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Myocardial Protection- an update

Dr. Md. Rezwanul Hoque

MBBS,MS,FCPS,FRCSG,FRCSEd Associate Professor Department of Cardiac Surgery BSMMU, Dhaka, Bangladesh

The term myocardial protection refers to strategies and methodologies used either to attenuate or to prevent postischemic myocardial dysfunction that occurs during and after heart surgery. Postischemic myocardial dysfunction is attributable, in part, to a phenomenon known as ischemia-reperfusion-induced injury.

Clinically, it manifests by low cardiac output and hypotension and may be subdivided into two subgroups: reversible injury and irreversible injury. The two typically are differentiated by the presence of electrocardiographic abnormalities, elevations in the levels of specific plasma enzymes or proteins such as creatine kinase and troponin I or T, and/or the presence of regional or global echocardiographic wall motion abnormalities.
Mentzer R Mi J r , Jahania M Si , Lasley R Di . Myocardial Protection. Cohn Lh, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:443-464.

An evolving strategy
The concept of myocardial protection has been continuously evolving since its introduction in the early 1950s. First experiments with cold crystalloid cardioplegia to the most recent findings on warm, enriched blood cardioplegia. Many controversies are still open to determine which is the most adequate of myocardial protection.

Myocardium- injury, ischemia, reperfusion, protection

Myocardial damage due to ischaemia, reperfusion and inflammatory response to cardiopulmonary by-pass. Potassium depolarizing diastolic arrest of the can not give full protection Ionic imbalance, substrate utilization, loss of intracellular high energy phosphate may occur. Alternative techniques of arrest, using agents that induce a polarized arrest or that influence intracellular calcium mechanisms, have the potential to improve myocardial protection and reduce damage during ischemic arrest.

Spectrum of myocardial injury

Acute ischemic dysfunction Preconditioning Stunning Hibernation Necrosis versus Apoptosis

Myocardium, Coronary Flow

Coronary blood flow: 250 ml/min
Entirely during diastole, depends on aortic diastolic pressure minus LVDP & duration of diastole

pressure < 150 mmHg

oxygenated by superb membrane oxygenator-the lungs

Cessation of Myocardial Blood Flow

Mitochondria cellular pO2 < 5mmHg within seconds oxidative phosporilation stops Cytosol anaerobic glycolysis glycogen glucose-6-phosphate pyruvate lactate cellular acidosis depletion of ATP

Effect of acute ischemia

Contractile dysfunction occurs within seconds of coronary artery occlusion. high-energy phosphates, lactic acid, and intracellular acidosis , anaerobic glycolysis replaces the Krebs cycle as the major source of adenosine triphosphate, ATP. Inability to maintain electrolyte gradients that require active transport cause cellular edema, intracellular Ca2+ overload, loss of membrane integrity, and ultimately, in the setting of terminal "no reflow" ischemia, cell necrosis.

Normal function before ischemia, cessation of contractility and ischemic contracture, then recovery following reperfusion

Ischaemic Preconditioning
adaptive mechanism induced by a brief period of reversible ischaemia increasing hearts resistance to a subsequent longer period of ischaemia

Reversible Slowed energy utilization Reduction in myocardial necrosis Most powerful endogenously mediated form of myocardial protection May be early & late phase preconditioning Recovery in hours/ days
A transient infusion of adenosine or certain adenosine receptor agonists prior to ischemia is associated with infarct size reduction similar to that of ischemic preconditioning.

IP only provides protection to the unprotected ischemic heart and that it may be detrimental to the human myocardium protected from ischemia using cardioplegia.

Partially reversible May be accompanied by endothelial dysfunction(NO) causing reduced coronary blood flow Result of ischemia/ reperfusion insult Function of the myocardium remains impaired (stunned) for a certain period despite reestablishment of flow Contractile proteins recover if the myocyte is reperfused before irreversible damage Mediated by increasing intracellular Ca++ accumulation Recovery in hours/ weeks Myocardial O2 consumption in stunned myocardium is relatively high compared with the reduced ventricular function.

The metabolism of this "oxygen paradox" could occur at different levels: basal metabolism, excitation-contraction coupling, and energy production. Although ventricular function is substantially depressed, O2 consumption in the stunned myocardium is normal or close to normal. The relatively high O2 consumption has also been attributed to repair processes taking place in stunned myocardium.
Cleveland JC, Meldrum DR, Rowland RT, et al: Ann Thorac Surg 1996;61:760-8

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) Partially reversible Related to poor myocardial blood flow Chronic Recovery in weeks/ months

Effect of revascularization on hibernation

Chronically underperfused myocardium can regain the ability to contract when flow is reestablished by CABG. Recovery time could be dependent on a number of factors, including duration of ischemia, severity of ischemia, degree of revascularisation (complete versus partial), and amount of myocyte dedifferentiation within the hibernating zone. Recovery that occurs over days to weeks after revascularisation of a hibernating segment might represent stunning. Recovery that occurs over a longer time period might represent the regeneration of myofibrils and repair of structural alterations that occurred during the chronic hibernating phase.

Irreversible Hypercontracture-Contracture band necrosis, stone heart Osmotic/ Ionic dysregulation, membrane injury Cell swelling and disruption Lysis Myocytes can undergo necrosis in the presence of apparently adequate coronary perfusion, as with catecholamine stress, loss of calcium homeostasis, or reoxygenation after anoxia.

Irreversible Death signal Cell shrinkage Cytoplasmic and nuclear condensation Phagocytosis Intracellular Ca2+overload during ischemia and reperfusion and reactive oxygen species (ROS) formation during reperfusion are thought to be the primary mediators of the intrinsic pathway of apoptosis.
Apoptosis is a form of cell death distinct from necrotic cell death. Genetically programmed and a physiologic process in various organ systems of body. Apoptosis occurs in dilated and ischemic cardiomyopathy, end-stage heart failure.

Ventricular dilatation and neurohormonal activation during heart failure lead to up regulation of transcription factors, induce myocyte hypertrophy, and prepare the cell for entry into the cell cycle.
However, terminally differentiated myocytes cannot divide, and failing to divide they undergo apoptosis.
Curr Opin Cardiol 2000, 15:183188 2000 Lippincott Williams & Wilkins

System involved in membrane injury

MAC( membrane attack complex) Adenosine dependent receptor K+ ATP dependent channel Sodium Hydrogen exchanger

Effects of ischemia on cell

Altered membrane potential Altered Ion distribution( Ca++, Na+) Cellular swelling Cytoskeletal disorganization Increased hypoxanthine Decreased ATP Decreased phosphocreatine Decreased Glutathione Cellular Acidosis

Within the endothelium, ischemia promotes expression of certain proinflammatory gene products (e.g., leukocyte adhesion molecules, cytokines) and bioactive agents (e.g., endothelin, thromboxane A2), while repressing other protective gene products (e.g., constitutive nitric oxide synthase, thrombomodulin) and bioactive agents (e.g., prostacyclin, nitric oxide).

Strategies for heart protection

Increase the Oxygen offer Decrease Oxygen demand Metabolic intervention Prevention of demand increase Substrate dispensability

Myocardial Protection
encompass all the strategies employed during cardiac surgery

preoperative phase operative phase global myocardial ischaemic time reperfusion postoperative phase

Keogh BE. Birmingham review course, 1998

Myocardial Protection Preoperative Phase

commences on admission optimising medical management maximise oxygen supply, reduce demand

stable patients- continue medication on the day of surgery unstable patients- prevent further ischaemic events

Myocardial Protection Operative Phase

coronary perfusion with oxygenated blood 1960s-Starr

normothermic ischaemic arrest 1960s-Cooley cardioplegic arrest

Normothermic Ischaemia
(canine heart)

20 minutes- completely reversible 40 minutes- half the cells are necrotic 1 hour- lethal for all cells

Jennings RB, Hawkins HK, Lowe JE, et al: Am J Pathol 1978;92:187-214

Determinants of Myocardial Oxygen Consumption

intramyocardial tension
ventricular pressure ventricular volume myocardial mass

heart rate contractile state basal metabolismforce-velocity relation maximal velocity of contraction

energy associated with shortening against load

external work (load and fiber shortening) internal work (series elastic component shortening)
Sonnenblick EH, Ross JJr, Braunwald E. Am J Cardiol 1968;22:328-36

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

Cleveland JC, Meldrum DR, Rowland RT, et al: Ann Thorac Surg 1996;61:760-8

Myocardial Oxygen Consumption (MVO2) using the Fick equation MVO2 = CBF x (CaO2 - CcsO2 ) CBF: coronary blood flow CaO2 : arterial oxygen content CcsO2: coronary sinus oxygen content

Myocardial O2 consumption ml/100gr/min

Temperature 0C Empty beating Empty fibrillating K+ cardioplegia

37 32 5.5 5.0 6.5 3.8 1.o 0.8

28 4.0 3.0 0.6

22 2.9 2.0 0.3

Reduction of Oxygen demand in different type of cardiac arrest

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

Reduction 90% 97% ~ 97%

Buckberg GD, Brazier JR, Nelson RL, et al; J Thorac Cardiovasc Surg 1977;73:87-94

Myocardial O2 consumption at 370C

Beating( full, perfused) Beating( empty, perfused) Fibrillating( empty, perfused) K+ cardioplegia( empty, cross clamp)

10ml/100gr/min 5.5ml/100gr/min 6.5 ml/100gr/min 1.0 ml/100gr/min

Myocardial protection( operative phase)

Mild to moderate hypothermia with cardioplegic arrest of heart under CPB Continuous or intermittent antegrade cardioplegia with normothermic CPB in

warm heart surgery .

Profound hypothermia ( <20degree centigrade ) with TCA Intermittent cross clamping with CPB, 2 minutes release after every 12 minutes X-clamp in fibrillating heart, no CP Fibrillating heart with CPB, no X-clamp Empty beating heart with CPB, no X-clamp Inflow occlusion for short procedure e.g. PA valvutomy

Beating heart surgery (CABG)

Beating heart, x-clamp, Aortic root perfusion with oxygenated blood for intracardiac procedure

lowers metabolic rate
Bigelow, Lindsay, Greenwood- 1950
Shumway and Lower- 1959

decrease myocardial energy requirements promoting electromechanical quiescence every 10 0C in temperature, VO2 halved regional variations!

Hypothermia- deleterious effect

Effects on ;
enzyme function membrane stability calcium sequestration glucose utilisation ATP generation and utilisation leftward shift of oxyhaemoglobin curve (impaired tissue oxygen uptake) and elevated pH osmotic homeostasis

Lichtenstein SV, Ashe KA, Dalati HE, et al. J Thorac Cardiovasc Surg 1991;101:269-74

Cardioplegic arrest
To provide the surgeons with optimal operating conditions. Acute or chronic ischemia may create conditions whereby cardioplegic induction is the first phase of myocardial reperfusion. It may be followed by reperfusion injury. The fundamental principle of cardio protection is to avoid unnecessary ischemia and to improve the unbalanced myocardial metabolic state.

Components of cardioplegia solution

Values are expressed in millimoles per liter unless otherwise noted.

Usual components* Calcium 1.5 0.5 Bicarbonate 20.0 pH 5.57.0 7.14 7.8 Osmolarity (mOsm/L) 320 275 Other components Procaine; mannitol Lactate; chlorine Acetate; gluconate; chloride Lidocaine

Solution Bretschnei ders no. 3 Lactated Ringers Tyers

Sodium 12.0 130.0 138.0

Potassium 10.0 24.0 25.0

Magnesium 2.0 1.5

St. Thomas no. 2 Roes Gay/Ebert Birmingha m








27.0 38.5 100.0

20.0 40.0 30.0



10.0 28.0

7.6 7.8 7.5

347 365 300-385

Cravers Lolleys


25.0 20.0

11.0 4.4


391 350

Glucose; tris buffer Glucose Glucose; chloride; albumin; mannitol Dextrose Dextrose; mannitol; insulin

History of cardioplegia invention

Hypothermia Cross-clamping-1956-cooley&debakey used 1969 Ventricular-fibrillation 1969-najafi 1972-stone heart phenomenon-Cooley 1956-potassium citratemelrose,ringer..used by the efflers group Potassium- used in 1973 in lower doses 20-30mmol/1000ml crystalloid In Europe additives (procaine. magnesium)



Ventricular myocyte action potential

Ferrari R, Opie LH, 1992 Atlas of the myocardium Raven Press Ltd.

Phase 0: rapid depolarisation (Na+ in) Phase 1: brief early repolarisation Phase 2: plateau (Ca 2+ in) Phase 3: rapid repolarisation (K+ out) Phase 4: resting membrane potential

Ventricular myocyte action potential

Phases 0 and 1 Opening of fast sodium channels Closure of potassium channels Phase 2 Calcium entry through L-type calcium channels Phase 3 Reopening of potassium channels Phase 4 Equilibrium potential for potassium

Potassium Depolarisation Arrest

Depolarising the cardiomyocyte membrane with hyperkalemia However certain membrane ion pumps are still operative and requires energy
sarcolemmal and sarcoplasmic reticular Ca2+ATPase Na+/K+ATPase

Cohen NM, Wise RM, Wechsler AS, et al. J Thorac Cardiovasc Surg 1993;106:317-28

Mechanism of cardioplegic protection

Mechanical arrest( K+ induced, 80% reduction in O2 consumption) Hypothermia( 10-15% further reduction in O2 consumption) Aerobic metabolism- Oxygenated cardioplegia Maintain hypothermic arrest with re administration every 1520 minutes Retrograde delivery LV & RV protection

Schematic representation of excitationcontraction coupling pathway (induction of action potential to initiation of contraction by release of intracellular calcium) and the targets within this pathway that are inhibited or activated by agents inducing depolarized arrest, polarized arrest, or arrest by influencing calcium mechanisms. BDM, 2,3-butanedione monoxime; Ca2+, calcium; K+, potassium; Mg2+, magnesium; Na+, sodium; SR, sarcoplasmic reticulum; TTX, tetrodotoxin.

Depolarized arrest

Most commonly used method-cardioplegic solution containing a concentration of potassium (usually 1540 mmol/L), to induce a depolarization of the membrane. Increasing the extracellular potassium concentration of the solution causes the resting membrane potential (Em) to depolarize; at each new potassium concentration, a new resting Em equilibrium is established. Depolarization to approximately 65 mV (corresponding to the inactivation threshold of the fast sodium channel) at a potassium concentration of approximately 10 mmol/L prevents the rapid sodium influx of the action potential and maintains diastole of the myocardium. As the potassium concentration increases, Em becomes more depolarized, but at approximately 40 mV (corresponding to a potassium concentration of about 30 mmol/L) the calcium channel will be activated, promoting calcium overload, which can lead to myocardial damage. Thus there is a relatively narrow window of potassium concentration for safe myocardial arrest with increased potassium; most hyperkalemic solutions use a potassium concentration around 1620 mmol/L (such as the St Thomas Hospital solution) and arrest at a membrane potential around 50 mV . However, at the levels of depolarization induced by these potassium concentrations, other noninactivating currents remain active.
Opie LH. Channels, pumps, and exchangers. In: The Heart: Physiology and Metabolism. 2nd edn. New York: Raven Press;1991:67101.

Depolarized arrest-contd
Voltage-dependent activation and inactivation gates of the sodium channel operate at different rates and cause a background influx of sodium via the sodium window current. This will increase the intracellular calcium concentrations as a consequence of mechanisms such as the sodiumcalcium exchanger, inducing contracture even in the arrested state and contributing to calcium overload and reperfusion injury . Critical energy supplies are depleted by energy-dependent transmembrane pumps that attempt to correct the abnormal ionic gradients. Thus, although hyperkalemia remains the most common means of cardiac arrest, it is not necessarily the optimum means of preventing myocardial damage during surgery. Alternative techniques may avoid the problems. Recent studies have concentrated on the induction of polarized arrest or arrest by influencing calcium mechanisms
Bers DM. ExcitationContraction Coupling and Cardiac Contractile Force. Dordrecht: Kluwer;1991:5960. Sternbergh WC, Brunsting LA, Abd-Elfattah AS, Wechsler AS. Basal metabolic energy requirements of polarized and depolarized arrest in rat heart. Am J Physiol. 1989;256:H846H851.

Polarized arrest
Polarized arrest involves maintaining the membrane potential of the arrested heart at or near the resting value. This should provide a number of advantages: maintained ionic balance (particularly of sodium and calcium) and reduced energy requirements. Polarized arrest can be achieved by either sodium channel blockade or potassium channel activation. Blocking the sodium channel directly prevents the rapid, sodium-induced depolarization of the action potential, and many agents (such as procaine and lidocaine) have previously been used as cardioplegic agents or as additives. Tetrodotoxin, a toxic but potent sodium channel blocker, is an effective and protective cardioplegic agent . Recent studies using this agent have demonstrated the benefit of polarized arrest over depolarized arrest for myocardial protection, with Em during ischemia being maintained around 70 mV and a reduced ionic imbalance, particularly when it is used in conjunction with agents inhibiting sodium influx (a sodiumhydrogen exchange inhibitor and a sodiumpotassiumchloride cotransport inhibitor) .

Tyers GFO, Todd GJ, Niebauer IM, Manley NJ, Waldhausen JA. Effect of intracoronary tetrodotoxin on recovery of the isolated working rat heart from sixty minutes of ischemia. Circulation. 1974;49/50(suppl II):II-175II-179.

Polarized arrest-contd
Potassium channel openers (such as aprikalim, pinacidil, and nicorandil) activate the ATP-dependent potassium channel (KATP channel). Because the relative membrane conductance of the myocardium to potassium is much greater than that to sodium, the myocardial resting Em (approximately 85 mV) is close to the equilibration potential of potassium (Ek of approximately 94 mV). Opening KATP channels increases the difference between these conductances, shifting Em towards Ek and thereby inducing a hyperpolarization relative to the previous Em ,but this only applies if the extracellular potassium concentration remains low. Adenosine has also been shown to act as a hyperpolarizing agent , and has been used to induce cardioplegic arrest, with mixed results . More recently, a combination of lidocaine, a sodium channel blocker, and adenosine has demonstrated effective myocardial protection compared with a hyperkalemic cardioplegic solution ; similarly, other studies have demonstrated effective combinations of arresting agents

Walgama OV, Shattock MJ, Chambers DJ. Myocardial arrest and protection: dual effect of a K-channel opener and Na-channel blocker as an alternative to hyperkalemia. J Mol Cell Cardiol. 2000;32:A41.

Influencing calcium mechanisms

Solutions with a zero, or very low, extracellular calcium concentration rapidly arrest the heart in diastole by inhibiting excitationcontraction coupling. This is the basis of some intracellular type cardioplegic solutions (particularly the original Bretschneider solution and the subsequent Histidine-Tryptophan-Ketoglutarate [HTK] [Custodiol] solution. The HTK solution has shown particular application for long-term preservation of hearts, in addition to other organs (kidney, liver, pancreas), before transplantation. An alternative approach is to influence the affinity of calcium for intracellular components, and there is current interest in agents that lead to reversible desensitization of the contractile apparatus for calcium. The most widely used is 2,3butanedione monoxime (BDM), which uncouples myofilament excitationcontraction coupling by inhibiting the formation of crossbridges . BDM has recently been used as a cardioplegic agent , demonstrating effective protective properties when compared with conventional depolarizing cardioplegia. Another agent with potential to improve myocardial protection by reducing the damaging effects of depolarized arrest is esmolol( multidose infusion at 1mmol/L), an ultra-short-acting -blocker with a half-life of only 9 min. It provides significantly improved protection during normothermic global ischemia compared with that obtained with a depolarizing cardioplegic solution

Cardioplegia- types
Crystalloid: Blood cardioplegia: (2:1, 4:1, 8:1, blood /CP only) Leukocyte depleted Inductionmaintenancereperfusion
Blood cardioplegic temperature cold (9 C) tepid (29 C) warm (37 C) Cardioplegia delivery Antegrade/ retrograde/ combined/simultaneous/ intermittent/continuous/ selective
0 0 0

Cold crystalloid cardioplegia

There are basically two types of crystalloid cardioplegic solutions: the intracellular type and the extracellular type. The intracellular types are characterized by absent or low concentrations of sodium and calcium. The extracellular types contain relatively higher concentrations of sodium, calcium, and magnesium. Both types avoid concentrations of potassium >40 mmol/L, contain bicarbonate for buffering, and are osmotically balanced. In both types, the concentration of potassium used ranges between 10 and 40 mmol/L (for potassium 1 mmol/L = 1 mEq/L).

Mentzer R Mi J r , Jahania M Si , Lasley R Di . Myocardial Protection. Cohn Lh, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:443-464.

Buckberg cardioplegia
4:1 blood plegia 3 solutions :induction maintaince reperfusion Cold------- 8-12 degrees Celsius Hot shot----37degrees Celsius Reperfusion 32degrees Celsius Delivery is fixed volume over time and pressure Additives Mg sulphate Dextrose 50%-35ml/500ml of solution Lignocaine 100mg after cross- clamping Adenosine Manitol

High potassium levels High dextrose levels Can complicate CPB Hot shot can cause excessive vasodilation Protocol may have to be modified for short aortic clamp times Aortic regurgitation Improved left ventricular function(echocardiography assessment)?????? Hearts may not need defibrillation Accurate Temperature control




Antegrade Cardioplegia
Produces prompt arrest

poor distribution in coronary patients unless delivered through the vein grafts

poor distribution in patients with aortic regurgitation

risk of ostial injury from direct perfusion (during AVR)

interruption of procedure during mitral surgery

Retrograde Cardioplegia
perfusion pressure < 40 mmHg prevent perivascular haemorrhage and oedema!
flow rate = 200mL/min

Retrograde Cardioplegia
Distribution of CP to regions supplied by occluded or stenosed vessels Improved subendocardial CP delivery Effective in AR & valve surgery Prevents atheroembolisation during re-do CABG May be given continuously Flushing of air and/or atheromatous debris
(sonicated albumin studies)

Shunting of CP into ventricular cavities via thebesian channels Perfusion defects especially right ventricle and posterior septal regions Venous variation

Blood Cardioplegia - 1980s

Improved oxygen carrying capacity and delivery until electromechanical quiescence developed Provide a method for intermittent reoxygenation of the heart during arrest. Enhanced myocardial oxygen consumption

Preserved high-energy phosphate stores

Buffering changes in ph Use of free radical scavengers (superoxide dismutase, catalase, and glutathione) Provide appropriate osmotic environment for myocardial cells and lessen the myocardial oedema

Cold Blood Cardioplegia

lowers myocardial oxygen demands

Hypothermic inhibition of mitochondrial enzymes Shifting oxyhaemoglobin dissociation curve to left Activating platelets, leukocytes, complement Impaired membrane stabilization

Warm Induction
resuscitation of the heart
Severe left ventricular dysfunction Cardiogenic shock
Preischaemic depletion of energy stores Warm induction showed improved aerobic metabolism and LV function in dogs Neurologic deficit is more in post-operative period when warm induction, maintenance and terminal hot-shots are given.
Rosenkranz ER, Vinten-Johansen J, Buckberg GD, et al. J Thorac Cardiovasc Surg 1982;84:667-77

Warm Reperfusion (hot-shot)

Early myocardial metabolic recovery while maintaining electro-mechanical arrest
Repletion of energy stores Maintenance of unnecessary contractile activity
Teoh KH, Christakis GT, Weisel RD, et al.
J Thorac Cardiovasc Surg 1986;91:888-95

Continuous Warm Cardioplegia

Avoidance of direct myocellular injury inflicted by any cold solution or environment
Lichtenstein SV, ashe KA, el dalati H, et al. J thorac cardiovasc surg 1991;102:207-14

Increased rate of perioperative stroke and neurological events (randomised trial-1001 patients)
Martin TD, Craver JM, Gott JP, et al.

Ann Thorac Surg 1994;57:298-304

Substrate Enhancement of Cardioplegia

Krebs-cycle intermediates
glutamate aspartate

Nitric oxide (NO) / L-arginine

Other consideration
Protect from rewarming Systemic hypothermia Aortic/ventricular vents Total bypass (caval oclusion) Acute Ischemia Warm induction Substrate enhancement Controlled reperfusion Warm,hypocalcemic,alkaline cardioplegia Retrograde or low flowpressure antegrade perfusion Energy replacement while arrested Uniform warming

Buffers for cardioplegia

Histidine NaHCO3 Slightly alkaline reperfusion Blood

Ventricular Fibrillation with Intermittent Aortic Cross-clamping

Used by 40% of surgeons in the UK for coronary surgery Induces global ischaemia with fibrillation, followed by anoxic arrest and electrical silence on the ECG

Keogh BE. Birmingham review course, 1998

Ventricular Fibrillation with Intermittent Aortic Cross-clamping

Cumulative cross-clamp times are less than with cardioplegia The myocardium is intermittently perfused with oxygenated blood Increasing areas of myocardium are reperfused during the course of the procedure
Anderson JR, Hossein-Nia M, Kallis P, et al. Ann Thorac Surg 1994;58:768-73

Reperfusion Phase
Cell damage following ischaemia is biphasic;
Injury being initiated during ischaemia Exacerbated during reperfusion

Free-radical Reperfusion Injury

Characterised by abnormal myocardial oxidative metabolism Mediated by the interaction of cyto-toxic oxygen free radicals, endothelial factors, and neutrophils Oxidising sarcolemmal phospholipids, and disrupting membrane integrity (lipid peroxidation) Delayed myocardial metabolic recovery
Weisel RD, Mickle DAG, Finkle CD, et al: Circulation 1989;80(suppl III):III-14-18

Free radicals are generated within 10 seconds of reperfusion after ischaemia

Zweier JL, flaherty JT, weisfeldt ML. Proc natl acad sci usa 1987;84:14041408

Strategies to Reduce Reperfusion Injury

Reduction of ischaemic insult prior to reperfusion Low pressure reperfusion Hypocalcaemic reperfusion Free radical scavenging Neutrophil filtration

Keogh BE. Birmingham review course, 1998

Therapies Under Investigation

superoxide dismutase catalase nitric oxide

ischaemic preconditioning hypothermia hypoxic reperfusion

mannitol allopurinol antioxidants
Grace PA. Bri J Surg 1994,81,637-647

Protection in the Failing Heart

Proper selection of patients
Good distal vessel quality

Prevent injury to the heart during anaesthesia and prior to CPB Myocardial protection schemes to enhance metabolic support
Kron IL. Ann Thorac Surg 1999;68:1971-3

Protection in the Failing Heart (EF<25%)

Preoperative IABP VAD/ Resynchronisation therapy Ultrafiltration during bypass Delayed sternal closure Triodothyronine (T3) Glucose-insulin-potassium solution Aspartate/glutamate

New research
Patients receiving the adenosine cardioplegia with an infusion of adenosine (200 g/kg per minute) 10 minutes before and 15 minutes after removal of the aortic cross-clamp showed beneficial effect regarding: highdose dopamine use, epinephrine use, insertion of an IABP, MI, or death. EXPEDITION study demonstrated that NHE-1(Careporide, SodiumHydrogen exchanger inhibitor) inhibition holds promise as a new class of drugs that could reduce myocardial injury associated with ischemiareperfusion injury significantly. There is only a modest amount of evidence that the NO mechanism can be manipulated to confer myocardial protection in humans. Mentzer R Mi J r , Jahania M Si , Lasley R Di . Myocardial Protection. Cohn Lh, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:443464. +8801711560305