cardioplegiaandsurgicalischemia-140514185549-phpapp02.ppt

Cardioplegia and Surgical Ischemia

1. Cardioplegia and Surgical
Ischemia
D.J.CHANBER* and D.J. HEARSE
*Cardiac surgical research/cardiothoracic surgery
Guy’s and St. Thomas’ NHS Trust and Cardiovascular
Research
King’s Centre for Cardiovascular Biology and Medicine
The Rayne institute. King’s college
St. Thomas’ Hospital. London SEI 7EH. England

2. I. Introduction

3. Ischemia
imbalance between energy
supply and demand
Buckberg GD
J Thorac Cardiovasc Surg
1991;102:895-903

4. Hypoxia
reduction in oxygen supply
and accumulation of the waste
products of metabolism
Pepper J.Myocardial protection (57-79)
Edited by pillaj R. wright J. surgery for
ischemic heart disease
1999, oxford university press

5. Introduction
►Ischemia of human heart
Only a few seconds or minutes (angioplasty or angina)
For hours (cardiac surgery or infarction)
For years (Chronic ischemic heart disease)
►This chapter focuses on the global ischemia
Protect against ischemic injury
Provide a motionless, bloodless field
Allow effective post-ischemic myocardial resuscitation

6. II. Ischemic Injury
►Acute ischemic disfunction
►Preconditioning
►Stunning
►Hibernation
►Necrosis vs. Apoptosis

7. Acute ischemic disfunction
►Reversible contractile failure
►Perfusionpressure
►O2 supply
►Inmediaterecovery

8. Preconditioning
►Reversible
►Slowed energy utilization
►Reduction in myocardial necrosis
►Increase protective abilities of myocardium
►Presented as a normal proper protective reaction of the
ischemic myocardium
►Recovery Hs,Ds

9. Stunning
►Partially Reversible
►May be accompanied by endothelial dysfunction (NO)
causing reduced coronary blood flow
►Result of ischemia-reperfusion insult
►Mediated by increased intracellular Ca accumulation
►Recovery in Hs,Wks

10. Hibernation
►Partially Reversible
►Related to poor myocardial blood flow
►Chronic
►Recovery Wks,Mo

11. Necrosis
►Irreversible
►Hypercontracture-“contractureband necrosis”, “stone
heart”
►Osmotic/ionicdysregulation, membraneinjury
►Cellswelling&disruption
►Lysis

12. Apoptosis
►Irreversible
►Deathsignal
►Cellshrinkage
►Cytoplasmicand nuclear condensation
►Phagocytosis

13. 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 Patrol 1978;92:187-214

14. Any strategy aimed at protection the ischemic
heart
►Reperfusion is an absolute requirement for the survival of
the ischemic tissue, reflow should be initiate at the earliest
possible opportunity.
►If early reperfusion cannot be achieved, should be made to
slow the rate of development of ischemic injury to delay
the onset of irreversible injury (necrosis).

15. Many factors that influence the rate at
ischemic injury evolves
►Collateral or noncoronary collateral flow delivered to the
ischemic tissue.
►Effects of diseases such as hypertrophy, DM, HT
►Heart rate, metabolic rate, and tissue temperature
►Metabolic responses to ischemia (substrate utilization).
►Nutritional and hormonal status.
►Age, sex.

16. noncoronarycollateral flow
►can deliver blood to the heart via bronchial, mediastinal,
tracheal, esophageal, and diaphragmatic arteries .
►Flow may vary from 3 –10 % of normal coronary flow
(normal 250 ml/Min).
►Advantage providing oxygen and substrates to the
ischemic tissue.
►Negative effect by washing out cold cardioprotective
solutions .
►Intro the heart at the onset of ischemia.

17. Brief history of the development of surgical
cardioprotection
►Since the introduction and acceptance in the early 1970’s
of modern surgical protection by Cardioplegia.
►A. Early Developments.
►B. The Reemergence of potassium Cardioplegia.

18. A. Early Developments
►Cool the whole patient to slow the rate of metabolism.
The chest was opened, operation, and closed rapidly before
rewarming.
►1953, Lewis and Tauficthe first open-heart (without the
CPB), ASD closure with circulatory arrest.
►1554, Gibbon development the heart lung machine
allowed brain ischemia but the heart become ischemic and
some operations, mortality rate 65%.
►Continue to beat intermittently.

19. John H. Gibbon

20. A. Early Developments
►1955, Melrose and colleagues introduced the concept of
“elective reversible cardiac arrest”.
Potassium citrate (77-309 mmlo/L) added to blood at 37
o
C.
In animals, potassium citrate 2.5%(77mmlo/L)in blood with good
results (1950-1960).
►Potassium citrate was associated with myocardial injury,
heart necrosis. As the use of potassium based Cardioplegia
was abandoned for about 15 years.
O

21. A. Early Developments
►1960s, continuous coronary perfusion, with electrically
induced ventricular fibrillation.
►1970s, Buckbergand colleagues demonstrated that
fibrillation caused sub endocardialnecrosis , LV fibrillation
out of favor
(avoid fibrillation > 32
o
C).
►Intermittent coronary perfusion.
►Ischemic preconditioning.

22. A. Early Developments
►In the late 1960s and early 1970s,
Shumway was protecting the heart with “profound” topical
hypothermia.
Cooley, normothermicischemia and first to describe the “stone
heart”.
►1960s, in Germany. Holscher, suggested magnesium
chloride plus procaine amide of cardioprotection.
►1960s, “bretschneidersolution” in Gottingen, German.
►1960s, Kirsch, in hamburg.

23. B. The Reemergence of potassium
Cardioplegia
►In the mid 1970s. In the United states.
►Gay and Ebert, 25 mmol/L potassium chloride in dog, good
protection.
►Roe and colleagues reported in 204 patients using
potassium Cardioplegiawith a mortality of 5.4 %.
►Tyersand co workers, over 100 patients using 25 mmol/L
potassium with good myocardial protection.

24. B. The Reemergence of potassium
Cardioplegia
►St. Thomas’ group rationalized the three main components
Rapid chemical arrest
Use of hypothermia
Addition of anti ischemic agents
►1975, Braimbridegwas first introduced St. Thomas’
Hospital Cardioplegia.
►This solution was modified to St. Thomas’ No.2

25. IV. Characteristics of cardioplegicprotection
►There are really only two types of cardioplegicsolution
Intracellular type (Bretschneidrsolution)
Extracellular type (St. Thomas’ , Buckbergsolution)
►Intracellular type used predominantly for preservation of
the heart and abdominal organs
►Extracellular type used predominantly for cardiac surgery

26. V. principles underlying the protection of the
heart
►Inducing rapid and complete Cardiac Arrest
►Slowing the onset of irreversible injury by Hypothermia
►Minimizing Damaging ischemic changes with Anti-ischemic
Agents
►Optimizing reperfusion to maximize Post ischemic Recovery
►Effective Cardioprotectionshould not ignore vascular and
conduction tissue
►Alternative approaches to limiting tissue injury during
cardiac surgery

27. A. Inducing rapid and complete Cardiac Arrest
►Myocardial O
2consumptions at 37
o
C
Beating (full,perfused) 10 ml/100gr/min
Beating (empty,perfused) 5.5 ml/100gr/min
Fibrilating(empty,perfused) 6.5 ml/100gr/min
Cardioplegia(empty,crossclamp) 1.0 ml/100gr/min

28. A. Inducing rapid and complete Cardiac Arrest
►Depolarized Arrest
►Polarized Arrest
►Inhibition of Ca influx

30. Depolarized Arrest
►Hyperkalemia
►Potassium concentration
between 15-20 mmol/L
(Membrane potential -50 -60 mV)

31. Polarized Arrest
Reduce Ionic movement
Threshold potential not be reached and window will not be
activated
Reduce myocardium energy
►Sodium Channel Blockade
►ATP sensitivity potassium Channel activation
►Adenosine
►Acetylcholine

32. Polarized Arrest
Sodium Channel Blockade
►Prevent sodium induced depolarization of the action
potential
►Local anesthetics -procaine 1 mmol/L+ CPS
-Lidocain+ CPS (-70 mV)
►Tetrodotoxin(a highly toxic but potent and rapidly
reversible sodium channel blocker)

33. Na channel activated and inactivated

34. Polarized Arrest
ATP sensitivity potassium Channel activation
►1983, Noma was described the cardiac ATP-s
►Potassium Channel openers (membrane potential < -70 mV)
►Enchant post ischemic recovery of function
►This protection effect was lost when add to St. Thomas CPS

35. Polarized Arrest
Adenosine
►1-10 mmol/L alone or with potassium, rapid arrest and
improve post ischemic compared to hyperkalemia alone
►Action; initial transient hyper polarization before
depolarization was thought to arrest SA node (10 mmol/L)
►Additive to CPS to enhance myocardial protection

36. Polarized Arrest
Acetylcholine
►1955 –1960, was used as a Cardioplegicagent by number
of surgeons
►Action; like adenosine by suppressing sinus nod and
blocking sinoatrialconduction (hyper polarization)
►Short-live during cardiac surgery
►Recovery of function depressed after longer arrest periods

37. Inhibition of calcium influx
►Hypocalcemia
►Calcium antagonists
►hypermagnesemia

39. Inhibition of calcium influx
Hypocalcemia
►Cainduced carelease.
►kirseh(caand Na free)
►Bretxcheidersolution
(low calcium)
►St. Thomas’ hospital solution.

40. Inhibition of calcium influx
Hypocalcemia
►Calcium free solution induce a lethal condition “calcium
paradox”
►Contain calcium, used clod and hypothermia, low sodium
and/or high magnesium.
►St. Thomas, CaClconcentration 1.2 mmol/L
*** Rapid diastolic arrest can be achieved by the depletion of
calcium

41. Inhibition of calcium influx
Calcium antagonists
►Reduce calcium influx through slow calcium channels
►Such as verapamil, nifedipine, and diltiazem
►Recovery function and high energy phosphates when
additive to potassium CPS
►Calcium overload by noncoronarycollateral
►High concentration may be prolong arrest
►No protective under hypothermic

42. Inhibition of calcium influx
hypermagnesemia
►Magnesium can arrest the heart at higher concentration
are needed to induce arrest
►Achieved by the displacement of calcium from the rapidly
exchangeable Sarcolemmal binding sites involved in
excitation contraction coupling
►Optimal protective concentration at 16 mmol/L (irrespective
of whether temperature)

44. B. Slowing the onset of irreversible injury by
hypothermia
►basal metabolism
in the absence of myocardial contraction, the myocytestill
requires oxygen for basic “house keeping” functions
►this basal cost can be further reduced with hypothermia

45. MyocardialO
2consumption
ml/100gr/min
Oxygen Demand reduction
►NormothermicArrest (37
o
C)1.00 mL/100g/min 90%
►Hypothermic Arrest (22
o
C) 0.30 mL/100g/min 97%
►Hypothermic Arrest (10
o
C)0.14 mL/100g/min ~ 97%
BuckbergGD, Brazier JR, Nelson RL, et al;
J ThoracCardiovascSurg1977;73:87-94

47. hypothermia
►lowers metabolic rate
►decrease myocardial energy requirements
►promoting electromechanical quiescence
►every 10
o
Cin temperature, enzyme activity halved
►regional variations !
Bigelow, Lindsay, Greenwood-1950
Shumway and Lower-1959

48. hypothermia
Effects on; Pitfalls
►enzyme function
►membrane stability
►calcium sequestration increase intra cellular Ca
►Sodium pump is inhibited
►glucose utilisation
►ATP generation and utilisation
►leftward shift of oxyhaemoglobincurve (impaired tissue
oxygen uptake) and elevated pH
►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 hypothermic
►Temperature around 10-15
o
C
were optimal.
►Water temperature 4
o
C, cooling
myocardium to 10-15
o
C

50. Minimizing damaging ischemic changes with
anti-ischemic agents
►Blood as a additive or a vehicle for Cardioplegia
►Oxygenation of Cardioplegia
►Agent that influence buffering and PH
►Calcium Antagonists
►Antioxidants and inhibitors of free oxygen radical
production
►Manipulation of metabolism and substrate utilization

51. Blood as a additive or a vehicle for
Cardioplegia
►Melrose and colleagues, The earliest blood CPS
►Late 1970s, Buckberg’s group was the first to study about
blood CPS (in dogs)
Cold blood CPS, recovery 80%after 2 Hr. ischemic arrest
Continuous perfusion, recovery 40%
Intermittent ischemic, recovery 17%
►Blood with crystalloid solution, LV stroke work index
improve after ischemic 2 hr.
►Used crystalloid only, LV stroke work index improve after
ischemic 24 hr.

52. Blood Cardioplegia
advantages
►improved oxygen carrying capacity and delivery until
electromechanical quiescence developed
►enhanced myocardial oxygen consumption
►Substrate preserved high-energy phosphate stores
►buffering changes in pH
►Free radical scavengers
►provide appropriate osmotic environment for myocardial
cells and lessen the myocardial oedema

53. Blood Cardioplegia
pitfalls
►Have added to the cost
►The high hematocrit and low temp, Induce a sludging
effect
►Operating field less clear when give Cardioplegia

54. Oxygenation of Cardioplegia
►Oxygen during cold ischemic arrest (either crystalloid or
blood CPS) sufficient to meet the reduced demands of
myocardial
►Warm induction arrest, preserved high-energy phosphate
stores
►Reperfusion with warm blood CPS (37
o
C), myocardial
metabolic recovery with out the energy consumption of
contraction

55. Agent that influence buffering and PH
►Acidosis the consequences of ischemia
►Buffers, prevent major pH change during ischemia
►Basic concepts of pH and temp. water shifts in alkaline
0.05 when temp decreases 1
o
C
(dissociation of water into H
+
is reduce)
►St. Thomas No. 2 pH 7.8 by the addition bicarbonate
►Crystalloid cardioplegic solution have little or only poor
buffering capacity
►Blood CPS have strong buffering capacity

56. Calcium Antagonists
►Depression of contractile function (reduce Ca influx
through the slow L type Ca channel)
►Protective intracellular Ca overload, from injury during
ischemia and reperfusion
►Optimal dose diltiazem, verapamil, nifedipine
►No protective effect when hypothermia (20
o
C)
►Buckberg blood CPS (CPD)

57. Antioxidants and inhibitors of free oxygen
radical production
►1980s, interest in free oxygen radicals
►Free radicals, Superoxide anion, hydroxyl radical, hydrogen
peroxide (from ischemia and reperfusion)
►Endogenous anti oxidant system
Superoxide dismutase and catalase (reduce when ischemic tissue)
►Allopurinol, Metal ion (copper and iron release when
hemolysis)
►deferoxamine (inhibit neutrophil activate)

58. Manipulation of metabolism and substrate
utilization
►Exogenous high-energy phosphates
Creatinephosphate 10 mmol/L with St. Thomas
►Adenosine and ATP catabolites
Only minimal or no beneficial effects on clinical outcome
►Amino acids
Glutamate aspartate (ATP storage)
Warm induction (37
o
C) of arrest, “active resuscitation”
►Glucose and glycolytic intermediates
Promote glycolytic anaerobic ATP (2 ATP)
Intracellular acidosis and lactate production

60. Optimizing reperfusion to maximize post
ischemic recovery
►Reperfusion phase
►cell damage following ischemia is biphasic;
injury being initiated during ischemia
exacerbated during reperfusion
►The best approach to avoiding reperfusion injury
Control ionic disturbances
Combat free radical production and oxidative stress
Optimize the recovery of energy metabolism

62. Control ionic disturbances
during reperfusion
►Hyperkalemia, myocardial metabolic recovery
►Hypocalcemia(avoid Caoverload, myocardium stunning)
Calcium antagonist, diltiazem300 microgram/Kg
►Reduction of reperfusion-induced sodium overload
Sodium/Proton exchange inhibitors, improve postischemia
During Ischemia, inNa/K pump was inhibit
Activates Na/H
+
to reduce cell acidosis (intracellular Na increased)
Promote Na/Caexchange (calcium overload)

63. Combat free radical production and
oxidative stress
►Supplementation of antioxidant enzyme
Superoxide dismutase, catalase, coenzyme Q10(ubiquinone) and
glutathione peroxidase with blood CPS (cocktail)
►Pharmacological inhibitor of radical production
Allopurinol or oxypurinol, deferoxamine
►Antineutrophil therapy
Mustine, monoclonal antibodies (prevent interaction neutrophil and
endothelium)
Neutrophil filters, free radicals are generated within 10
seconds of reperfusion after ischemia

66. Optimize the recovery of energy metabolism
►Amino acid glutamate and aspartate
(Krebs-cycle intermediates)
►Pyruvate (2 mmol/L) with glucose, prevent free radical
generation

67. Effective cardioprotection should not ignore
Effects of Hyperkalemia on the endothelium
►Global ischemia and reperfusion induce injury
►Potassium were concentration dependent
►Blood based CPS protect endothelium during ischemia (but
injury during reperfusion)
►Reperfusion, arise oxygen free radical resulting inactivation
of nitric oxide path way
(used super oxide dismutase)
►Neutrophil-endothelium interaction, prevention by various
inhibitory mediators

68. Effective cardioprotectionshould not ignore
Effects of Hyperkalemia on conduction tissue of heart
►More tolerant to ischemia than the myocyte
►Reperfusion increase such prolonged heart block and
supraventricular tachyarrhythmias
►Low amplitude electrical activity, lower atrial septum, AV
node-His bundle complex, and ventricular (add Cachannel
blockers)
►Blood CPS avoided with preexistingsconduction problems;
but these are relatively short-lived

69. Ischemic Preconditioning
“adaptive mechanism induced by a brief period of reversible
ischemia increasing heart’s resistance to a subsequent
longer period of ischemia”
►most powerful endogenously mediated form of myocardial
protection
►? slowing ATP depletion, limitation of acidosis
►? mediator-adenosine