2. Surgically induced myocardial ischemia
Secondary to aortic cross-clamping
Cessation of coronary blood flow to the myocardium
Oxygen delivery is insufficient to meet basal myocardial requirements
Preserve cellular membrane stability and viability
3. HISTORICAL DEVELOPMENT
Gibbons’ and open heart surgery, soon became obvious that aortic cross-
clamping was necessary -
To provide a bloodless field so its easy for repair of intracardiac defects
To prevent air embolism when the left side of the heart was opened
To avoid a turgid myocardium resistant to retraction.
4. Melrose and colleagues introduced the concept of “elective cardiac
arrest” by
rapidly injecting of 2.5% potassium citrate solution in warm blood to
arrest the heart into the aortic root
associated with development of severe myocardial necrosis
5. During the 1960s, evolution of two distinct technical pathways for
management of ischemic arrest of heart
The “rapid operators”
short ischemic times with the use of normothermic ischemic arrest,
“stone heart” syndrome related to ischemic contracture of the
myocardium associated with low levels of high-energy phosphate
moieties
6. Intermittent aortic cross-clamping
Involving reperfusion of the coronary circulation for 5 minutes after
15 minutes of ischemic arrest
7. Fibrillatory Arrest
Glenn and Sewell as a means of avoiding air embolism.
Buckberg and Hottenrot and coworkers demonstrated subendocardial
ischemia and necrosis with this technique, particularly in the
hypertrophied ventricle.
8. Continuous Coronary Perfusion
In an attempt to mimic the physiologic state, continuous coronary perfusion with a beating heart at
normothermia or mild hypothermia at 32° C to prevent the onset of ventricular fibrillation became
the preferred technique of myocardial preservation in the late 1960s and early 1970s,particularly after
the report by McGoon and colleagues, 17 of 100 consecutive aortic valve replacements with no
deaths.
9. Hypothermia
The earliest attempts to perform open heart surgery before the advent of the heart-lung machine
used systemic hypothermia produced by surface cooling not only to protect the heart but to protect
the brain and other organs during circulatory arrest.
Hypothermia protects the ischemic myocardium by decreasing heart rate, slows the rate of high-
energy phosphate degradation and decreases myocardial oxygen consumption
systemic hypothermia is necessary, particularly in the presence of coronary obstruction, ventricular
hypertrophy, rewarming of the right ventricle by the liver’s acting as a “heat sink,” and environmental
rewarming.
In an attempt to overcome this problem, Shumway and associates28 introduced th concept of
profound local (topical) hypothermia by filling the pericardial sac with ice-cold saline.29
10. Reintroduction of Cardioplegia
Cardioplegia had been abandoned for alternative techniques in the United States after the adverse
experience with the Melrose potassium solution
in Germany, Bretschneider continued studying induced cardiac arrest with use of a histidine protein
buffer, sodium poor, calcium-free, procaine-containing solution (Bretschneider solution). Clinical
application soon followed,
11. Kirsch and asssociates using a magnesium aspartate– procaine solution.
Hearse and coworkers introduced the concept of using an extracellular rather than an intracellular
solution (St. Thomas’ solution), which was first applied clinically by Braimbridge and coworkers
On the basis of improved clinical outcomes, North American investigators35-38 initiated experimental
studies using potassium cardioplegia followed by clinical reports39,40 demonstrating the efficacy of
cardioplegia.
12. BIOLOGY OF SURGICALLY INDUCED MYOCARDIAL ISCHEMIA
cellular metabolism,
ion transport,
electrical activity,
contractile function,
vascular responsiveness,
tissue ultrastructure, changes in nuclear and mitochondrial DNA,
release of free radical oxygen species, and
activation of inflammatory components
13. Myocardial Oxygen Consumption
Because the heart is an obligate aerobic organ, it depends on a continuous supply of oxygen to
maintain normal function. Myocardial oxygen reserve is exhausted within 8 seconds after the onset of
normothermic global ischemia.
Myocardial oxygen consumption (MV O2) is compartmentalized into the oxygen needed for external
work of contraction and the unloaded contraction, such as basal metabolism, excitation-contraction
coupling, and heat production.
A unique aspect of myocardial energetics is that 75% of the coronary arterial oxygen presented to the
myocardium is extracted during a single passage through the heart; thus, depressed coronary venous
oxygen content persists despite a wide range of cardiac workloads.
Therefore, the heart is susceptible to the limitations of oxygen delivery, whereby an increase in MV O2
can be met only by augmentation of coronary blood flow. This is diametrically opposite to skeletal
muscle, in which increase oxygen demand can initially be met by an increase in oxygen extraction.
Clinically, a marked increase in coronary blood flow is observed at the beginning of the reperfusion
period, after the aortic clamp is removed
14. Biochemical Alterations
Under aerobic conditions, the heart derives its energy primarily from mitochondrial oxidative
processes, using substrates such as glucose, free fatty acids, lactate, pyruvate, acetate, ketone
and amino acids.51,52 However, oxidation of fatty acids provides the major source of energy
production and is used in preference to carbohydrates.53
As tissue PO2 falls, oxidative phosphorylation, electron transport, and mitochondrial adenosine
triphosphate(ATP) production cease. Early in ischemia, the heart depends on the energy production
glycogenolysis and aerobic glycolysis (Pasteur effect). However, unlike other organs, the heart
requires a minimum threshold of ATP to prevent irreversible ischemic contracture
Reduced mitochondrial activity leads to the accumulation of glycolytic intermediaries, reduced
and the reduction of pyruvate to lactate. The resultant severe intracellular acidosis impairs
function, enzyme transport, and cell membrane integrity. This results in a cellular loss of potassium
and pathologic accumulation of sodium, calcium, and water
15. Ischemia-Reperfusion Injury
Ischemia-reperfusion injury occurs as the result of cessation of coronary blood flow such that oxygen
delivery to the myocardium is insufficient to meet basal myocardial oxygen requirements to preserve
cellular membrane stability and viability.
Reversible ischemia-reperfusion injury may be manifested as either stunning or hibernation.
Stunning “describes the mechanical dysfunction that persists after reperfusion despite the absence of
myocellular damage and despite the return of normal or near-normal perfusion.
A second form of reversible ischemia-reperfusion injury is hibernation, which is a syndrome of
reversible, chronically reduced contractile function as a result of one or more recurrent episodes of
acute or persistent ischemia, referred to as chronic stunning.
16. As in stunning, hibernating myocardium is viable but not functional and is reversible with coronary revascularization
There is good clinical evidence that despite seemingly adequate application of modern methods o myocardial
protection, all patients undergoing cardiac surgery have varying degrees of myocardial stunning
Evidence to support this concept is based on the requirement of inotropic support for separation from bypass for hours
or days after surgery in some patients who are eventually weaned from these drugs as the stunning bates, without
objective evidence of a myocardial infarction
Two major theories have been proposed as possible mechanisms leading to ischemia-reperfusion injury
The calcium hypothesis suggests that the inability of the myocyte to modulate intracellular and intraorganellar calcium
homeostasis induces a cascade of events culminating in cell injury and death
Ischemia leads to the induction of metabolic acidosis and the activation of the sodium-proton exchanger, resulting in the
transport of hydrogen ions to the extracellular space and the movement of sodium into the cytosol. As the sodium
calcium exchanger is activated, sodium is transported to the extracellular space and calcium is taken up into the cytosol,
increasing cytosolic calcium concentration ([Ca2+ ]i ).
Increased [Ca2+ ]i accumulation is also augmented by ischemia-induced depolarization of the membrane potential,
which allows the opening of the L -type calcium channels and further calcium entry into the myocyte.
17. Cellular and cytosolic calcium-dependent phospholipases and proteases are activated, inducing
membrane injury and the further entry of calcium into the cell.
These processes alter myocardial cellular homeostasis, leading to cellular dysfunction or, if they are
of sufficient duration or intensity, cell injury or death.
Alternative explanations include the concept of reperfusion induced myocardial contracture
resulting from rapid re-energization of contractile cells with persistent calcium overload affecting
myofibrillar calcium sensitivity
The free radical hypothesis suggests that the accumulation of partially reduced molecular oxygen,
collectively known as reactive oxygen species, during the early stages of reperfusion causes
myocardial cellular damage and cell death through microsomal peroxidation of the cellular
phospholipid layer, leading to loss of cellular integrity and function
The generation of reactive oxygen species is believed to be mediated by xanthine oxidase, activation
of neutrophils, or dysfunction of the mitochondrial electron transport chain.
18. Alternative explanations include the concept of lethal reperfusion injury, defined as death of
myocardial cells that were viable immediately before reperfusion.
Yellon and Hausenloy, described alternative cardioprotective strategies to manage this injury by
reperfusion injury salvage kinase pathways and targeting mitochondrial permeability transition pores
to avoid mitochondrial calcium overload.
Cyclosporine, a potent inhibitor of mitochondrial permeability transition pores, has recently been
shown to limit infarct size after percutaneous coronary intervention during acute myocardial
infarction.
19. Irreversible Cell Injury
Irreversible cell injury, described ultrastructurally by Schaper and coworkers,
Necrosis is initiated by noncellular mechanisms with cell swelling, depletion of ATP stores, and
disruption of the cellular membrane involving fluid and electrolyte alterations.
In contrast, apoptosis (programmed cell death) characterized by a discrete set of biochemical and
morphologic events involving the regulated action of catabolic enzymes (proteases and nucleases) that
results in the ordered disassembly of the cell, distinct from cell death provoked by external injury
20. Inflammation
Inflammation - secondary mechanism contributing to injury after reperfusion.
Initiated through complement activation leading to the sequential formation of a membrane attack
complex, which creates a cellular lesion and eventual cell lysis
Cytokines, vasoactive and chemotactic agents, adhesive molecule expression, and leukocyte and
platelet activation participate in the inflammatory process, producing cytotoxic molecules that
facilitate cell death
Oxygen-derived free radical scavengers have also been used to limit reperfusion injury
Tissue factor, an inflammatory and procoagulant mediator, initiates the extrinsic coagulation cascade,
resulting in thrombin generation and fibrin deposition, and may be related to the no-reflow
phenomenon.
Clinical use of anti-inflammatory awaiting clinical trials because studies up until now have not shown
any “meaningful cardioprotective effect.
In addition, endothelium-dependent microvascular responses and coronary artery spasm may be
related to reduced myocardial perfusion after reperfusion
21. Effects of Age
The vulnerability of the heart to ischemia-reperfusion injury is altered with temporal development.
The newborn heart is more resistant to the effects of ischemia reperfusion
Developmental differences in calcium transport and sequestration, and it is better able to restore
myocardial function and myocardial high-energy phosphate stores after an ischemic event
in the neonate, during ischemia, anaerobic glycolysis is the only metabolic pathway that can produce
high-energy phosphates
In the adult heart, functional recovery is significantly delayed, and the recovery of high-energy
phosphate stores is slower in returning to preischemic levels. As the heart ages, there are anatomic,
mechanical, ultrastructural, and biochemical alterations that compromise the adaptive response of
heart
22. As a result, the senescent myocardium is less tolerant than the mature myocardium to surgically
induced ischemia.
Morphologically, with age, left ventricular mass is increased and the size of the left ventricular cavity is
reduced, accompanied by increased calcification of the valve annulus and coronary arteries.
Ultrastructurally, there is decreased mitochondria-to-myofibril ratio, cardiac myocyte enlargement, and
loss of mitochondrial organization as well as alteration in myocardial contractile properties
As a consequence of these changes, cardiac surgical operative mortality increases with age
23. Ventricular Hypertrophy
Increased myocardial mass is an adaptive response to prolonged increases in myocardial workload as a
result pressure or volume overload. If it is untreated, progressive ventricular hypertrophy results in
ventricular dilation and contractile dysfunction.
Hypertrophied hearts have an increased vulnerability to ischemic injury, which has been attributed to
accelerated loss of high-energy phosphate moieties,98 increased accumulation of lactate and hydrogen
earlier onset of ischemic contracture and accelerated calcium overload after reperfusion.
With ventricular hypertrophy, epicardial coronary arterie dilate in response to increased oxygen demands,
and decreased capillary density and vascular dilation reserve in the subendocardial regions result in
increased ischemi vulnerability.
Subendocardial ischemia leading to necrosis can occur during periods of hypotension, inadequate
cardiopulmonary bypass, and ventricular fibrillation.
The hypertrophied heart is particularly susceptibl to ischemic injury in the early postoperative period, whe
hypotension associated with surgically induced myocardia stunning, hypothermia, and vasoconstrictor
are present.
24. Basic principles for adequate myocardial protection include
(1) Rapid induction of arrest
(2) Mild or moderate hypothermia
(3) Appropriate buffering of the cardioplegic solution
(4) Avoidance of myocardial edema, and
(5) Avoidance of substrate depletion
25. Rapid Cardiac Arrest
excitation-contraction coupling pathway”
Minimizes the depletion of high-energy phosphate moieties
Potassium is the most common agent used for chemical
cardioplegia
Rapid diastolic arrest
26.
27. Adenosine cardioplegia benefits
Rapid induction
Ca blockdge
Prevent K+ related calcium overload
Disadvantage
Rapidly clear from the system .i.e within 10sec
28. Hypothermia
Cornerstone for myocardial protection
10 celcius dropped in temperature associated by 50% reduction in
during surgically induced ischemia
Warm (34-37)0 c, Tepid(28-32)0 c, moderate(22-25)0 c
29.
30. Limitation of hypothermia
Coronary artery obstruction
Ventricular hypertropy
Noncoronary collateral blood flow
Heat sink from liver
Anterior heart by environment
31. Buffering of the Cardioplegic Solution
To combat the intracellular acidosis associated with surgically induced myocardial ischemia.
Myocardium has the highest oxygen use of any organ
Reinfusion of cardioplegia every 20-30mins
Hypothermia pH rises 0.0134 units for each decrease in degree centigrade
Bicarbonate, phosphate, aminosulfonic acid, tris(hydroxymethyl)aminomethane (THAM), and histidine
buffer
32. Avoidance of Myocardial Edema
Directly modulated by osmolarity and onconicity of cardioplegia
Isotonic solutions in the range of 290 to 330 mOsm/liter or slightly hyperosmolar solutions
Inert sugars including mannitol and sorbitol
Oncotic solution albumin and macromolecules
33. Crystalloid Cardioplegia
Hyperkalemic diastolic arrest, were clinically used in Europe in the early 1970s and in the United States
in the late 1970s
Minimal amounts (0.6 mL/100 mL of a PO2 at 100 mm Hg at 150 C) of dissolved oxygen, whereas the
myocardium consumes 0.7-0.9 mL of oxygen per 100 g at 15° C
To overcome the oxygen deficit issue, oxygenation of crystalloid cardioplegia has been clinically used
as well hypothermia
Demonstrated a decrease in creatine kinase MB levels in patients when the cross-clamping time
exceeded 29 minutes
34. Ringer solution (NaCl 147.3 mmol/ liter; K+ 4.02 mmol/liter; and CaCl2, 2.25 mmol/liter) to which was
added 24 mmol/liter of potassium chloride to effect a total dose of 28 mmol/liter, 7 g/liter of glucose,
and 0.8 mL of THAM
35. the operating room temperature is cooled to(17° C to 19° C) to avoid warming of the anterior surface
of the heart by convection and radiation from high intensity lighting.
Cardiopulmonary bypass is initiated at a temperature of 28° C
Systemic perfusate temperature is temporarily decreased to 10° C to 15° C to “precool” the heart
(infusion hypothermia), and iced saline slush is placed into the pericardial sac to achieve rapid
myocardial cooling
When a myocardial temperature of 28° C is reached, the ascending aorta is cross-clamped and cold
crystalloid cardioplegia solution at a temperature of 5° C is infuse
The myocardial temperature rapidly decreases to 10° C to 15° C, and asystole usually occurs within 10
to 15 seconds.
36. If there is any electrocardiographic activity or observed ventricular motion, the solution is reinfused at
a volume of 5 mL/kg
Five minutes before removal of the aortic clamp, the systemic perfusate temperature is raised to 30° C,
and flow is increased to 2.2 liter/min/m2 .
After the aortic cross-clamp is removed, the perfusate temperature is raised to 38° C and the room
temperature is raised to 25° C to 30° C.
Cardiopulmonary bypass is continued until the esophageal temperature is 37° C and the rectal
temperature is in the range of 35° C to 37° C.
Rewarming is usually necessary in the early postoperative period.
37. Blood Cardioplegia
In an attempt to avoid the oxygen deficits associated with crystalloid cardioplegia, blood was
introduced as a suitable vehicle to obtain optimum oxygenation
superior to oxygenated crystalloid cardioplegia
In addition to the enhanced ability to exchange oxygen and carbon dioxide, the physiologic
advantages of blood include the buffering and reducing capacity, the presence of colloid to avoid
adverse oncotic pressure gradients, and the presence of oxygen free radical scavengers
Certain limitation
4:1 blood to crystalloid solution
38.
39. Miniplegia, or whole blood cardioplegia using minimal amounts of
potassium and magnesium to achieve arrest, avoids the problem of
hemodilution, eliminates concerns about buffering, and avoids
pharmaceutical costs
