Myocardial Protection- An Update

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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

Transcript of Myocardial Protection- An Update

Page 1: Myocardial Protection- An Update

Myocardial Protection- an update

Dr. Md. Rezwanul HoqueMBBS,MS,FCPS,FRCSG,FRCSEdAssociate ProfessorDepartment of Cardiac SurgeryBSMMU, Dhaka, Bangladesh

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Definition• 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.

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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.

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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.

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Spectrum of myocardial injury

• Acute ischemic dysfunction• Preconditioning • Stunning• Hibernation• Necrosis versus Apoptosis

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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”

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Cessation of Myocardial Blood Flow

Mitochondria

cellular pO2 < 5mmHg within seconds

oxidative phosporilation stops

Cytosolanaerobic glycolysis

glycogenglucose-6-phosphatepyruvatelactate

cellular acidosisdepletion of ATP

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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.

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

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Ischaemic Preconditioning“adaptive mechanism induced by a brief period of reversible ischaemia increasing heart’s 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.

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Stunning• 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

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Hibernation

• 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

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Effect of revascularization on hibernation

• Chronically underperfused myocardium can regain the ability to contract when flow is re-established 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.

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Necrosis

• 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.

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Apoptosis

• 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, 15:183–188 © 2000 Lippincott Williams & Wilkins

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System involved in membrane injury

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

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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).

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Strategies for heart protection

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

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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

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Myocardial ProtectionPreoperative 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

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Myocardial Protection Operative Phase

• coronary perfusion with oxygenated blood 1960’s-Starr

• normothermic ischaemic arrest

1960’s-Cooley

• cardioplegic arrest

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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

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Determinants of Myocardial Oxygen Consumption

• intramyocardial tensionventricular pressureventricular volumemyocardial mass

• heart rate• contractile state

force-velocity relationmaximal velocity of contraction

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

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

• energy associated with shortening against loadexternal work (load and fiber

shortening)internal work (series elastic

component shortening)

Sonnenblick EH, Ross JJr, Braunwald E. Am J Cardiol 1968;22:328-36

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Myocardial Oxygen Consumption (MVO2)

using the Fick equationMVO2 = CBF x (CaO2 - CcsO2 )

CBF: coronary blood flowCaO2 : arterial oxygen content

CcsO2: coronary sinus oxygen content

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Myocardial O2 consumption ml/100gr/min

• Temperature 0C 37 32 28 22• Empty beating 5.5 5.0 4.0 2.9• Empty fibrillating 6.5 3.8 3.0 2.0• K+ cardioplegia 1.o 0.8 0.6 0.3

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Reduction of Oxygen demand in different type of cardiac arrest

Oxygen Demand Reduction

Normothermic Arrest (37oC) 1mL/100g/min 90%Hypothermic Arrest (22oC) 0.30 mL/100g/min 97%Hypothermic Arrest (10oC) 0.14 mL/100g/min ~ 97%

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

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Myocardial O2 consumption at 370C

• Beating( full, perfused) 10ml/100gr/min• Beating( empty, perfused) 5.5ml/100gr/min• Fibrillating( empty, perfused) 6.5 ml/100gr/min• K+ cardioplegia( empty, 1.0 ml/100gr/min cross clamp)

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Myocardial protection( operative phase)

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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

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Hypothermia

• 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!

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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

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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.

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Components of cardioplegia solutionUsual components*

Solution Sodium Potassium Magnesium Calcium Bicarbonate pH Osmolarity (mOsm/L)

Other components

Bretschneider’s no. 3

12.0 10.0 2.0 – – 5.5–7.0 320 Procaine; mannitol

Lactated Ringer’s

130.0 24.0 – 1.5 – 7.14 – Lactate; chlorine

Tyer’s 138.0 25.0 1.5 0.5 20.0 7.8 275 Acetate; gluconate; chloride

St. Thomas no. 2

110.0 16.0 16.0 1.2 10.0 7.8 324 Lidocaine

Roe’s 27.0 20.0 1.5 – – 7.6 347 Glucose; tris buffer

Gay/Ebert 38.5 40.0 – – 10.0 7.8 365 GlucoseBirmingham

100.0 30.0 – 0.7 28.0 7.5 300-385 Glucose; chloride; albumin; mannitol

Craver’s 154.0 25.0 – – 11.0 – 391 DextroseLolley’s – 20.0 – – 4.4 7.78 350 Dextrose;

mannitol; insulin

* Values are expressed in millimoles per liter unless otherwise noted.

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History of cardioplegia invention

• Hypothermia• Cross-clamping-1956-cooley&debakey –used 1969• Ventricular-fibrillation 1969-najafi• 1972-stone heart phenomenon-Cooley• 1956-potassium citrate—melrose,ringer..used by the effler’s

group• Potassium- used in 1973 in lower doses• 20-30mmol/1000ml crystalloid• In Europe additives (procaine. magnesium)

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Ventricular myocyte action potential

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

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

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Phases 0 and 1Opening of fast sodium channelsClosure of potassium channels

Phase 2Calcium entry through L-type calcium

channelsPhase 3

Reopening of potassium channelsPhase 4

Equilibrium potential for potassium

Ventricular myocyte action potential

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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

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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 15-

20 minutes• Retrograde delivery LV & RV protection

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Schematic representation of excitation–contraction 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.

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Depolarized arrest• Most commonly used method-cardioplegic solution containing a

concentration of potassium (usually 15–40 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 16–20 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;1991:67–101.

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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 sodium–calcium 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. Excitation–Contraction Coupling and Cardiac Contractile Force. Dordrecht: Kluwer;1991:59–60. 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:H846–H851.

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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 sodium–hydrogen exchange inhibitor and a sodium–potassium–chloride 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-175–II-179.

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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.

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Influencing calcium mechanisms

• Solutions with a zero, or very low, extracellular calcium concentration rapidly arrest the heart in diastole by inhibiting excitation–contraction 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 2,3-butanedione monoxime (BDM), which uncouples myofilament excitation–contraction 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 β-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

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Cardioplegia- types

• Crystalloid: • Blood cardioplegia:

(2:1, 4:1, 8:1, blood /CP only)

• Leukocyte depleted• Induction-

maintenance-reperfusion

• Blood cardioplegic temperature

• cold (9 0C)• tepid (29 0C)• warm (37 0C)• Cardioplegia delivery• Antegrade/ retrograde/

combined/simultaneous/intermittent/continuous/selective

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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.

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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

• Disadvantages• High potassium levels• High dextrose levels • Can complicate CPB• Hot shot can cause excessive vaso-

dilation• Protocol may have to be modified for

short aortic clamp times• Aortic regurgitation

• Advantages• Improved left ventricular

function(echocardiography assessment)??????

• Hearts may not need defibrillation• Accurate Temperature control

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Antegrade Cardioplegia

Advantages• Produces prompt arrest pitfalls

• 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

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Retrograde Cardioplegia

• perfusion pressure < 40 mmHgprevent perivascular haemorrhage and oedema!

• flow rate = 200mL/min

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Retrograde Cardioplegia

Advantages

• 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

Pitfalls

• Shunting of CP into ventricular cavities via thebesian channels

• Perfusion defects especially right ventricle and posterior septal regions

• Venous variation

(sonicated albumin studies)

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Blood Cardioplegia - 1980’s• 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

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Cold Blood Cardioplegia

Advantages

• lowers myocardial oxygen demands

Pitfalls

• Hypothermic inhibition of mitochondrial enzymes

• Shifting oxyhaemoglobin dissociation curve to left

• Activating platelets, leukocytes, complement

• Impaired membrane stabilization

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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 dogsNeurologic 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

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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

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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

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Substrate Enhancement of Cardioplegia

• Krebs-cycle intermediates– glutamate

– aspartate

• Insulin

• Nitric oxide (NO) / L-arginine

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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 flow-

pressure antegrade perfusion Energy replacement while

arrested Uniform warming

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Buffers for cardioplegia

• THAM

• Histidine

• NaHCO3

• Slightly alkaline reperfusion

• Blood

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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

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Ventricular Fibrillation with Intermittent Aortic Cross-clamping

Advantages• 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

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Reperfusion Phase

Cell damage following ischaemia is biphasic;

– Injury being initiated during ischaemia– Exacerbated during reperfusion

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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

• Free radicals are generated within 10 seconds of reperfusion after ischaemia

Zweier JL, flaherty JT, weisfeldt ML.Proc natl acad sci usa 1987;84:1404-

1408Weisel RD, Mickle DAG, Finkle CD, et al: Circulation 1989;80(suppl III):III-14-18

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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

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Therapies Under Investigation

Physiological superoxide dismutasecatalasenitric oxide

Pharmacological mannitolallopurinol antioxidants

Physical ischaemic preconditioninghypothermiahypoxic reperfusion

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

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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

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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

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New research

• Patients receiving the adenosine cardioplegia with an infusion of adenosine (200 µg/kg per minute) 10 minutes before and 15 minutes after removal of the aortic cross-clamp showed beneficial effect regarding: high-dose dopamine use, epinephrine use, insertion of an IABP, MI, or death.

• EXPEDITION study demonstrated that NHE-1(Careporide, Sodium-Hydrogen exchanger inhibitor) inhibition holds promise as a new class of drugs that could reduce myocardial injury associated with ischemia-reperfusion 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, 2008:443-464.

Page 67: Myocardial Protection- An Update

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