegic solution perfuse beyond stenosis Cardioplegic solution perfuse beyond stenosis Problems: Problems: RV not adequately protected RV not adequately protected Risk of coronary sinus perforation / myocardial hemorrage / edema Risk of coronary sinus perforation / myocardial hemorrage / edema Infusion pressure kept < 50mmHg Infusion pressure kept < 50mmHg Antegrade + retrograde More prompt arrest More prompt arrest Better disribution of solution Better disribution of solution
Hypothermia Basal metabolism 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 This basal cost can be further reduced with hypothermia–
Hypothermia Oxygen Demand reduction Oxygen Demand reduction Normothermic Arrest (37 o C) 1mL/100g/min 90% Normothermic Arrest (37 o C) 1mL/100g/min 90% Hypothermic Arrest (22 o C) 0.30 mL/100g/min 97% Hypothermic Arrest (22 o C) 0.30 mL/100g/min 97% Hypothermic Arrest (10 o C)0.14 mL/100g/min ~ 97% Hypothermic Arrest (10 o C)0.14 mL/100g/min ~ 97%
Hypothermia Decreased metabolic rate Decreased metabolic rate Ischemia: intracellular pH ….. nonionised : ionised substrate ratio… NI substrate escapeout of cell. Ischemia: intracellular pH ….. nonionised : ionised substrate ratio… NI substrate escapeout of cell. Hypothermia NI:I ratio Hypothermia NI:I ratio Semiliquid to semisolid memebrane.. calcium influx. Semiliquid to semisolid memebrane.. calcium influx. glutamate release in brain… ca sequest. glutamate release in brain… ca sequest.
Hypothermia Total extracorporeal circulation Total extracorporeal circulation Surface cooling Surface cooling Surface cooling with partial CPB Surface cooling with partial CPB Deep hypothermic total circulatory arrest Deep hypothermic total circulatory arrest Low-flow, profoundly hypothermic perfusion Low-flow, profoundly hypothermic perfusion All cooling for 30mins before starting CPB
Problems of hypothermia DHCA can cause seizures, stroke, change in mental status and muscle tone, post pump choreoathetosis. DHCA can cause seizures, stroke, change in mental status and muscle tone, post pump choreoathetosis. Neocortex, hippocampus, striatum Neocortex, hippocampus, striatum Loss of cerebral autoregulation<15°C Loss of cerebral autoregulation<15°C Coagulopathy,acidosis,enzyme dysfunction Coagulopathy,acidosis,enzyme dysfunction Along with alkalosis, shift Bohr’s oxy- dissociation curve to left. Along with alkalosis, shift Bohr’s oxy- dissociation curve to left.
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).
Rewarming <10-12°C gradient between venous blood and water temperature….also between arterial blood entering and core temperature. <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°C CPB withdrawn when bladder temp is 37°C Prevent hyperthermia Prevent hyperthermia Esophageal/PAC temp not reliable Esophageal/PAC temp not reliable Alpha stat method to correct pH……. probably better neuro. outcome in profound hypothermia Alpha stat method to correct pH……. probably better neuro. outcome in profound hypothermia
Reperfusion Cell damage following ischaemia is biphasic; Cell damage following ischaemia is biphasic; – injury being initiated during ischaemia – exacerbated during reperfusion
Components: Intracell Ca2+ overload during isch & reper Oxidative stress induced by reactive oxygen species (ROS) Ischemia ↓ endogenous antioxidant defense Loss of cell memb integrity
conjugated dienes are “chemical signatures” of oxygen free-radical lipid peroxidation conjugated 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 ischaemia free radicals are generated within 10 seconds of reperfusion after ischaemia Zweier JL, Flaherty JT, Weisfeldt ML. Proc Natl Acad Sci USA 1987;84:
Reduce reperfusion injury Reduce ionic calcium conc. in reperfusate Reduce ionic calcium conc. in reperfusate 1.0 meq/L…chelate with CPD 1.0 meq/L…chelate with CPD pH of pH of Reperfusate pressure 50 mm Hg & osmolality of 350 mOsm..reduce edema Reperfusate pressure 50 mm Hg & osmolality of 350 mOsm..reduce edema Maintaining potassium arrest Maintaining potassium arrest Infusing at 37°C Infusing at 37°C
Calcium regulation Hallmark of reperfusion is Ca uptake Hallmark of reperfusion is Ca uptake Post ischemic failure of normal sequestration by SR / contractile app. Post ischemic failure of normal sequestration by SR / contractile app. Calcium phosphate crystal deposition in mitochondrial matrix Calcium phosphate crystal deposition in mitochondrial matrix Damage to respiratory chain and failure of ATP production Damage to respiratory chain and failure of ATP production
Other measures: Antioxidants- Vit E, glutathione OFR scavengers-SOD, catalase, peroxidase, allopurinol, mannitol, CoQ10, deferoxamine mesylate WBC filters
At 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
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%.
Complications of protective strategies RV dysfunction..rewarming / poor distribution…topical cooling RV dysfunction..rewarming / poor distribution…topical cooling Coronary ostial stenosis..soft tipped cannula/leakage around cannula Coronary ostial stenosis..soft tipped cannula/leakage around cannula Endothelial damage to vein graft from hyperkalemic crystalloid cardioplegic Endothelial damage to vein graft from hyperkalemic crystalloid cardioplegic Coronary sinus injury Coronary sinus injury Infusion pressure <50mmHg through sinus Infusion pressure <50mmHg through sinus
Energy depleted heart Cardiogenic shock/ unstable angina Cardiogenic shock/ unstable angina Preop stabilisation with IABP / pharmacological support / MechVent Preop stabilisation with IABP / pharmacological support / MechVent Prompt amino acid enriched warm blood cardioplegia Prompt amino acid enriched warm blood cardioplegia Followed by cold cardioplegia Followed by cold cardioplegia Both antegrade + retrograde flow Both antegrade + retrograde flow
PROTECTION STRATEGIES UNDER INVESTIGATION
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.
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.
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 CAD…net production of urate increased in ischemia.
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 > 3 hrs Preconditioning failed to protect the mid and subepicardial myocardium
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
adenosine subtype 1 (A1) receptor ischemic stimulus G protein and protein kinase C (PKC). ATP–regulated potassium channel (KATP). protective effect IP involves a complex cascade of intracellular events amplified effector ?
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.
Anesthetic preconditioning Isoflurane was administered in the pre–cardiopulmonary bypass (CPB) period Isoflurane 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
DogsDogs 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
Sevoflurane 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
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.
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.
opioids Hibernating 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. Drugs
MYOCARD PROTECTION- OPCAB Short-acting beta blocker esmolol Cariporide and aprotinin- associated with a marked attenuation of stunning. Cariporide
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
Thank you Dr. Narender to continue……. THANK YOU!
Pediatric CPB Immature handling of calcium Immature handling of calcium Immature myocardium can use carbo/ aa/ketones/MCFA/LCFA. Immature myocardium can use carbo/ aa/ketones/MCFA/LCFA. Hypoglycemia / hemodilution Hypoglycemia / hemodilution Resistant to ischemia : Resistant to ischemia : 1. increased gycolytic cabability 2. decreased 5’nucleotidase..increased ATP
SUPPLY…. DEMAND ……………………………………………….LA or PA wedge Ao TTI DPTI Buckberg 1972 DPTI: diastolic pressure time index TTI: tension time index
Protection strategies Design of cardioplegic solution Design of cardioplegic solution Temperature Temperature Electromechanical work state Electromechanical work state pH pH Metabolic substrates/additives Metabolic substrates/additives
Protection techniques Systemic hypothermia with VF Systemic hypothermia with VF Ischemic arrest with hypothermia Ischemic arrest with hypothermia Continuous coronary perfusion Continuous coronary perfusion Chemical cardioplegia Chemical cardioplegia
Coming off bypass Problems: Systemic rewarming and aortic unclamping…tachy/fever/ increased SVR / rise in circulating catecholamines Systemic rewarming and aortic unclamping…tachy/fever/ increased SVR / rise in circulating catecholamines More compliant heart..greater LVED More compliant heart..greater LVED Acute withdrawal of CCB/BB Acute withdrawal of CCB/BB Coronary vasospasm Coronary vasospasm Elevated O 2 req. of recovering myocardium Elevated O 2 req. of recovering myocardium
Solutions: Reinstitute bypass in ventricular distension Reinstitute bypass in ventricular distension Optimise hemodynamic parameters Optimise hemodynamic parameters High dose ionotropes better avoided High dose ionotropes better avoided Adequate preload Adequate preload Afterload reduction or IABP Afterload reduction or IABP Bleeding corrected Bleeding corrected Failure to achieve separation….IABP/LVAD Failure to achieve separation….IABP/LVAD
Cessation of Myocardial Blood Flow Cessation of Myocardial Blood Flow mitochondria cellular pO 2 < 5mmHg within seconds oxidative phosporilation stops cytosol anaerobic glycolysis glycogenglucose-6-phosphatepyruvatelactate cellular acidosis depletion of ATP