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Cardioplegia

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Raja Lahiri

This document discusses various topics related to cardioplegia, including alternative arresting agents and additives, crystalloid versus blood cardioplegia, and potential new technologies. It provides details on adenosine receptors, minute work and oxygen demand, alternative arresting agents such as beta blockers and adenocaine, agents affecting calcium transport, and ways to avoid substrate depletion. It compares crystalloid and blood cardioplegia, outlining advantages and disadvantages of each. Finally, it discusses novel strategies for cardioprotection such as ischemic preconditioning, post-conditioning, and remote ischemic preconditioning.

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Cardioplegia session -Dr Raja Lahiri
Topics  Alternative arresting agents & additives  Crystalloid vs Blood cardioplegia  Potential newer technology
Cardioplegia
Cardioplegia
Adenosine receptors  Four types of adenosine receptors: A1, A2a, A2b, A3  Activation of adenosine A 1 receptors leads to: ◦ inhibition of cyclic AMP production ◦ inhibition of the slow calcium channel ◦ opening of an adenosine-activated ATPsensitive potassium (K ATP ) channel  This leads to hyperpolarization, which delays conduction through the AV node and slows the ventricular response to atrial tachycardia.  It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls.  Activation of A2A receptors produces a constellation of responses that in general can be classified as anti- inflammatory  Pretreatment with adenosine confers a cardioprotective effect during ischemia and can inhibit the inflammatory responses initiated by ischemia and reperfusion
Cardioplegia
Minute work & Oxygen demand  Minute work = Heart rate x Stroke volume x Pressure  However, minute work is not the direct determinant of oxygen consumption  The primary determinant of oxygen demand is the wall tension or stress developed in each cardiac cycle.  The energetic cost of ejecting blood from the ventricular chamber is approximately 20 to 30% of that required for isovolumic contraction.  An increase in afterload requires greater energy than an increase in volume ejected.  Oxygen consumption is also increased as the heart dilates and begins ejection from a greater diastolic volume.  Cardiac efficiency = Work/MVO2
Alternative arresting agents & Additives  Beta Blockers: ◦ As the ascending aorta is clamped, the non- exocytotic release of norepinephrine from the cardiac sympathetic nerves acts on β-adrenergic receptors on the outer surface of the sarcolemma, causing an increase in cAMPdependent protein kinase activity, phosphorylation of the calcium release channels, and increased Ca2+ influx, resulting in increased Ca2+-dependent contractility and rapid depletion of glycogen stores. ◦ Early studies suggested that long-acting beta blockers improved myocardialprotection during ischemia but unfortunately have a prolonged negative inotropic effect, which limits their clinical use.
 Beta blockers such as propranolol have been used as an adjunct to anesthesia to block β-adrenergic– stimulating episodes associated with coronary ischemia during the course of the operative procedure.  Ultra-short-acting cardioselective beta blockers such as landiolol and esmolol provide polarized cardiac arrest by maintaining the membrane potential at or near the resting membrane potential  Esmolol has been used to enhance myocardial protection during intermittent arrest and has been shown to provide myocardial preservation equivalent to or better than cold crystalloid or blood cardioplegia.  With esmolol cardioplegia, there is a slow undulating ventricular contraction that may decrease myocardial edema but does not provide a quiescent operating field
Adenocaine  Adenosine-lidocaine (adenocaine) cardioplegia provides an exciting alternative to depolarizing cardioplegia.  Adenosine-lidocaine cardioplegia has been shown to provide a shorter time to electromechanical arrest, greater postischemic recoveries of aortic flow, a lower coronary vascular resistance during infusion, and greater MVO2 as compared to St. Thomas’ Hospital solution, while maintaining the myocardial cell membrane potential at its resting state
Agents Affecting Calcium Transport The infusion of calcium-free cardioplegic solutions induces rapid diastolic cardiac arrest by inhibiting excitation-coupling and increases permeability of the sarcolemma.  When a calcium-containing perfusate is then reinfused, during reperfusion, there is a rapid influx of calcium into the cell, resulting in myocardial contracture and extensive ultrastructural damage, the “calcium paradox.”  Calcium antagonist agents administered before ischemia have been proposed as a possible mechanism to reduce ischemic cellular injury.  Calcium channel blocking agents, including verapamil, diltiazem, and nifedipine, prevent calcium-induced calcium release in myocardial cells and, as an adjunct to normothermic cardioplegia, have been shown to improve postischemic systolic function.  Calcium blockers have no effect if they are administered before reperfusion, are temperature dependent, and have limited effect during hypothermia.  Because high concentrations are required for cardioprotection, their prolonged membrane binding prevents rapid recovery, thus limiting their clinical usefulness.
 Magnesium: ◦ Magnesium inhibits calcium entry into the cell by displacing calcium from its binding sites in the sarcolemmal membrane. ◦ It has limited use as an arresting agent because high concentrations are required, cardiac arrest is delayed, and postischemic functional recovery is decreased in comparison to potassium cardioplegia. ◦ The advantages of magnesium have been shown to be optimal when it is included with high-potassium cardioplegia, in which it has been demonstrated to ameliorate cytosolic, nuclear, and mitochondrial calcium accumulation; preserve high-energy phosphate moieties; and enhance postischemic functional recovery.
Avoidance of Substrate Depletion  Metabolic substrates have been added to cardioplegic solutions to enhance anaerobic metabolism during ischemia or to provide citric acid cycle intermediaries to facilitate homeostasis during reperfusion.  Agents used include glucose and insulin; nucleosides, such as adenosine, aspartate, and glutamate; and L-arginine to stimulate nitric oxide production.  Although metabolic substrate enhancement has been used in various clinical situations, none has achieved universal adoption.
Blood v/s Crystalloid cardioplegia  Crystalloid cardioplegia: ◦ these solutions contain minimal amounts (0.6 mL/100 mL at a PO2 of 100 mm Hg at a temperature of 10° C) of dissolved oxygen, whereas the myocardium consumes 0.33 mL of oxygen per 100 g at 15° C. ◦ Because even a short period of ischemia results in the gradual accumulation of oxygen debt, moderate to severe myocardial hypothermia is necessary to prevent the rapid degradation of energy stores ◦ To overcome the oxygen deficit issue, oxygenation of crystalloid cardioplegia has been clinically used and has demonstrated a decrease in creatine kinase MB levels
Clinical steps for myocardial protection with use of crystalloid cardioplegia 1. Before the onset of surgery, the operating room temperature is cooled to 17° C to 19° C to avoid warming of the anterior surface of the heart by convection and radiation from highintensity lighting. 2. Cardiopulmonary bypass is initiated at a temperature of 28° C. 3. A myocardial electrocardiographic lead and temperature probe are placed on the anterior wall of the right ventricle because it constitutes two thirds of the anterior surface of the heart, and its rewarming during surgically induced ischemia may partially explain the occasional observation of selective right ventricular failure after the termination of bypass 4. an insulation pad is placed in the posterior pericardial sac and along the left ventricular lateral wall to protect the left phrenic nerve from thermal injury associated with regional
5. The systemic perfusate temperature is temporarily decreased to 10° C to 15° C to “precool” the heart (infusion hypothermia), and iced saline slush is placed into the pericardial sac to achieve rapid myocardial cooling 6. When a myocardial temperature of 28° C is reached, the ascending aorta is cross-clamped and cold crystalloid cardioplegia solution at a temperature of 5° C is infused into the aortic root at a pressure not exceeding 90 mm Hg @10ml/kg 7. At the termination of the initial cardioplegic infusion, the systemic temperature is elevated to 20° C, and the systemic perfusion flow rate is decreased from 2.2 to 1.5 liter/min/m2 .Increase in myocardial temperature above 20° C or if there is any electrocardiographic activity or observed ventricular motion, the solution is reinfused at a volume of 5 mL/kg. 8. Five minutes before removal of the aortic clamp, the systemic perfusate temperature is raised to 30° C, and flow is increased to 2.2 liter/min/m2. 9. After the aortic cross-clamp is removed, the perfusate temperature is raised to 38° C and the room temperature is raised to 25° C to 30° C. 10. Cardiopulmonary bypass is continued until the esophageal temperature is 37° C and the rectal temperature is in the range of 35° C to 37° C.
Disadvantage of crystalloid cardioplegia  Extensive rewarming period, which may exceed 30 to 45 minutes.  Slow recovery of myocardial metabolism  Poor response to postoperative hemodynamic stress  Gradual accumulation of oxygen debt and myocardial damage if adequate hypothermia not maintained
Blood Cardioplegia  Advantages: ◦ Optimum oxygenation (superior to oxygenated crystalloids) ◦ Better removal of carbon-dioxide ◦ Buffering action and reducing agent ◦ Presence of colloid avoids adverse oncotic pressure gradients ◦ presence of oxygen free radical scavengers ◦ Preserves microvascular responses compared with crystalloid cardioplegia
Blood Cardioplegia  Concerns: ◦ the hypothermic shift to the left of the oxyhemoglobin dissociation curve, thereby reducing the release of oxygen at the tissue level ◦ the experimental evidence that blood cardioplegia may not protect the myocardium at low temperatures ◦ the potential of hypothermia induced sludging and red cell rouleau formation.
Warm blood cardioplegia  In 1982 Rosenkranz and colleagues reported that warm induction with normothermic blood cardioplegia, with multidose cold blood cardioplegia maintenance of arrest, resulted in better recovery of function in canines than a similar protocol using cold blood induction  In 1986, Teoh and colleagues provided experimental evidence that a terminal infusion of warm blood cardioplegia before removing the cross-clamp (a “hot shot”) accelerated myocardial metabolic recovery  This was followed by a report in 1991 by Lichtenstein and colleagues that normothermic blood cardioplegia in humans is an effective cardio-protective approach.
 Despite these encouraging reports, there are concerns that for any given patient, it is difficult to determine how long a warm heart can tolerate an ischemic insult if the infusion is interrupted or flow rates are reduced owing to an obscured surgical field or a maldistribution of the cardioplegic solution.  Another concern is the report by Martin and colleagues that warm cardioplegia is associated with a threefold increased incidence of neurologic deficits.  Subsequent studies have indicated however that appropriately designed protocols using intermittent antegrade warm blood cardioplegia provide clinically acceptable myocardial protection
Tepid blood cardioplegia  Both cold blood (4 to 10°C) and warm blood cardioplegic solutions (37°C) have temperature- related advantages and disadvantages.  Hayashida and colleagues were one of the first groups to study specifically the efficacy of tepid blood (29°C) cardioplegia. Their study showed that tepid antegrade cardioplegia was the most effective in reducing anaerobic lactate acid release during the arrest period.  Mallidi et al showed that warm or tepid blood cardioplegia may be associated with better early and late event-free survivals after CABG  Although tepid blood cardioplegia may be safe and effective, the majority of studies have been single- center studies conducted in relatively small cohorts of patients. Whether tepid cardioplegia confers superior protection over other current methodologies remains to be determined.
Miniplegia  The use of undiluted blood cardioplegia, or “miniplegia” (using a minimum amount of crystalloid additives), also has been reported to be effective.  Petrucci et al. studied the use of all blood miniplegia in a clinically relevant swine preparation and compared miniplegia with crystalloid cardioplegia.  They concluded that the use of all blood miniplegia was effective or superior in the acutely ischemic heart.  Rousou and colleagues showed that it is the level of hypothermia that is important in blood cardioplegia, not necessarily the hematocrit.
Advantages of Blood cardioplegia (1) provides an oxygenated environment and a method for intermittent reoxygenation of the heart during arrest (2) limits hemodilution when large volumes of cardioplegic solution are used (3) affords an excellent buffering capacity and osmotic properties (4) allows for electrolyte composition and pH that are physiologic (5) offers a number of endogenous antioxidants and free-radical scavengers (6) is less complex than other solutions to prepare.
Cardioplegia
Cardioplegia
Novel strategies for cardioprotection  Physiologic: ◦ Ischaemic preconditioning ◦ Post conditioning ◦ Remote ischaemic preconditioning ◦ Autophagy  Pharmacologic: ◦ Adenosine ◦ Acadesine ◦ Sodium-Hydrogen exchanger inhibitors ◦ Glucose-Insulin-Potassium (GIK)
Ischaemic preconditioning  “Precondition with ischemia” is an endogenous adaptive phenomenon whereby the heart becomes more tolerant to a period of prolonged ischemia if first exposed to brief episodes of coronary artery occlusion.  IPC has been demonstrated to persist as long as 1 to 2 hours after the ischemic preconditioning stimulus & becomes ineffective when the sustained ischemic insult exceeds 3 hours  A second phase of protection appears 24 hours later and is sustained for up to 72 hours. This has been referred to as the second window of protection, late- phase preconditioning, or delayed preconditioning.  Unlike classic IPC, which protects only against infarction, the late phase protects against both infarction and myocardial stunning.
1
Clinical relevance of IPC  Patients experiencing angina before an MI have a better in-hospital prognosis and a reduced incidence of cardiogenic shock, fewer and less severe episodes of congestive heart failure, and smaller infarcts as assessed by cardiac enzyme release and better long term survival rates  Patients who undergo percutaneous coronary interventions (PCI) have an enhanced tolerance to ischemia after the first balloon inflation, provided that the first balloon inflation exceeds 60 to 90 seconds  Intermittent cross-clamping with the heart paced at 90 beats per minute to induce ischemia, followed by 2 minutes of reperfusion before a 10- minute period of global ischemia and ventricular fibrillation has shown attenuation of troponin release
Post conditioning  First reported by Zhao et al in canine model  Rapid intermittent interruptions of blood flow in the early phase of reperfusion, i.e., relief of ischemia in a stuttered or staccato manner.  The reduction in infarct size appears to be comparable with that observed with IPC.  Patients receiving brief balloon inflations/deflations in the initial minutes of reperfusion during PCI exhibited smaller ST- segment changes and lower levels of total creatine kinase release compared with patients that were not subjected to stuttering reperfusion  Luo et al in their study on post-op patients after total correction of TOF showed that aortic reclamping for 30 seconds and declamping for 30 seconds, repeated twice, reduced perioperative troponin T and CK-MB release and decreased the need for inotropic support after surgery
Remote Ischaemic Preconditioning  Remote ischemic preconditioning is a phenomenon whereby brief ischemia of one organ or tissue confers protection on a distant naive organ or tissue against a sustained ischemia- reperfusion injury  Brief intermittent lower limb ischemia was associated with attenuated troponin release and a reduction in the need for postoperative inotropic support in children undergoing congenital heart surgery  Similar findings were demonstrated in adult patients undergoing CABG where RIPC was induced by three 5-minute cycles of right forearm ischemia by inflating a blood pressure cuff on the upper arm to 200 mm Hg with an intervening 5-
Autophagy  Autophagy is the process whereby a doublemembrane structure called the autophagosome sequesters cytoplasmic components such as ubiquitinated protein aggregates or organelles including mitochondria, peroxisomes, and endoplasmic reticulum.  It is involved in degradation of long-lived proteins and the removal of excess or damaged organelles  The outer autophagosomal membrane fuses with a lysosomal membrane to deliver its contents into an autophagolysosome where the cargo is degraded by lysosomal hydrolases and the resulting macromolecules recycled
Cardioplegia
 Autophagy has been reported to be upregulated in isolated cells subjected to simulated ischemia and reperfusion and rodent models of ex vivo and in vivo ischemia reperfusion injury.  Gurusamy et al. investigated the role of autophagy during ischemia-reperfusion injury and reported that increased BAG- 1 expression in the heart correlated with the onset of protection in an in vivo model of myocardial stunning.  Studies suggest that upregulation of autophagy promotes survival during stress such as ischemia-reperfusion  There is also direct evidence that autophagy plays an important role in mediating ischemic and pharmacologic preconditioning.  Autophagy may serve as an important mediator of protection of the preconditioning agent CCPA. A more detailed understanding of the role of autophagy in myocardial protection may lead to a new therapeutic approach to the management and treatment of ischemia-reperfusion injury.
Adenosine  There is considerable experimental evidence that activation of various adenosine receptor subtypes results in cardioprotection similar to that induced by IPC.  Preischemic administration of the nucleoside adenosine retards the rate of ischemia-induced ATP depletion, prolongs the time to onset of ischemic contracture, attenuates myocardial stunning, enhances postischemic myocardial energetics, and reduces infarct size  Recent preclinical reports suggest that an adenosine A 2b receptor agonist confers cardioprotection when administered before the onset of ischemia (preconditioning) and at reperfusion (postconditioning)  In clinical trials, low dose adenosine administration showed no benefit on patient outcome  However, trials involving administration of high doses of adenosine in CABG patients showed reduction in postbypass inotropic drug utilization, improved regional wall motion, and global function measured by transthoracic echocardiography  Its clinical use is limited because large doses are associated with marked hypotension in patients not on cardiopulmonary bypass.
Acadesine  This agent is a member of a class of drugs referred to as adenosine regulating agents. It is a purine nucleoside analog that raises adenosine tissue levels selectively during ischemic conditions  Early preclinical studies have indicated that acadesine treatment: ◦ (1) improves left ventricular wall motion after intermittent ischemia ◦ (2) attenuates frequency of ventricular arrhythmias ◦ (3) attenuates myocardial stunning and preserves myocardial function after cardiac arrest and cold cardioplegia.  Mangano et al. examined the two-year all cause mortality after perioperative MI in a follow-up of the Acadesine 1024 Trial. Although the primary outcome was negative, the findings at two years among patients experiencing post
Sodium-Hydrogen Exchange inhibitors  The sodium-hydrogen exchangers (NHEs) are a family of membrane proteins with nine isoforms that are involved in the transport of hydrogen ions in exchange for sodium ions.  NHE-1 is the isoform that is expressed in the heart and may play a minor role in the normal excitation-contraction coupling process; however, it has been implicated in the etiology of arrhythmias, stunning, apoptosis, necrosis associated with acute myocardial ischemia-reperfusion injury, postinfarction ventricular remodeling, and heart failure
 The driving forces for Na + /H + exchange are the relative transmembrane N + and H + gradients.  During ischemia, cytoplasmic pH falls as low as 6.6 because of increased production of H + from anaerobic glycolysis, but upon reperfusion, NHE-1 is activated to restore intracellular pH by exchange of intracellular protons for extracellular sodium.  The resulting accumulation of intracellular Na + is further exacerbated by diminished activity of Na + /K + ATPase as a result of ischemia and lowered ATP availability.  The increased intracellular Na + competes for sites on the Na + /Ca ++ exchanger and can actually drive it to run in reverse, resulting in cytosolic calcium overload.  Calcium overload has numerous adverse consequences including activation of calcium- dependent proteases and phospholipases, gap junction dysfunction, culminating in membrane rupture and cell death
 The EXPEDITION trial was initiated to address the safety and efficacy of NHE-1 inhibition by cariporide in the prevention of death or MI in patients undergoing CABG surgery.  Although cariporide treatment was effective in reducing the incidence of nonfatal MI, its efficacy was associated with toxicity, and the overall assessment of benefits and risks associated with cariporide indicated that the imbalances in the safety profile outweighed the reduction in the observed MI rate  The importance of the study, however, is that myocardial necrosis after CABG is higher than previously appreciated and it suggested NHE-1 inhibitors represent a new class of drugs that hold promise for reduction of myocardial infarction associated with ischemiareperfusion injury.
Glucose Insulin Potassium  There are numerous studies that suggest glucose- insulin-potassium (GIK) infusions are effective in reducing perioperative MIs, postischemic myocardial dysfunction, and atrial fibrillation in patients undergoing heart surgery.  The rationale for this form of treatment is based on the concept that insulin stimulates potassium reuptake through stimulation of the Na + ,K + - ATPase while it stimulates glucose uptake for glycolytic energy production.  High glucose, insulin, and an increased glycolytic flux also increase pyruvate generation and in turn preserve the citric acid cycle.  Additionally, glycolytic ATP protects membranes, drives uptake of Ca 2+ by the sarcoplasmic reticulum, and improves sodium homeostasis of ischemic
 Despite a strong rationale for its application in surgery, the efficacy of GIK in heart surgery remains controversial, due to mixed results with the use of GIK to treat patients with acute myocardial infarction  Although a metaanalysis of randomized studies using GIK suggests that it may improve postoperative recovery of contractile function and reduce atrial arrhythmias, the individual studies have involved small numbers of patients and, therefore, insufficiently powered to detect efficacy.  Until a large randomized, multicenter clinical trial has been performed, the use of GIK as a form of myocardial protection will remain controversial.
Myocardial protection during beating heart surgery  The acceptance of OPCAB is due in part to the development and refinement of a myriad of surgical aids that allow for stabilization and local immobilization of the heart during grafting.  Ischemia during temporary occlusion of a coronary artery during OPCAB may last from 6 to 25 minutes based on the surgeon’s experience, quality and size of the vessel, and adequacy of the exposure.  Most patients with preexisting severe coronary heart disease have experienced self-limiting episodes of ischemia during daily life and may have imparted a certain degree of tolerance to the surgically induced ischemia.  This tolerance has been documented using ECGs, transesophageal echocardiography, and continuous SVO2 monitoring
 In order to better understand the differences between OPCAB and onpump surgery, Chowdhury et al. investigated the release pattern of various cardiac biomarkers in 50 patients undergoing cardioplegic and noncardioplegic coronary artery bypass surgery  They observed a greater release of cardiac troponin I, high-sensitivity C-reactive protein, and heart-type fatty acid binding protein in the cardioplegic group.  They concluded that OPCAB surgery is associated with less injury
 One approach to minimizing the risk of injury is to reduce myocardial oxygen demand. Pharmacologic beta-blockade is frequently instituted to reduce inotropy and achieve negative chronotropy using ultra-short-acting beta blockers such as esmolol and labetalol  Another approach is to optimize the systemic mean blood pressures while reducing afterload.  Calcium channel blockers, such as diltiazem, have been used to afford an effective reduction in blood pressure while minimizing a depression in myocardial contractility that may occur with beta blockers.  Patients who become hypertensive during the operation may benefit from intravenous nitrates, which allows for coronary vasodilation and increased blood flow via collaterals.  Gentle core cooling, by allowing the body temperature to drift to 35–36°C and deepening the level of anesthesia are concurrent measures that can also be employed.
Cardioplegia

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Cardioplegia

  • 2. Topics  Alternative arresting agents & additives  Crystalloid vs Blood cardioplegia  Potential newer technology
  • 5. Adenosine receptors  Four types of adenosine receptors: A1, A2a, A2b, A3  Activation of adenosine A 1 receptors leads to: ◦ inhibition of cyclic AMP production ◦ inhibition of the slow calcium channel ◦ opening of an adenosine-activated ATPsensitive potassium (K ATP ) channel  This leads to hyperpolarization, which delays conduction through the AV node and slows the ventricular response to atrial tachycardia.  It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls.  Activation of A2A receptors produces a constellation of responses that in general can be classified as anti- inflammatory  Pretreatment with adenosine confers a cardioprotective effect during ischemia and can inhibit the inflammatory responses initiated by ischemia and reperfusion
  • 7. Minute work & Oxygen demand  Minute work = Heart rate x Stroke volume x Pressure  However, minute work is not the direct determinant of oxygen consumption  The primary determinant of oxygen demand is the wall tension or stress developed in each cardiac cycle.  The energetic cost of ejecting blood from the ventricular chamber is approximately 20 to 30% of that required for isovolumic contraction.  An increase in afterload requires greater energy than an increase in volume ejected.  Oxygen consumption is also increased as the heart dilates and begins ejection from a greater diastolic volume.  Cardiac efficiency = Work/MVO2
  • 8. Alternative arresting agents & Additives  Beta Blockers: ◦ As the ascending aorta is clamped, the non- exocytotic release of norepinephrine from the cardiac sympathetic nerves acts on β-adrenergic receptors on the outer surface of the sarcolemma, causing an increase in cAMPdependent protein kinase activity, phosphorylation of the calcium release channels, and increased Ca2+ influx, resulting in increased Ca2+-dependent contractility and rapid depletion of glycogen stores. ◦ Early studies suggested that long-acting beta blockers improved myocardialprotection during ischemia but unfortunately have a prolonged negative inotropic effect, which limits their clinical use.
  • 9.  Beta blockers such as propranolol have been used as an adjunct to anesthesia to block β-adrenergic– stimulating episodes associated with coronary ischemia during the course of the operative procedure.  Ultra-short-acting cardioselective beta blockers such as landiolol and esmolol provide polarized cardiac arrest by maintaining the membrane potential at or near the resting membrane potential  Esmolol has been used to enhance myocardial protection during intermittent arrest and has been shown to provide myocardial preservation equivalent to or better than cold crystalloid or blood cardioplegia.  With esmolol cardioplegia, there is a slow undulating ventricular contraction that may decrease myocardial edema but does not provide a quiescent operating field
  • 10. Adenocaine  Adenosine-lidocaine (adenocaine) cardioplegia provides an exciting alternative to depolarizing cardioplegia.  Adenosine-lidocaine cardioplegia has been shown to provide a shorter time to electromechanical arrest, greater postischemic recoveries of aortic flow, a lower coronary vascular resistance during infusion, and greater MVO2 as compared to St. Thomas’ Hospital solution, while maintaining the myocardial cell membrane potential at its resting state
  • 11. Agents Affecting Calcium Transport The infusion of calcium-free cardioplegic solutions induces rapid diastolic cardiac arrest by inhibiting excitation-coupling and increases permeability of the sarcolemma.  When a calcium-containing perfusate is then reinfused, during reperfusion, there is a rapid influx of calcium into the cell, resulting in myocardial contracture and extensive ultrastructural damage, the “calcium paradox.”  Calcium antagonist agents administered before ischemia have been proposed as a possible mechanism to reduce ischemic cellular injury.  Calcium channel blocking agents, including verapamil, diltiazem, and nifedipine, prevent calcium-induced calcium release in myocardial cells and, as an adjunct to normothermic cardioplegia, have been shown to improve postischemic systolic function.  Calcium blockers have no effect if they are administered before reperfusion, are temperature dependent, and have limited effect during hypothermia.  Because high concentrations are required for cardioprotection, their prolonged membrane binding prevents rapid recovery, thus limiting their clinical usefulness.
  • 12.  Magnesium: ◦ Magnesium inhibits calcium entry into the cell by displacing calcium from its binding sites in the sarcolemmal membrane. ◦ It has limited use as an arresting agent because high concentrations are required, cardiac arrest is delayed, and postischemic functional recovery is decreased in comparison to potassium cardioplegia. ◦ The advantages of magnesium have been shown to be optimal when it is included with high-potassium cardioplegia, in which it has been demonstrated to ameliorate cytosolic, nuclear, and mitochondrial calcium accumulation; preserve high-energy phosphate moieties; and enhance postischemic functional recovery.
  • 13. Avoidance of Substrate Depletion  Metabolic substrates have been added to cardioplegic solutions to enhance anaerobic metabolism during ischemia or to provide citric acid cycle intermediaries to facilitate homeostasis during reperfusion.  Agents used include glucose and insulin; nucleosides, such as adenosine, aspartate, and glutamate; and L-arginine to stimulate nitric oxide production.  Although metabolic substrate enhancement has been used in various clinical situations, none has achieved universal adoption.
  • 14. Blood v/s Crystalloid cardioplegia  Crystalloid cardioplegia: ◦ these solutions contain minimal amounts (0.6 mL/100 mL at a PO2 of 100 mm Hg at a temperature of 10° C) of dissolved oxygen, whereas the myocardium consumes 0.33 mL of oxygen per 100 g at 15° C. ◦ Because even a short period of ischemia results in the gradual accumulation of oxygen debt, moderate to severe myocardial hypothermia is necessary to prevent the rapid degradation of energy stores ◦ To overcome the oxygen deficit issue, oxygenation of crystalloid cardioplegia has been clinically used and has demonstrated a decrease in creatine kinase MB levels
  • 15. Clinical steps for myocardial protection with use of crystalloid cardioplegia 1. Before the onset of surgery, the operating room temperature is cooled to 17° C to 19° C to avoid warming of the anterior surface of the heart by convection and radiation from highintensity lighting. 2. Cardiopulmonary bypass is initiated at a temperature of 28° C. 3. A myocardial electrocardiographic lead and temperature probe are placed on the anterior wall of the right ventricle because it constitutes two thirds of the anterior surface of the heart, and its rewarming during surgically induced ischemia may partially explain the occasional observation of selective right ventricular failure after the termination of bypass 4. an insulation pad is placed in the posterior pericardial sac and along the left ventricular lateral wall to protect the left phrenic nerve from thermal injury associated with regional
  • 16. 5. The systemic perfusate temperature is temporarily decreased to 10° C to 15° C to “precool” the heart (infusion hypothermia), and iced saline slush is placed into the pericardial sac to achieve rapid myocardial cooling 6. When a myocardial temperature of 28° C is reached, the ascending aorta is cross-clamped and cold crystalloid cardioplegia solution at a temperature of 5° C is infused into the aortic root at a pressure not exceeding 90 mm Hg @10ml/kg 7. At the termination of the initial cardioplegic infusion, the systemic temperature is elevated to 20° C, and the systemic perfusion flow rate is decreased from 2.2 to 1.5 liter/min/m2 .Increase in myocardial temperature above 20° C or if there is any electrocardiographic activity or observed ventricular motion, the solution is reinfused at a volume of 5 mL/kg. 8. Five minutes before removal of the aortic clamp, the systemic perfusate temperature is raised to 30° C, and flow is increased to 2.2 liter/min/m2. 9. After the aortic cross-clamp is removed, the perfusate temperature is raised to 38° C and the room temperature is raised to 25° C to 30° C. 10. Cardiopulmonary bypass is continued until the esophageal temperature is 37° C and the rectal temperature is in the range of 35° C to 37° C.
  • 17. Disadvantage of crystalloid cardioplegia  Extensive rewarming period, which may exceed 30 to 45 minutes.  Slow recovery of myocardial metabolism  Poor response to postoperative hemodynamic stress  Gradual accumulation of oxygen debt and myocardial damage if adequate hypothermia not maintained
  • 18. Blood Cardioplegia  Advantages: ◦ Optimum oxygenation (superior to oxygenated crystalloids) ◦ Better removal of carbon-dioxide ◦ Buffering action and reducing agent ◦ Presence of colloid avoids adverse oncotic pressure gradients ◦ presence of oxygen free radical scavengers ◦ Preserves microvascular responses compared with crystalloid cardioplegia
  • 19. Blood Cardioplegia  Concerns: ◦ the hypothermic shift to the left of the oxyhemoglobin dissociation curve, thereby reducing the release of oxygen at the tissue level ◦ the experimental evidence that blood cardioplegia may not protect the myocardium at low temperatures ◦ the potential of hypothermia induced sludging and red cell rouleau formation.
  • 20. Warm blood cardioplegia  In 1982 Rosenkranz and colleagues reported that warm induction with normothermic blood cardioplegia, with multidose cold blood cardioplegia maintenance of arrest, resulted in better recovery of function in canines than a similar protocol using cold blood induction  In 1986, Teoh and colleagues provided experimental evidence that a terminal infusion of warm blood cardioplegia before removing the cross-clamp (a “hot shot”) accelerated myocardial metabolic recovery  This was followed by a report in 1991 by Lichtenstein and colleagues that normothermic blood cardioplegia in humans is an effective cardio-protective approach.
  • 21.  Despite these encouraging reports, there are concerns that for any given patient, it is difficult to determine how long a warm heart can tolerate an ischemic insult if the infusion is interrupted or flow rates are reduced owing to an obscured surgical field or a maldistribution of the cardioplegic solution.  Another concern is the report by Martin and colleagues that warm cardioplegia is associated with a threefold increased incidence of neurologic deficits.  Subsequent studies have indicated however that appropriately designed protocols using intermittent antegrade warm blood cardioplegia provide clinically acceptable myocardial protection
  • 22. Tepid blood cardioplegia  Both cold blood (4 to 10°C) and warm blood cardioplegic solutions (37°C) have temperature- related advantages and disadvantages.  Hayashida and colleagues were one of the first groups to study specifically the efficacy of tepid blood (29°C) cardioplegia. Their study showed that tepid antegrade cardioplegia was the most effective in reducing anaerobic lactate acid release during the arrest period.  Mallidi et al showed that warm or tepid blood cardioplegia may be associated with better early and late event-free survivals after CABG  Although tepid blood cardioplegia may be safe and effective, the majority of studies have been single- center studies conducted in relatively small cohorts of patients. Whether tepid cardioplegia confers superior protection over other current methodologies remains to be determined.
  • 23. Miniplegia  The use of undiluted blood cardioplegia, or “miniplegia” (using a minimum amount of crystalloid additives), also has been reported to be effective.  Petrucci et al. studied the use of all blood miniplegia in a clinically relevant swine preparation and compared miniplegia with crystalloid cardioplegia.  They concluded that the use of all blood miniplegia was effective or superior in the acutely ischemic heart.  Rousou and colleagues showed that it is the level of hypothermia that is important in blood cardioplegia, not necessarily the hematocrit.
  • 24. Advantages of Blood cardioplegia (1) provides an oxygenated environment and a method for intermittent reoxygenation of the heart during arrest (2) limits hemodilution when large volumes of cardioplegic solution are used (3) affords an excellent buffering capacity and osmotic properties (4) allows for electrolyte composition and pH that are physiologic (5) offers a number of endogenous antioxidants and free-radical scavengers (6) is less complex than other solutions to prepare.
  • 27. Novel strategies for cardioprotection  Physiologic: ◦ Ischaemic preconditioning ◦ Post conditioning ◦ Remote ischaemic preconditioning ◦ Autophagy  Pharmacologic: ◦ Adenosine ◦ Acadesine ◦ Sodium-Hydrogen exchanger inhibitors ◦ Glucose-Insulin-Potassium (GIK)
  • 28. Ischaemic preconditioning  “Precondition with ischemia” is an endogenous adaptive phenomenon whereby the heart becomes more tolerant to a period of prolonged ischemia if first exposed to brief episodes of coronary artery occlusion.  IPC has been demonstrated to persist as long as 1 to 2 hours after the ischemic preconditioning stimulus & becomes ineffective when the sustained ischemic insult exceeds 3 hours  A second phase of protection appears 24 hours later and is sustained for up to 72 hours. This has been referred to as the second window of protection, late- phase preconditioning, or delayed preconditioning.  Unlike classic IPC, which protects only against infarction, the late phase protects against both infarction and myocardial stunning.
  • 29. 1
  • 30. Clinical relevance of IPC  Patients experiencing angina before an MI have a better in-hospital prognosis and a reduced incidence of cardiogenic shock, fewer and less severe episodes of congestive heart failure, and smaller infarcts as assessed by cardiac enzyme release and better long term survival rates  Patients who undergo percutaneous coronary interventions (PCI) have an enhanced tolerance to ischemia after the first balloon inflation, provided that the first balloon inflation exceeds 60 to 90 seconds  Intermittent cross-clamping with the heart paced at 90 beats per minute to induce ischemia, followed by 2 minutes of reperfusion before a 10- minute period of global ischemia and ventricular fibrillation has shown attenuation of troponin release
  • 31. Post conditioning  First reported by Zhao et al in canine model  Rapid intermittent interruptions of blood flow in the early phase of reperfusion, i.e., relief of ischemia in a stuttered or staccato manner.  The reduction in infarct size appears to be comparable with that observed with IPC.  Patients receiving brief balloon inflations/deflations in the initial minutes of reperfusion during PCI exhibited smaller ST- segment changes and lower levels of total creatine kinase release compared with patients that were not subjected to stuttering reperfusion  Luo et al in their study on post-op patients after total correction of TOF showed that aortic reclamping for 30 seconds and declamping for 30 seconds, repeated twice, reduced perioperative troponin T and CK-MB release and decreased the need for inotropic support after surgery
  • 32. Remote Ischaemic Preconditioning  Remote ischemic preconditioning is a phenomenon whereby brief ischemia of one organ or tissue confers protection on a distant naive organ or tissue against a sustained ischemia- reperfusion injury  Brief intermittent lower limb ischemia was associated with attenuated troponin release and a reduction in the need for postoperative inotropic support in children undergoing congenital heart surgery  Similar findings were demonstrated in adult patients undergoing CABG where RIPC was induced by three 5-minute cycles of right forearm ischemia by inflating a blood pressure cuff on the upper arm to 200 mm Hg with an intervening 5-
  • 33. Autophagy  Autophagy is the process whereby a doublemembrane structure called the autophagosome sequesters cytoplasmic components such as ubiquitinated protein aggregates or organelles including mitochondria, peroxisomes, and endoplasmic reticulum.  It is involved in degradation of long-lived proteins and the removal of excess or damaged organelles  The outer autophagosomal membrane fuses with a lysosomal membrane to deliver its contents into an autophagolysosome where the cargo is degraded by lysosomal hydrolases and the resulting macromolecules recycled
  • 35.  Autophagy has been reported to be upregulated in isolated cells subjected to simulated ischemia and reperfusion and rodent models of ex vivo and in vivo ischemia reperfusion injury.  Gurusamy et al. investigated the role of autophagy during ischemia-reperfusion injury and reported that increased BAG- 1 expression in the heart correlated with the onset of protection in an in vivo model of myocardial stunning.  Studies suggest that upregulation of autophagy promotes survival during stress such as ischemia-reperfusion  There is also direct evidence that autophagy plays an important role in mediating ischemic and pharmacologic preconditioning.  Autophagy may serve as an important mediator of protection of the preconditioning agent CCPA. A more detailed understanding of the role of autophagy in myocardial protection may lead to a new therapeutic approach to the management and treatment of ischemia-reperfusion injury.
  • 36. Adenosine  There is considerable experimental evidence that activation of various adenosine receptor subtypes results in cardioprotection similar to that induced by IPC.  Preischemic administration of the nucleoside adenosine retards the rate of ischemia-induced ATP depletion, prolongs the time to onset of ischemic contracture, attenuates myocardial stunning, enhances postischemic myocardial energetics, and reduces infarct size  Recent preclinical reports suggest that an adenosine A 2b receptor agonist confers cardioprotection when administered before the onset of ischemia (preconditioning) and at reperfusion (postconditioning)  In clinical trials, low dose adenosine administration showed no benefit on patient outcome  However, trials involving administration of high doses of adenosine in CABG patients showed reduction in postbypass inotropic drug utilization, improved regional wall motion, and global function measured by transthoracic echocardiography  Its clinical use is limited because large doses are associated with marked hypotension in patients not on cardiopulmonary bypass.
  • 37. Acadesine  This agent is a member of a class of drugs referred to as adenosine regulating agents. It is a purine nucleoside analog that raises adenosine tissue levels selectively during ischemic conditions  Early preclinical studies have indicated that acadesine treatment: ◦ (1) improves left ventricular wall motion after intermittent ischemia ◦ (2) attenuates frequency of ventricular arrhythmias ◦ (3) attenuates myocardial stunning and preserves myocardial function after cardiac arrest and cold cardioplegia.  Mangano et al. examined the two-year all cause mortality after perioperative MI in a follow-up of the Acadesine 1024 Trial. Although the primary outcome was negative, the findings at two years among patients experiencing post
  • 38. Sodium-Hydrogen Exchange inhibitors  The sodium-hydrogen exchangers (NHEs) are a family of membrane proteins with nine isoforms that are involved in the transport of hydrogen ions in exchange for sodium ions.  NHE-1 is the isoform that is expressed in the heart and may play a minor role in the normal excitation-contraction coupling process; however, it has been implicated in the etiology of arrhythmias, stunning, apoptosis, necrosis associated with acute myocardial ischemia-reperfusion injury, postinfarction ventricular remodeling, and heart failure
  • 39.  The driving forces for Na + /H + exchange are the relative transmembrane N + and H + gradients.  During ischemia, cytoplasmic pH falls as low as 6.6 because of increased production of H + from anaerobic glycolysis, but upon reperfusion, NHE-1 is activated to restore intracellular pH by exchange of intracellular protons for extracellular sodium.  The resulting accumulation of intracellular Na + is further exacerbated by diminished activity of Na + /K + ATPase as a result of ischemia and lowered ATP availability.  The increased intracellular Na + competes for sites on the Na + /Ca ++ exchanger and can actually drive it to run in reverse, resulting in cytosolic calcium overload.  Calcium overload has numerous adverse consequences including activation of calcium- dependent proteases and phospholipases, gap junction dysfunction, culminating in membrane rupture and cell death
  • 40.  The EXPEDITION trial was initiated to address the safety and efficacy of NHE-1 inhibition by cariporide in the prevention of death or MI in patients undergoing CABG surgery.  Although cariporide treatment was effective in reducing the incidence of nonfatal MI, its efficacy was associated with toxicity, and the overall assessment of benefits and risks associated with cariporide indicated that the imbalances in the safety profile outweighed the reduction in the observed MI rate  The importance of the study, however, is that myocardial necrosis after CABG is higher than previously appreciated and it suggested NHE-1 inhibitors represent a new class of drugs that hold promise for reduction of myocardial infarction associated with ischemiareperfusion injury.
  • 41. Glucose Insulin Potassium  There are numerous studies that suggest glucose- insulin-potassium (GIK) infusions are effective in reducing perioperative MIs, postischemic myocardial dysfunction, and atrial fibrillation in patients undergoing heart surgery.  The rationale for this form of treatment is based on the concept that insulin stimulates potassium reuptake through stimulation of the Na + ,K + - ATPase while it stimulates glucose uptake for glycolytic energy production.  High glucose, insulin, and an increased glycolytic flux also increase pyruvate generation and in turn preserve the citric acid cycle.  Additionally, glycolytic ATP protects membranes, drives uptake of Ca 2+ by the sarcoplasmic reticulum, and improves sodium homeostasis of ischemic
  • 42.  Despite a strong rationale for its application in surgery, the efficacy of GIK in heart surgery remains controversial, due to mixed results with the use of GIK to treat patients with acute myocardial infarction  Although a metaanalysis of randomized studies using GIK suggests that it may improve postoperative recovery of contractile function and reduce atrial arrhythmias, the individual studies have involved small numbers of patients and, therefore, insufficiently powered to detect efficacy.  Until a large randomized, multicenter clinical trial has been performed, the use of GIK as a form of myocardial protection will remain controversial.
  • 43. Myocardial protection during beating heart surgery  The acceptance of OPCAB is due in part to the development and refinement of a myriad of surgical aids that allow for stabilization and local immobilization of the heart during grafting.  Ischemia during temporary occlusion of a coronary artery during OPCAB may last from 6 to 25 minutes based on the surgeon’s experience, quality and size of the vessel, and adequacy of the exposure.  Most patients with preexisting severe coronary heart disease have experienced self-limiting episodes of ischemia during daily life and may have imparted a certain degree of tolerance to the surgically induced ischemia.  This tolerance has been documented using ECGs, transesophageal echocardiography, and continuous SVO2 monitoring
  • 44.  In order to better understand the differences between OPCAB and onpump surgery, Chowdhury et al. investigated the release pattern of various cardiac biomarkers in 50 patients undergoing cardioplegic and noncardioplegic coronary artery bypass surgery  They observed a greater release of cardiac troponin I, high-sensitivity C-reactive protein, and heart-type fatty acid binding protein in the cardioplegic group.  They concluded that OPCAB surgery is associated with less injury
  • 45.  One approach to minimizing the risk of injury is to reduce myocardial oxygen demand. Pharmacologic beta-blockade is frequently instituted to reduce inotropy and achieve negative chronotropy using ultra-short-acting beta blockers such as esmolol and labetalol  Another approach is to optimize the systemic mean blood pressures while reducing afterload.  Calcium channel blockers, such as diltiazem, have been used to afford an effective reduction in blood pressure while minimizing a depression in myocardial contractility that may occur with beta blockers.  Patients who become hypertensive during the operation may benefit from intravenous nitrates, which allows for coronary vasodilation and increased blood flow via collaterals.  Gentle core cooling, by allowing the body temperature to drift to 35–36°C and deepening the level of anesthesia are concurrent measures that can also be employed.