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1. Cardioplegia and SurgicalCardioplegia and Surgical
IschemiaIschemia
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 CardiovascularGuy’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
3. IschemiaIschemia
imbalance between energyimbalance between energy
supply and demandsupply and demand
Buckberg GDBuckberg GD
J Thorac Cardiovasc SurgJ Thorac Cardiovasc Surg
1991;102:895-9031991;102:895-903
4. HypoxiaHypoxia
reduction in oxygen supplyreduction in oxygen supply
and accumulation of the wasteand accumulation of the waste
products of metabolismproducts of metabolism
Pepper J.Myocardial protection (57-79)Pepper J.Myocardial protection (57-79)
Edited by pillaj R. wright J. surgery forEdited by pillaj R. wright J. surgery for
ischemic heart diseaseischemic heart disease
1999, oxford university press1999, oxford university press
5. IntroductionIntroduction
► Ischemia of human heartIschemia of human heart
Only a few seconds or minutes (angioplasty or angina)Only a few seconds or minutes (angioplasty or 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 ischemiaThis 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 resuscitationAllow effective post-ischemic myocardial resuscitation
6. II. Ischemic InjuryII. Ischemic Injury
► Acute ischemic disfunctionAcute ischemic disfunction
► PreconditioningPreconditioning
► StunningStunning
► HibernationHibernation
► Necrosis vs. ApoptosisNecrosis vs. Apoptosis
8. 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 thePresented as a normal proper protective reaction of the
ischemic myocardiumischemic myocardium
► Recovery Hs,DsRecovery Hs,Ds
9. StunningStunning
► Partially ReversiblePartially Reversible
► May be accompanied by endothelial dysfunction (NO)May be accompanied by endothelial dysfunction (NO)
causing reduced coronary blood flowcausing reduced coronary blood flow
► Result of ischemia-reperfusion insultResult of ischemia-reperfusion insult
► Mediated by increased intracellular Ca accumulationMediated by increased intracellular Ca accumulation
► Recovery in Hs,WksRecovery in Hs,Wks
13. 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
14. Any strategy aimed at protection the ischemicAny strategy aimed at protection the ischemic
heartheart
► Reperfusion is an absolute requirement for the survival ofReperfusion is an absolute requirement for the survival of
the ischemic tissue, reflow should be initiate at the earliestthe ischemic tissue, reflow should be initiate at the earliest
possible opportunity.possible opportunity.
► If early reperfusion cannot be achieved, should be made toIf early reperfusion cannot be achieved, should be made to
slow the rate of development of ischemic injury to delay theslow the rate of development of ischemic injury to delay the
onset of irreversible injury (necrosis).onset of irreversible injury (necrosis).
15. Many factors that influence the rate atMany factors that influence the rate at
ischemic injury evolvesischemic injury evolves
► Collateral or noncoronary collateral flow delivered to theCollateral or noncoronary collateral flow delivered to the
ischemic tissue.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 utilization).Metabolic responses to ischemia (substrate utilization).
► Nutritional and hormonal status.Nutritional and hormonal status.
► Age, sex.Age, sex.
16. noncoronary collateral flownoncoronary collateral flow
► can deliver blood to the heart via bronchial, mediastinal,can deliver blood to the heart via bronchial, mediastinal,
tracheal, esophageal, and diaphragmatic arteries .tracheal, esophageal, and diaphragmatic arteries .
► Flow may vary from 3 – 10Flow may vary from 3 – 10 %% of normal coronary flowof normal coronary flow
(normal 250 ml/Min).(normal 250 ml/Min).
► Advantage providing oxygen and substrates to theAdvantage providing oxygen and substrates to the
ischemic tissue.ischemic tissue.
► Negative effect by washing out cold cardioprotectiveNegative effect by washing out cold cardioprotective
solutions .solutions .
► Intro the heart at the onset of ischemia.Intro the heart at the onset of ischemia.
17. Brief history of the development of surgicalBrief history of the development of surgical
cardioprotectioncardioprotection
► Since the introduction and acceptance in the early 1970’sSince the introduction and acceptance in the early 1970’s
of modern surgical protection by Cardioplegia .of modern surgical protection by Cardioplegia .
► A. Early Developments.A. Early Developments.
► B. The Reemergence of potassium Cardioplegia.B. The Reemergence of potassium Cardioplegia.
18. A. Early DevelopmentsA. Early Developments
► Cool the whole patient to slow the rate of metabolism.Cool the whole patient to slow the rate of metabolism.
The chest was opened, operation, and closed rapidly beforeThe chest was opened, operation, and closed rapidly before
rewarming.rewarming.
► 1953, Lewis and Taufic the first open-heart (without the1953, Lewis and Taufic the first open-heart (without the
CPB), ASD closure with circulatory arrest.CPB), ASD closure with circulatory arrest.
► 1554, Gibbon development the heart lung machine1554, Gibbon development the heart lung machine
allowed brain ischemia but the heart become ischemic andallowed brain ischemia but the heart become ischemic and
some operations, mortality rate 65some operations, mortality rate 65%%..
► Continue to beat intermittently.Continue to beat intermittently.
20. A. Early DevelopmentsA. Early Developments
► 1955, Melrose and colleagues introduced the concept of1955, Melrose and colleagues introduced the concept of
“elective reversible cardiac arrest”.“elective reversible cardiac arrest”.
Potassium citrate (77-309 mmlo/L) added to blood at 37Potassium citrate (77-309 mmlo/L) added to blood at 37 oo
C.C.
In animals, potassium citrate 2.5In animals, potassium citrate 2.5%(%(77mmlo/L77mmlo/L)) in blood with goodin blood with good
results (1950-1960).results (1950-1960).
► Potassium citrate was associated with myocardial injury,Potassium citrate was associated with myocardial injury,
heart necrosis. As the use of potassium basedheart necrosis. As the use of potassium based
Cardioplegia was abandoned for about 15 years.Cardioplegia was abandoned for about 15 years.
O
21. A. Early DevelopmentsA. Early Developments
► 1960s, continuous coronary perfusion, with electrically1960s, continuous coronary perfusion, with electrically
induced ventricular fibrillation.induced ventricular fibrillation.
► 1970s, Buckberg and colleagues demonstrated that1970s, Buckberg and colleagues demonstrated that
fibrillation caused sub endocardial necrosis , LV fibrillationfibrillation caused sub endocardial necrosis , LV fibrillation
out of favorout of favor
(avoid fibrillation > 32(avoid fibrillation > 32 oo
C).C).
► Intermittent coronary perfusion.Intermittent coronary perfusion.
► Ischemic preconditioning.Ischemic preconditioning.
22. 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” topicalShumway was protecting the heart with “profound” topical
hypothermia.hypothermia.
Cooley, normothermic ischemia and first to describe the “stoneCooley, normothermic ischemia and first to describe the “stone
heart”.heart”.
► 1960s, in Germany. Holscher, suggested magnesium1960s, in Germany. Holscher, suggested magnesium
chloride plus procaine amide of cardioprotection.chloride plus procaine amide of cardioprotection.
► 1960s, “bretschneider solution” in Gottingen, German.1960s, “bretschneider solution” in Gottingen, German.
► 1960s, Kirsch, in hamburg.1960s, Kirsch, in hamburg.
23. B. The Reemergence of potassiumB. 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 dog, goodGay and Ebert, 25 mmol/L potassium chloride in dog, good
protection.protection.
► Roe and colleagues reported in 204 patients usingRoe and colleagues reported in 204 patients using
potassium Cardioplegia with a mortality of 5.4potassium Cardioplegia with a mortality of 5.4 %%..
► Tyers and co workers, over 100 patients using 25 mmol/LTyers and co workers, over 100 patients using 25 mmol/L
potassium with good myocardial protection.potassium with good myocardial protection.
24. B. The Reemergence of potassiumB. The Reemergence of potassium
CardioplegiaCardioplegia
► St. Thomas’ group rationalized the three main componentsSt. Thomas’ group rationalized the three main components
Rapid chemical arrestRapid chemical arrest
Use of hypothermiaUse of hypothermia
Addition of anti ischemic agentsAddition 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
25. IV. Characteristics of cardioplegic protectionIV. Characteristics of cardioplegic protection
► There are really only two types of cardioplegic solutionThere are really only two types of cardioplegic solution
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 preservation ofIntracellular type used predominantly for preservation of
the heart and abdominal organsthe heart and abdominal organs
► Extracellular type used predominantly for cardiac surgeryExtracellular type used predominantly for cardiac surgery
26. V. principles underlying the protection of theV. principles underlying the protection of the
heartheart
► 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-ischemicMinimizing Damaging ischemic changes with Anti-ischemic
AgentsAgents
► Optimizing reperfusion to maximize Post ischemicOptimizing reperfusion to maximize Post ischemic
RecoveryRecovery
► Effective Cardioprotection should not ignore vascular andEffective Cardioprotection should not ignore vascular and
conduction tissueconduction tissue
► Alternative approaches to limiting tissue injury duringAlternative approaches to limiting tissue injury during
cardiac surgerycardiac surgery
27. A. Inducing rapid and complete Cardiac ArrestA. Inducing rapid and complete Cardiac Arrest
► Myocardial OMyocardial O22 consumptions at 37consumptions at 37 oo
CC
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
28. A. Inducing rapid and complete Cardiac ArrestA. Inducing rapid and complete Cardiac Arrest
► Depolarized ArrestDepolarized Arrest
► Polarized ArrestPolarized Arrest
► Inhibition of Ca influxInhibition of Ca influx
31. Polarized ArrestPolarized Arrest
Reduce Ionic movementReduce Ionic movement
Threshold potential not be reached and window will not beThreshold 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
32. Polarized ArrestPolarized Arrest
Sodium Channel BlockadeSodium Channel Blockade
► Prevent sodium induced depolarization of the actionPrevent sodium induced depolarization of the action
potentialpotential
► Local anestheticsLocal 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 rapidlyTetrodotoxin (a highly toxic but potent and rapidly
reversible sodium channel blocker)reversible sodium channel blocker)
34. Polarized ArrestPolarized 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 < -70 mV)Potassium Channel openers (membrane potential < -70 mV)
► Enchant post ischemic recovery of functionEnchant post ischemic recovery of function
► This protection effect was lost when add to St. Thomas CPSThis protection effect was lost when add to St. Thomas CPS
35. Polarized ArrestPolarized Arrest
AdenosineAdenosine
► 1-10 mmol/L alone or with potassium, rapid arrest and1-10 mmol/L alone or with potassium, rapid arrest and
improve post ischemic compared to hyperkalemia aloneimprove post ischemic compared to hyperkalemia alone
► Action; initial transient hyper polarization beforeAction; initial transient hyper polarization before
depolarization was thought to arrest SA node (10 mmol/L)depolarization was thought to arrest SA node (10 mmol/L)
► Additive to CPS to enhance myocardial protectionAdditive to CPS to enhance myocardial protection
36. Polarized ArrestPolarized Arrest
AcetylcholineAcetylcholine
► 1955 – 1960, was used as a Cardioplegic agent by number1955 – 1960, was used as a Cardioplegic agent by number
of surgeonsof surgeons
► Action; like adenosine by suppressing sinus nod andAction; 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 periodsRecovery of function depressed after longer arrest periods
37. Inhibition of calcium influxInhibition of calcium influx
► HypocalcemiaHypocalcemia
► Calcium antagonistsCalcium antagonists
► hypermagnesemiahypermagnesemia
38.
39. Inhibition of calcium influxInhibition of calcium influx
HypocalcemiaHypocalcemia
► Ca induced ca release.Ca induced ca release.
► kirsehkirseh (ca and Na free)(ca and Na free)
► Bretxcheider solutionBretxcheider solution
(low calcium)(low calcium)
► St. Thomas’ hospital solution.St. Thomas’ hospital solution.
40. Inhibition of calcium influxInhibition of calcium influx
HypocalcemiaHypocalcemia
► Calcium free solution induce a lethal condition “calciumCalcium free solution induce a lethal condition “calcium
paradox”paradox”
► Contain calcium, used clod and hypothermia, low sodiumContain calcium, used clod and hypothermia, low sodium
and/or high magnesium.and/or high magnesium.
► St. Thomas, CaCl concentration 1.2 mmol/LSt. Thomas, CaCl concentration 1.2 mmol/L
****** Rapid diastolic arrest can be achieved by the depletion ofRapid diastolic arrest can be achieved by the depletion of
calciumcalcium
41. Inhibition of calcium influxInhibition of calcium influx
Calcium antagonistsCalcium antagonists
► Reduce calcium influx through slow calcium channelsReduce calcium influx through slow calcium channels
► Such as verapamil, nifedipine, and diltiazemSuch as verapamil, nifedipine, and diltiazem
► Recovery function and high energy phosphates whenRecovery function and high energy phosphates when
additive to potassium CPSadditive 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 hypothermicNo protective under hypothermic
42. Inhibition of calcium influxInhibition of calcium influx
hypermagnesemiahypermagnesemia
► Magnesium can arrest the heart at higher concentrationMagnesium can arrest the heart at higher concentration
are needed to induce arrestare needed to induce arrest
► Achieved by the displacement of calcium from the rapidlyAchieved by the displacement of calcium from the rapidly
exchangeable Sarcolemmal binding sites involved inexchangeable Sarcolemmal binding sites involved in
excitation contraction couplingexcitation contraction coupling
► Optimal protective concentration at 16 mmol/LOptimal protective concentration at 16 mmol/L (irrespective of(irrespective of
whether temperature)whether temperature)
43.
44. B. Slowing the onset of irreversible injury byB. Slowing the onset of irreversible injury by
hypothermiahypothermia
► basal metabolismbasal metabolism
in the absence of myocardial contraction, the myocyte stillin the absence of myocardial contraction, the myocyte still
requires oxygen for basic “house keeping” functionsrequires oxygen for basic “house keeping” functions
► this basal cost can be further reduced with hypothermiathis basal cost can be further reduced with hypothermia
47. hypothermiahypothermia
► lowers metabolic ratelowers metabolic rate
► decrease myocardial energy requirementsdecrease myocardial energy requirements
► promoting electromechanical quiescencepromoting electromechanical quiescence
► every 10every 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
48. hypothermiahypothermia
Effects on; PitfallsEffects on; Pitfalls
► enzyme functionenzyme function
► membrane stabilitymembrane stability
► calcium sequestration increase intra cellular Cacalcium sequestration increase intra cellular Ca
► Sodium pump is inhibitedSodium pump is inhibited
► glucose utilisationglucose utilisation
► ATP generation and utilisationATP generation and utilisation
► leftward shift of oxyhaemoglobin curve (impaired tissueleftward shift of oxyhaemoglobin curve (impaired tissue
oxygen uptake) and elevated pHoxygen 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
49. The optimal temperature during hypothermicThe optimal temperature during hypothermic
► Temperature around 10-15Temperature around 10-15 oo
CC
were optimal.were optimal.
► Water temperature 4Water temperature 4 oo
C, coolingC, cooling
myocardium to 10-15myocardium to 10-15 oo
CC
50. Minimizing damaging ischemic changes withMinimizing damaging ischemic changes with
anti-ischemic agentsanti-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 radicalAntioxidants and inhibitors of free oxygen radical
productionproduction
► Manipulation of metabolism and substrate utilizationManipulation of metabolism and substrate utilization
51. Blood as a additive or a vehicle forBlood 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 aboutLate 1970s, Buckberg’s group was the first to study about
blood CPS (in dogs)blood CPS (in dogs)
Cold blood CPS, recovery 80Cold blood CPS, recovery 80%% after 2 Hr. ischemic arrestafter 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 indexBlood 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 afterUsed crystalloid only, LV stroke work index improve after
ischemic 24 hr.ischemic 24 hr.
52. Blood CardioplegiaBlood Cardioplegia
advantagesadvantages
► improved oxygen carrying capacity and delivery untilimproved oxygen carrying capacity and delivery until
electromechanical quiescence developedelectromechanical 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 myocardialprovide appropriate osmotic environment for myocardial
cells and lessen the myocardial oedemacells and lessen the myocardial oedema
53. Blood CardioplegiaBlood Cardioplegia
pitfallspitfalls
► Have added to the costHave added to the cost
► The high hematocrit and low temp, Induce a sludging effectThe high hematocrit and low temp, Induce a sludging effect
► Operating field less clear when give CardioplegiaOperating field less clear when give Cardioplegia
54. Oxygenation of CardioplegiaOxygenation of Cardioplegia
► Oxygen during cold ischemic arrest (either crystalloid orOxygen during cold ischemic arrest (either crystalloid or
blood CPS) sufficient to meet the reduced demands ofblood CPS) sufficient to meet the reduced demands of
myocardialmyocardial
► Warm induction arrest,Warm induction arrest, preserved high-energy phosphatepreserved high-energy phosphate
storesstores
► Reperfusion with warm blood CPS (37Reperfusion with warm blood CPS (37 oo
C), myocardialC), myocardial
metabolic recovery with out the energy consumption ofmetabolic recovery with out the energy consumption of
contractioncontraction
55. 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 alkalineBasic concepts of pH and temp. water shifts in alkaline
0.05 when temp decreases 10.05 when temp decreases 1 oo
CC
(dissociation of water into H(dissociation of water into H++
is reduce)is reduce)
► St. Thomas No. 2 pH 7.8 by the addition bicarbonateSt. Thomas No. 2 pH 7.8 by the addition bicarbonate
► Crystalloid cardioplegic solution have little or only poorCrystalloid cardioplegic solution have little or only poor
buffering capacitybuffering capacity
► Blood CPS have strong buffering capacityBlood CPS have strong buffering capacity
56. Calcium AntagonistsCalcium Antagonists
► Depression of contractile function (reduce Ca influxDepression of contractile function (reduce Ca influx
through the slow L type Ca channel)through the slow L type Ca channel)
► Protective intracellular Ca overload, from injury duringProtective intracellular Ca overload, from injury during
ischemia and reperfusionischemia and reperfusion
► Optimal dose diltiazem, verapamil, nifedipineOptimal dose diltiazem, verapamil, nifedipine
► No protective effect when hypothermia (20No protective effect when hypothermia (20 oo
C)C)
► Buckberg blood CPS (CPD)Buckberg blood CPS (CPD)
57. Antioxidants and inhibitors of free oxygenAntioxidants and inhibitors of free oxygen
radical productionradical 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 tissue)Superoxide dismutase and catalase (reduce when ischemic tissue)
► Allopurinol, Metal ion (copper and iron release whenAllopurinol, Metal ion (copper and iron release when
hemolysis)hemolysis)
► deferoxamine (inhibit neutrophil activate)deferoxamine (inhibit neutrophil activate)
58. Manipulation of metabolism and substrateManipulation of metabolism and substrate
utilizationutilization
► Exogenous high-energy phosphatesExogenous 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 acidsAmino acids
Glutamate aspartate (ATP storage)Glutamate aspartate (ATP storage)
Warm induction (37Warm induction (37 oo
C) 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
59.
60. Optimizing reperfusion to maximize postOptimizing 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
61.
62. Control ionic disturbancesControl ionic disturbances
during reperfusionduring reperfusion
► Hyperkalemia, myocardial metabolic recoveryHyperkalemia, myocardial metabolic recovery
► Hypocalcemia (avoid Ca overload, myocardium stunning)Hypocalcemia (avoid Ca overload, myocardium stunning)
Calcium antagonist, diltiazem 300 microgram/KgCalcium antagonist, diltiazem 300 microgram/Kg
► Reduction of reperfusion-induced sodium overloadReduction 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 increased)to reduce cell acidosis (intracellular Na increased)
Promote Na/Ca exchange (calcium overload)Promote Na/Ca exchange (calcium overload)
63. Combat free radical production andCombat free radical production and
oxidative stressoxidative stress
► Supplementation of antioxidant enzymeSupplementation of antioxidant enzyme
Superoxide dismutase, catalase, coenzyme Q10(ubiquinone) andSuperoxide dismutase, catalase, coenzyme Q10(ubiquinone) and
glutathione peroxidase with blood CPS (cocktail)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 neutrophil andMustine, monoclonal antibodies (prevent interaction neutrophil and
endothelium)endothelium)
Neutrophil filters,Neutrophil filters, free radicals are generated within 10free radicals are generated within 10
seconds of reperfusion after ischemiaseconds of reperfusion after ischemia
64.
65.
66. Optimize the recovery of energy metabolismOptimize the recovery of energy metabolism
► Amino acid glutamate and aspartateAmino acid glutamate and aspartate
(Krebs-cycle intermediates)(Krebs-cycle intermediates)
► Pyruvate (2 mmol/L) with glucose, prevent free radicalPyruvate (2 mmol/L) with glucose, prevent free radical
generationgeneration
67. Effective cardioprotection should not ignoreEffective cardioprotection should not ignore
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 ischemia (butBlood based CPS protect endothelium during ischemia (but
injury during reperfusion)injury during reperfusion)
► Reperfusion, arise oxygen free radical resulting inactivationReperfusion, arise oxygen free radical resulting inactivation
of nitric oxide path wayof nitric oxide path way
(used super oxide dismutase)(used super oxide dismutase)
► Neutrophil-endothelium interaction, prevention by variousNeutrophil-endothelium interaction, prevention by various
inhibitory mediatorsinhibitory mediators
68. Effective cardioprotection should not ignoreEffective cardioprotection should not ignore
Effects of Hyperkalemia on conduction tissue of heartEffects of Hyperkalemia on conduction tissue of heart
► More tolerant to ischemia than the myocyteMore tolerant to ischemia than the myocyte
► Reperfusion increase such prolonged heart block andReperfusion increase such prolonged heart block and
supraventricular tachyarrhythmiassupraventricular tachyarrhythmias
► Low amplitude electrical activity, lower atrial septum, AVLow amplitude electrical activity, lower atrial septum, AV
node-His bundle complex, and ventricular (add Ca channelnode-His bundle complex, and ventricular (add Ca channel
blockers)blockers)
► Blood CPS avoided with preexistings conduction problems;Blood CPS avoided with preexistings conduction problems;
but these are relatively short-livedbut these are relatively short-lived
69. Ischemic PreconditioningIschemic Preconditioning
““adaptive mechanism induced by a brief period of reversibleadaptive mechanism induced by a brief period of reversible
ischemia increasing heart’s resistance to a subsequentischemia increasing heart’s resistance to a subsequent
longer period of ischemia”longer period of ischemia”
► most powerful endogenously mediated form of myocardialmost powerful endogenously mediated form of myocardial
protectionprotection
► ? slowing ATP depletion, limitation of acidosis? slowing ATP depletion, limitation of acidosis
► ? mediator- adenosine? mediator- adenosine