Cardioplegia and Cardioplegia and Surgical IschemiaSurgical Ischemia

D.J.CHANBER* and D.J. HEARSED.J.CHANBER* and D.J. HEARSE

*Cardiac surgical research/cardiothoracic surgery*Cardiac surgical research/cardiothoracic surgery

Guy’s and St. Thomas’ NHS Trust and Cardiovascular Guy’s and St. Thomas’ NHS Trust and Cardiovascular ResearchResearch

King’s Centre for Cardiovascular Biology and MedicineKing’s Centre for Cardiovascular Biology and Medicine

The Rayne institute. King’s collegeThe Rayne institute. King’s college

St. Thomas’ Hospital. London SEI 7EH. EnglandSt. Thomas’ Hospital. London SEI 7EH. England

I. IntroductionI. Introduction

IschemiaIschemia imbalance between imbalance between energy supply and energy supply and

demanddemand

Buckberg GDBuckberg GD

J Thorac Cardiovasc Surg J Thorac Cardiovasc Surg

1991;102:895-9031991;102:895-903

HypoxiaHypoxiareduction in oxygen supply reduction in oxygen supply

and accumulation of the and accumulation of the waste products of waste products of

metabolismmetabolism

Pepper J.Myocardial protection Pepper J.Myocardial protection (57-79)(57-79)

Edited by pillaj R. wright J. surgery Edited by pillaj R. wright J. surgery for ischemic heart diseasefor ischemic heart disease

1999, oxford university press1999, oxford university press

IntroductionIntroduction

► Ischemia of human heart Ischemia of human heart Only a few seconds or minutes (angioplasty or Only a few seconds or minutes (angioplasty or

angina)angina) For hours (cardiac surgery or infarction)For hours (cardiac surgery or infarction) For years (Chronic ischemic heart disease)For years (Chronic ischemic heart disease)

► This chapter focuses on the global ischemia This chapter focuses on the global ischemia Protect against ischemic injuryProtect against ischemic injury Provide a motionless, bloodless fieldProvide a motionless, bloodless field Allow effective post-ischemic myocardial Allow effective post-ischemic myocardial

resuscitationresuscitation

II. Ischemic InjuryII. Ischemic Injury

► Acute ischemic disfunctionAcute ischemic disfunction► PreconditioningPreconditioning► StunningStunning► HibernationHibernation► Necrosis vs. ApoptosisNecrosis vs. Apoptosis

Acute ischemic disfunctionAcute ischemic disfunction

► Reversible contractile failureReversible contractile failure► Perfusion pressurePerfusion pressure► O2 supplyO2 supply► Inmediate recoveryInmediate recovery

PreconditioningPreconditioning

► ReversibleReversible► Slowed energy utilizationSlowed energy utilization► Reduction in myocardial necrosisReduction in myocardial necrosis► Increase protective abilities of myocardiumIncrease protective abilities of myocardium► Presented as a normal proper protective reaction of Presented as a normal proper protective reaction of

the ischemic myocardiumthe ischemic myocardium► Recovery Hs,DsRecovery Hs,Ds

StunningStunning

► Partially ReversiblePartially Reversible► May be accompanied by endothelial dysfunction May be accompanied by endothelial dysfunction

(NO) causing reduced coronary blood flow(NO) causing reduced coronary blood flow► Result of ischemia-reperfusion insultResult of ischemia-reperfusion insult► Mediated by increased intracellular Ca Mediated by increased intracellular Ca

accumulationaccumulation► Recovery in Hs,WksRecovery in Hs,Wks

HibernationHibernation

► Partially ReversiblePartially Reversible► Related to poor myocardial blood flowRelated to poor myocardial blood flow► ChronicChronic► Recovery Wks,MoRecovery Wks,Mo

NecrosisNecrosis

► IrreversibleIrreversible► Hyper contracture - “contracture band necrosis”, Hyper contracture - “contracture band necrosis”,

“stone heart”“stone heart”► Osmotic/ionic dysregulation, membrane injuryOsmotic/ionic dysregulation, membrane injury► Cell swelling&disruptionCell swelling&disruption► LysisLysis

ApoptosisApoptosis

► IrreversibleIrreversible► Death signalDeath signal► Cell shrinkage Cell shrinkage ► Cytoplasmic and nuclear condensationCytoplasmic and nuclear condensation► PhagocytosisPhagocytosis

Normothermic IschaemiaNormothermic Ischaemia(canine heart)(canine heart)

► 20 minutes- completely reversible20 minutes- completely reversible

► 40 minutes- half the cells are necrotic40 minutes- half the cells are necrotic

► 1 hour- lethal for all cells1 hour- lethal for all cells

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

Any strategy aimed at protection the Any strategy aimed at protection the ischemic heart ischemic heart

► Reperfusion is an absolute requirement for the Reperfusion is an absolute requirement for the survival of the ischemic tissue, reflow should be survival of the ischemic tissue, reflow should be initiate at the earliest possible opportunity.initiate at the earliest possible opportunity.

► If early reperfusion cannot be achieved, should be If early reperfusion cannot be achieved, should be made to slow the rate of development of ischemic made to slow the rate of development of ischemic injury to delay the onset of irreversible injury injury to delay the onset of irreversible injury (necrosis).(necrosis).

Many factors that influence the rate at Many factors that influence the rate at ischemic injury evolvesischemic injury evolves

► Collateral or noncoronary collateral flow delivered Collateral or noncoronary collateral flow delivered to the ischemic tissue.to the ischemic tissue.

► Effects of diseases such as hypertrophy, DM, HTEffects of diseases such as hypertrophy, DM, HT► Heart rate, metabolic rate, and tissue temperatureHeart rate, metabolic rate, and tissue temperature► Metabolic responses to ischemia (substrate Metabolic responses to ischemia (substrate

utilization).utilization).► Nutritional and hormonal status.Nutritional and hormonal status.► Age, sex.Age, sex.

noncoronary collateral flownoncoronary collateral flow

► can deliver blood to the heart via bronchial, can deliver blood to the heart via bronchial, mediastinal, tracheal, esophageal, and mediastinal, tracheal, esophageal, and diaphragmatic arteries .diaphragmatic arteries .

► Flow may vary from 3 – 10 Flow may vary from 3 – 10 % % of normal coronary of normal coronary flow flow (normal 250 ml/Min).(normal 250 ml/Min).

► Advantage providing oxygen and substrates to the Advantage providing oxygen and substrates to the ischemic tissue.ischemic tissue.

► Negative effect by washing out cold Negative effect by washing out cold cardioprotective solutions .cardioprotective solutions .

► Intro the heart at the onset of ischemia.Intro the heart at the onset of ischemia.

Brief history of the development of Brief history of the development of surgical cardioprotectionsurgical cardioprotection

► Since the introduction and acceptance in the early Since the introduction and acceptance in the early 1970’s of modern surgical protection by 1970’s of modern surgical protection by Cardioplegia .Cardioplegia .

► A. Early Developments.A. Early Developments.

► B. The Reemergence of potassium Cardioplegia.B. The Reemergence of potassium Cardioplegia.

A. Early DevelopmentsA. Early Developments

► Cool the whole patient to slow the rate of Cool the whole patient to slow the rate of metabolism.metabolism.

The chest was opened, operation, and closed The chest was opened, operation, and closed rapidly before rewarming.rapidly before rewarming.

► 1953, Lewis and Taufic the first open-heart 1953, Lewis and Taufic the first open-heart (without the CPB), ASD closure with circulatory (without the CPB), ASD closure with circulatory arrest.arrest.

► 1554, Gibbon development the heart lung machine 1554, Gibbon development the heart lung machine allowed brain ischemia but the heart become allowed brain ischemia but the heart become ischemic and some operations, mortality rate 65ischemic and some operations, mortality rate 65%%..

► Continue to beat intermittently.Continue to beat intermittently.

John HJohn H . . GibbonGibbon

A. Early DevelopmentsA. Early Developments

► 1955, Melrose and colleagues introduced the 1955, Melrose and colleagues introduced the concept of “elective reversible cardiac arrest”.concept of “elective reversible cardiac arrest”. Potassium citrate (77-309 mmlo/L) added to blood at 37 Potassium citrate (77-309 mmlo/L) added to blood at 37

ooC.C. In animals, potassium citrate 2.5In animals, potassium citrate 2.5%(%(77mmlo/L77mmlo/L)) in blood with in blood with

good results (1950-1960).good results (1950-1960).

► Potassium citrate was associated with myocardial Potassium citrate was associated with myocardial injury, heart necrosis. As the use of potassium injury, heart necrosis. As the use of potassium based Cardioplegia was abandoned for about 15 based Cardioplegia was abandoned for about 15 years. years.

O

A. Early DevelopmentsA. Early Developments

► 1960s, continuous coronary perfusion, with 1960s, continuous coronary perfusion, with electrically induced ventricular fibrillation. electrically induced ventricular fibrillation.

► 1970s, Buckberg and colleagues demonstrated that 1970s, Buckberg and colleagues demonstrated that fibrillation caused sub endocardial necrosis , LV fibrillation caused sub endocardial necrosis , LV fibrillation out of favor fibrillation out of favor

(avoid fibrillation > 32 (avoid fibrillation > 32 o o C).C).► Intermittent coronary perfusion.Intermittent coronary perfusion.► Ischemic preconditioning.Ischemic preconditioning.

A. Early DevelopmentsA. Early Developments

► In the late 1960s and early 1970s, In the late 1960s and early 1970s, Shumway was protecting the heart with “profound” topical Shumway was protecting the heart with “profound” topical

hypothermia.hypothermia. Cooley, normothermic ischemia and first to describe the Cooley, normothermic ischemia and first to describe the

“stone heart”.“stone heart”.

► 1960s, in Germany. Holscher, suggested 1960s, in Germany. Holscher, suggested magnesium chloride plus procaine amide of magnesium chloride plus procaine amide of cardioprotection.cardioprotection.

► 1960s, “bretschneider solution” in Gottingen, 1960s, “bretschneider solution” in Gottingen, German.German.

► 1960s, Kirsch, in hamburg. 1960s, Kirsch, in hamburg.

B. The Reemergence of potassium B. The Reemergence of potassium CardioplegiaCardioplegia

► In the mid 1970s. In the United states.In the mid 1970s. In the United states.► Gay and Ebert, 25 mmol/L potassium chloride in Gay and Ebert, 25 mmol/L potassium chloride in

dog, good protection. dog, good protection. ► Roe and colleagues reported in 204 patients using Roe and colleagues reported in 204 patients using

potassium Cardioplegia with a mortality of 5.4 potassium Cardioplegia with a mortality of 5.4 %%..► Tyers and co workers, over 100 patients using 25 Tyers and co workers, over 100 patients using 25

mmol/L potassium with good myocardial protection.mmol/L potassium with good myocardial protection.

B. The Reemergence of potassium B. The Reemergence of potassium CardioplegiaCardioplegia

► St. Thomas’ group rationalized the three main St. Thomas’ group rationalized the three main components components Rapid chemical arrestRapid chemical arrest Use of hypothermiaUse of hypothermia Addition of anti ischemic agents Addition of anti ischemic agents

► 1975, Braimbrideg was first introduced St. Thomas’ 1975, Braimbrideg was first introduced St. Thomas’ Hospital Cardioplegia.Hospital Cardioplegia.

► This solution was modified to St. Thomas’ No.2This solution was modified to St. Thomas’ No.2

IV. Characteristics of cardioplegic IV. Characteristics of cardioplegic protectionprotection

► There are really only two types of cardioplegic There are really only two types of cardioplegic solutionsolution Intracellular type (Bretschneidr solution)Intracellular type (Bretschneidr solution) Extracellular type (St. Thomas’ , Buckberg solution)Extracellular type (St. Thomas’ , Buckberg solution)

► Intracellular type used predominantly for Intracellular type used predominantly for preservation of the heart and abdominal organspreservation of the heart and abdominal organs

► Extracellular type used predominantly for cardiac Extracellular type used predominantly for cardiac surgerysurgery

V. principles underlying the protection of V. principles underlying the protection of the heart the heart

► Inducing rapid and complete Cardiac ArrestInducing rapid and complete Cardiac Arrest► Slowing the onset of irreversible injury by HypothermiaSlowing the onset of irreversible injury by Hypothermia► Minimizing Damaging ischemic changes with Anti-Minimizing Damaging ischemic changes with Anti-

ischemic Agentsischemic Agents► Optimizing reperfusion to maximize Post ischemic Optimizing reperfusion to maximize Post ischemic

RecoveryRecovery► Effective Cardioprotection should not ignore vascular Effective Cardioprotection should not ignore vascular

and conduction tissueand conduction tissue► Alternative approaches to limiting tissue injury during Alternative approaches to limiting tissue injury during

cardiac surgerycardiac surgery

A. Inducing rapid and complete Cardiac A. Inducing rapid and complete Cardiac ArrestArrest

► Myocardial OMyocardial O22 consumptions at 37 consumptions at 37 ooCC

Beating (full,perfused) 10 ml/100gr/minBeating (full,perfused) 10 ml/100gr/min Beating (empty,perfused) 5.5 ml/100gr/minBeating (empty,perfused) 5.5 ml/100gr/min Fibrilating(empty,perfused) 6.5 ml/100gr/minFibrilating(empty,perfused) 6.5 ml/100gr/min Cardioplegia(empty,crossclamp) 1.0 ml/100gr/minCardioplegia(empty,crossclamp) 1.0 ml/100gr/min

A. Inducing rapid and complete Cardiac A. Inducing rapid and complete Cardiac ArrestArrest

► Depolarized ArrestDepolarized Arrest

► Polarized ArrestPolarized Arrest

► Inhibition of Ca influxInhibition of Ca influx

Depolarized ArrestDepolarized Arrest

► Hyperkalemia

► Potassium concentration between 15-20 mmol/L

(Membrane potential -50 -60 mV)

Polarized ArrestPolarized Arrest

Reduce Ionic movement Reduce Ionic movement Threshold potential not be reached and window will not be Threshold potential not be reached and window will not be

activatedactivated Reduce myocardium energyReduce myocardium energy

► Sodium Channel BlockadeSodium Channel Blockade► ATP sensitivity potassium Channel activationATP sensitivity potassium Channel activation► AdenosineAdenosine► AcetylcholineAcetylcholine

Polarized Arrest Polarized Arrest Sodium Channel BlockadeSodium Channel Blockade

► Prevent sodium induced depolarization of the action Prevent sodium induced depolarization of the action potentialpotential

► Local anesthetics Local anesthetics - procaine 1 mmol/L+ CPS- procaine 1 mmol/L+ CPS

- Lidocain + CPS (-70 mV)- Lidocain + CPS (-70 mV)

► Tetrodotoxin (a highly toxic but potent and rapidly Tetrodotoxin (a highly toxic but potent and rapidly reversible sodium channel blocker)reversible sodium channel blocker)

Na channel activated and Na channel activated and inactivatedinactivated

Polarized Arrest Polarized Arrest ATP sensitivity potassium Channel activationATP sensitivity potassium Channel activation

► 1983, Noma was described the cardiac ATP-s1983, Noma was described the cardiac ATP-s► Potassium Channel openers (membrane potential < -Potassium Channel openers (membrane potential < -

70 mV)70 mV)► Enchant post ischemic recovery of functionEnchant post ischemic recovery of function► This protection effect was lost when add to St. This protection effect was lost when add to St.

Thomas CPSThomas CPS

Polarized Arrest Polarized Arrest AdenosineAdenosine

► 1-10 mmol/L alone or with potassium, rapid arrest 1-10 mmol/L alone or with potassium, rapid arrest and improve post ischemic compared to and improve post ischemic compared to hyperkalemia alone hyperkalemia alone

► Action; initial transient hyper polarization before Action; initial transient hyper polarization before depolarization was thought to arrest SA node (10 depolarization was thought to arrest SA node (10 mmol/L) mmol/L)

► Additive to CPS to enhance myocardial protection Additive to CPS to enhance myocardial protection

Polarized Arrest Polarized Arrest AcetylcholineAcetylcholine

► 1955 – 1960, was used as a Cardioplegic agent by 1955 – 1960, was used as a Cardioplegic agent by number of surgeons number of surgeons

► Action; like adenosine by suppressing sinus nod and Action; like adenosine by suppressing sinus nod and blocking sinoatrial conduction (hyper polarization)blocking sinoatrial conduction (hyper polarization)

► Short-live during cardiac surgeryShort-live during cardiac surgery► Recovery of function depressed after longer arrest Recovery of function depressed after longer arrest

periodsperiods

Inhibition of calcium influxInhibition of calcium influx

► HypocalcemiaHypocalcemia

► Calcium antagonistsCalcium antagonists

► hypermagnesemiahypermagnesemia

Inhibition of calcium influxInhibition of calcium influxHypocalcemiaHypocalcemia

► Ca induced ca release.Ca induced ca release.► kirseh kirseh (ca and Na free)(ca and Na free)► Bretxcheider solution Bretxcheider solution (low calcium)(low calcium)► St. Thomas’ hospital St. Thomas’ hospital

solution.solution.

Inhibition of calcium influxInhibition of calcium influxHypocalcemiaHypocalcemia

► Calcium free solution induce a lethal condition Calcium free solution induce a lethal condition “calcium paradox”“calcium paradox”

► Contain calcium, used clod and hypothermia, low Contain calcium, used clod and hypothermia, low sodium and/or high magnesium. sodium and/or high magnesium.

► St. Thomas, CaCl concentration 1.2 mmol/L St. Thomas, CaCl concentration 1.2 mmol/L

*** *** Rapid diastolic arrest can be achieved by the Rapid diastolic arrest can be achieved by the depletion of depletion of

calciumcalcium

Inhibition of calcium influx Inhibition of calcium influx Calcium antagonistsCalcium antagonists

► Reduce calcium influx through slow calcium Reduce calcium influx through slow calcium channelschannels

► Such as verapamil, nifedipine, and diltiazemSuch as verapamil, nifedipine, and diltiazem► Recovery function and high energy phosphates Recovery function and high energy phosphates

when additive to potassium CPSwhen additive to potassium CPS► Calcium overload by noncoronary collateralCalcium overload by noncoronary collateral► High concentration may be prolong arrestHigh concentration may be prolong arrest► No protective under hypothermic No protective under hypothermic

Inhibition of calcium influx Inhibition of calcium influx hypermagnesemiahypermagnesemia

► Magnesium can arrest the heart at higher Magnesium can arrest the heart at higher concentration are needed to induce arrestconcentration are needed to induce arrest

► Achieved by the displacement of calcium from the Achieved by the displacement of calcium from the rapidly exchangeable Sarcolemmal binding sites rapidly exchangeable Sarcolemmal binding sites involved in excitation contraction couplinginvolved in excitation contraction coupling

► Optimal protective concentration at 16 mmol/L Optimal protective concentration at 16 mmol/L (irrespective of whether temperature)(irrespective of whether temperature)

B. Slowing the onset of irreversible B. Slowing the onset of irreversible injury by hypothermiainjury by hypothermia

► basal metabolism basal metabolism

in the absence of myocardial contraction, the in the absence of myocardial contraction, the myocyte still requires oxygen for basic “house myocyte still requires oxygen for basic “house keeping” functions keeping” functions

► this basal cost can be further reduced with this basal cost can be further reduced with hypothermiahypothermia

Myocardial OMyocardial O22 consumption consumptionml/100gr/minml/100gr/min

Oxygen DemandOxygen Demand reductionreduction

► Normothermic Arrest (Normothermic Arrest (C)C) 1.00 mL/100g/min 90% 1.00 mL/100g/min 90%► Hypothermic Arrest (22 Hypothermic Arrest (22 C) 0.30 mL/100g/minC) 0.30 mL/100g/min 97% 97% ► Hypothermic Arrest (10 Hypothermic Arrest (10 C)C) 0.14 mL/100g/min 0.14 mL/100g/min ~ 97%~ 97%

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

hypothermiahypothermia

► lowers metabolic rate lowers metabolic rate ► decrease myocardial energy requirementsdecrease myocardial energy requirements► promoting electromechanical quiescencepromoting electromechanical quiescence► every 10 every 10 oo

C in temperature, enzyme activity halvedC in temperature, enzyme activity halved► regional variations ! regional variations !

Bigelow, Lindsay, Greenwood- 1950Bigelow, Lindsay, Greenwood- 1950

Shumway and Lower- 1959Shumway and Lower- 1959

hypothermiahypothermia

Effects on; PitfallsEffects on; Pitfalls► enzyme functionenzyme function► membrane stabilitymembrane stability► calcium sequestration increase intra cellular Ca calcium sequestration increase intra cellular Ca ► Sodium pump is inhibitedSodium pump is inhibited► glucose utilisationglucose utilisation► ATP generation and utilisation ATP generation and utilisation ► leftward shift of oxyhaemoglobin curve (impaired leftward shift of oxyhaemoglobin curve (impaired

tissue oxygen uptake) and elevated pHtissue oxygen uptake) and elevated pH► osmotic homeostasis (cell swelling)osmotic homeostasis (cell swelling)

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

The optimal temperature during The optimal temperature during hypothermichypothermic

► Temperature around 10-15 Temperature around 10-15 ooC were optimal.C were optimal.

► Water temperature 4 Water temperature 4 ooC, C, cooling myocardium to 10-cooling myocardium to 10-15 15 ooC C

Minimizing damaging ischemic changes Minimizing damaging ischemic changes with anti-ischemic agentswith anti-ischemic agents

► Blood as a additive or a vehicle for CardioplegiaBlood as a additive or a vehicle for Cardioplegia► Oxygenation of CardioplegiaOxygenation of Cardioplegia► Agent that influence buffering and PHAgent that influence buffering and PH► Calcium AntagonistsCalcium Antagonists► Antioxidants and inhibitors of free oxygen radical Antioxidants and inhibitors of free oxygen radical

productionproduction► Manipulation of metabolism and substrate Manipulation of metabolism and substrate

utilizationutilization

Blood as a additive or a vehicle for Blood as a additive or a vehicle for CardioplegiaCardioplegia

► Melrose and colleagues, The earliest blood CPSMelrose and colleagues, The earliest blood CPS► Late 1970s, Buckberg’s group was the first to study Late 1970s, Buckberg’s group was the first to study

about blood CPS (in dogs)about blood CPS (in dogs) Cold blood CPS, recovery 80Cold blood CPS, recovery 80%% after 2 Hr. ischemic arrest after 2 Hr. ischemic arrest Continuous perfusion, recovery 40Continuous perfusion, recovery 40%% Intermittent ischemic, recovery 17Intermittent ischemic, recovery 17%%

► Blood with crystalloid solution, LV stroke work index Blood with crystalloid solution, LV stroke work index improve after ischemic 2 hr.improve after ischemic 2 hr.

► Used crystalloid only, LV stroke work index improve Used crystalloid only, LV stroke work index improve after ischemic 24 hr.after ischemic 24 hr.

Blood CardioplegiaBlood Cardioplegia

advantagesadvantages

► improved oxygen carrying capacity and delivery improved oxygen carrying capacity and delivery until electromechanical quiescence developeduntil electromechanical quiescence developed

► enhanced myocardial oxygen consumptionenhanced myocardial oxygen consumption

► Substrate preserved high-energy phosphate storesSubstrate preserved high-energy phosphate stores

► buffering changes in pHbuffering changes in pH

► Free radical scavengersFree radical scavengers ► provide appropriate osmotic environment for provide appropriate osmotic environment for

myocardial cells and lessen the myocardial oedemamyocardial cells and lessen the myocardial oedema

Blood CardioplegiaBlood Cardioplegia

pitfallspitfalls

► Have added to the costHave added to the cost► The high hematocrit and low temp, Induce a The high hematocrit and low temp, Induce a

sludging effect sludging effect ► Operating field less clear when give CardioplegiaOperating field less clear when give Cardioplegia

Oxygenation of CardioplegiaOxygenation of Cardioplegia

► Oxygen during cold ischemic arrest (either Oxygen during cold ischemic arrest (either crystalloid or blood CPS) sufficient to meet the crystalloid or blood CPS) sufficient to meet the reduced demands of myocardialreduced demands of myocardial

► Warm induction arrest, Warm induction arrest, preserved high-energy preserved high-energy phosphate storesphosphate stores

► Reperfusion with warm blood CPS (37 Reperfusion with warm blood CPS (37 ooC), C), myocardial metabolic recovery with out the energy myocardial metabolic recovery with out the energy consumption of contraction consumption of contraction

Agent that influence buffering and PHAgent that influence buffering and PH

► Acidosis the consequences of ischemiaAcidosis the consequences of ischemia► Buffers, prevent major pH change during ischemiaBuffers, prevent major pH change during ischemia► Basic concepts of pH and temp. water shifts in Basic concepts of pH and temp. water shifts in

alkaline 0.05 when temp decreases 1 alkaline 0.05 when temp decreases 1 ooC C

(dissociation of water into H(dissociation of water into H++ is reduce) is reduce)► St. Thomas No. 2 pH 7.8 by the addition St. Thomas No. 2 pH 7.8 by the addition

bicarbonatebicarbonate► Crystalloid cardioplegic solution have little or only Crystalloid cardioplegic solution have little or only

poor buffering capacitypoor buffering capacity► Blood CPS have strong buffering capacityBlood CPS have strong buffering capacity

Calcium AntagonistsCalcium Antagonists

► Depression of contractile function (reduce Ca Depression of contractile function (reduce Ca influx through the slow L type Ca channel)influx through the slow L type Ca channel)

► Protective intracellular Ca overload, from injury Protective intracellular Ca overload, from injury during ischemia and reperfusionduring ischemia and reperfusion

► Optimal dose diltiazem, verapamil, nifedipineOptimal dose diltiazem, verapamil, nifedipine► No protective effect when hypothermia (20 No protective effect when hypothermia (20 ooC) C) ► Buckberg blood CPS (CPD)Buckberg blood CPS (CPD)

Antioxidants and inhibitors of free Antioxidants and inhibitors of free oxygen radical productionoxygen radical production

► 1980s, interest in free oxygen radicals1980s, interest in free oxygen radicals► Free radicals, Superoxide anion, hydroxyl radical, Free radicals, Superoxide anion, hydroxyl radical,

hydrogen peroxide (from ischemia and reperfusion)hydrogen peroxide (from ischemia and reperfusion)► Endogenous anti oxidant systemEndogenous anti oxidant system

Superoxide dismutase and catalase (reduce when ischemic Superoxide dismutase and catalase (reduce when ischemic tissue)tissue)

► Allopurinol, Metal ion (copper and iron release when Allopurinol, Metal ion (copper and iron release when hemolysis)hemolysis)

► deferoxamine (inhibit neutrophil activate) deferoxamine (inhibit neutrophil activate)

Manipulation of metabolism and Manipulation of metabolism and substrate utilizationsubstrate utilization

► Exogenous high-energy phosphates Exogenous high-energy phosphates Creatine phosphate 10 mmol/L with St. ThomasCreatine phosphate 10 mmol/L with St. Thomas

► Adenosine and ATP catabolitesAdenosine and ATP catabolites Only minimal or no beneficial effects on clinical outcomeOnly minimal or no beneficial effects on clinical outcome

► Amino acids Amino acids Glutamate aspartate (ATP storage)Glutamate aspartate (ATP storage) Warm induction (37 Warm induction (37 ooC) of arrest, “active resuscitation” C) of arrest, “active resuscitation”

► Glucose and glycolytic intermediatesGlucose and glycolytic intermediates Promote glycolytic anaerobic ATP (2 ATP)Promote glycolytic anaerobic ATP (2 ATP) Intracellular acidosis and lactate productionIntracellular acidosis and lactate production

Optimizing reperfusion to maximize post Optimizing reperfusion to maximize post ischemic recoveryischemic recovery

► Reperfusion phaseReperfusion phase► cell damage following ischemia is biphasic;cell damage following ischemia is biphasic;

injury being initiated during ischemiainjury being initiated during ischemia exacerbated during reperfusionexacerbated during reperfusion

► The best approach to avoiding reperfusion injuryThe best approach to avoiding reperfusion injury Control ionic disturbancesControl ionic disturbances Combat free radical production and oxidative stressCombat free radical production and oxidative stress Optimize the recovery of energy metabolismOptimize the recovery of energy metabolism

Control ionic disturbances Control ionic disturbances during reperfusionduring reperfusion

► Hyperkalemia, myocardial metabolic recoveryHyperkalemia, myocardial metabolic recovery► Hypocalcemia (avoid Ca overload, myocardium Hypocalcemia (avoid Ca overload, myocardium

stunning)stunning) Calcium antagonist, diltiazem 300 microgram/Kg Calcium antagonist, diltiazem 300 microgram/Kg

► Reduction of reperfusion-induced sodium overload Reduction of reperfusion-induced sodium overload Sodium/Proton exchange inhibitors, improve postischemiaSodium/Proton exchange inhibitors, improve postischemia

During Ischemia, inNa/K pump was inhibitDuring Ischemia, inNa/K pump was inhibit Activates Na/HActivates Na/H++ to reduce cell acidosis (intracellular Na to reduce cell acidosis (intracellular Na

increased)increased) Promote Na/Ca exchange (calcium overload) Promote Na/Ca exchange (calcium overload)

Combat free radical production and Combat free radical production and oxidative stressoxidative stress

► Supplementation of antioxidant enzymeSupplementation of antioxidant enzyme Superoxide dismutase, catalase, coenzyme Q10(ubiquinone) Superoxide dismutase, catalase, coenzyme Q10(ubiquinone)

and glutathione peroxidase with blood CPS (cocktail)and glutathione peroxidase with blood CPS (cocktail)

► Pharmacological inhibitor of radical productionPharmacological inhibitor of radical production Allopurinol or oxypurinol, deferoxamineAllopurinol or oxypurinol, deferoxamine

► Antineutrophil therapyAntineutrophil therapy Mustine, monoclonal antibodies (prevent interaction Mustine, monoclonal antibodies (prevent interaction

neutrophil and endothelium)neutrophil and endothelium)

Neutrophil filters, Neutrophil filters, free radicals are generated within free radicals are generated within 10 seconds of reperfusion after ischemia10 seconds of reperfusion after ischemia

Optimize the recovery of energy Optimize the recovery of energy metabolismmetabolism

► Amino acid glutamate and aspartateAmino acid glutamate and aspartate

(Krebs-cycle intermediates)(Krebs-cycle intermediates)► Pyruvate (2 mmol/L) with glucose, prevent free Pyruvate (2 mmol/L) with glucose, prevent free

radical generationradical generation

Effective cardioprotection should not Effective cardioprotection should not ignoreignore

Effects of Hyperkalemia on the endotheliumEffects of Hyperkalemia on the endothelium

► Global ischemia and reperfusion induce injuryGlobal ischemia and reperfusion induce injury► Potassium were concentration dependentPotassium were concentration dependent► Blood based CPS protect endothelium during Blood based CPS protect endothelium during

ischemia (but injury during reperfusion)ischemia (but injury during reperfusion)► Reperfusion, arise oxygen free radical resulting Reperfusion, arise oxygen free radical resulting

inactivation of nitric oxide path wayinactivation of nitric oxide path way (used super oxide dismutase)(used super oxide dismutase)► Neutrophil-endothelium interaction, prevention by Neutrophil-endothelium interaction, prevention by

various inhibitory mediators various inhibitory mediators

Effective cardioprotection should not Effective cardioprotection should not ignoreignore

Effects of Hyperkalemia on conduction tissue of Effects of Hyperkalemia on conduction tissue of heartheart

► More tolerant to ischemia than the myocyteMore tolerant to ischemia than the myocyte► Reperfusion increase such prolonged heart block and Reperfusion increase such prolonged heart block and

supraventricular tachyarrhythmiassupraventricular tachyarrhythmias► Low amplitude electrical activity, lower atrial septum, Low amplitude electrical activity, lower atrial septum,

AV node-His bundle complex, and ventricular (add Ca AV node-His bundle complex, and ventricular (add Ca channel blockers)channel blockers)

► Blood CPS avoided with preexistings conduction Blood CPS avoided with preexistings conduction problems; but these are relatively short-livedproblems; but these are relatively short-lived

Ischemic PreconditioningIschemic Preconditioning

““adaptive mechanism induced by a brief period of adaptive mechanism induced by a brief period of reversible ischemia increasing heart’s resistance to reversible ischemia increasing heart’s resistance to a subsequent longer period of ischemia”a subsequent longer period of ischemia”

► most powerful endogenously mediated form of most powerful endogenously mediated form of myocardial protectionmyocardial protection

► ? slowing ATP depletion, limitation of acidosis ? slowing ATP depletion, limitation of acidosis ► ? mediator- adenosine? mediator- adenosine