Post on 05-Jan-2016
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CPB & Myocardial Protection
Seoul National University HospitalDepartment of Thoracic & Cardiovascular Surgery
Reperfusion-induced Injury
1. Definition
A paradox extension of ischemic damage, which
occurs during reperfusion after myocardial ischemia
1) Reperfusion arrhythmia
2) Myocardial stunning
2. Mechanisms
1) Impaired calcium homeostasis
2) Oxygen free radical during early reperfusion
Optimal Organ Preservation
1. Prevention of ischemia-reperfusion injury
2. Minimization of cell swelling and edema
3. Prevention of intracellular acidosis
4. Provision of substrate for regeneration of high-energy phosphate on reperfusion
Adverse Effects of Cooling in Myocardial Protection
1. Impairs the Na-K adenosine triphosphate (ATPase)
2. Impairs the mitochondrial adenosine triphosphate
(ATP) translocase
3. Impairs sarcoplasmic reticular Ca ATPase
4. Impairs oxygen–hemoglobin dissociation
Thus hindering cell volume control, energy metabolism,
Ca sequestration, and oxygen delivery
Disadvantages of Hypothermia on Myocardial Protection
1. Effects on membrane stability
2. Effects on enzyme function
3. Effects on tissue calcium accumulation
4. Effects on cellular volume regulation
Edema after CBP in Neonate
1. Capillary permeability is naturally higher in younger
people
2. Greater exposure to bypass prosthetic surface area
relative to neonate’s endothelial surface area
3. Larger ratio of prime volume to blood volume than in
older
4. Exposure to greater extremes of temperature as well as
low-flow or circulatory arrest, thereby increasing the
risk of ischemia-reperfusion injury
Coronary Vasomotor Dysfunction
• Endothelial dependant cyclic guanosine monophosphate – mediated vasorelaxation (response to acetylcholine)
• Endothelial independant cyclic GMP-mediated vasorelaxation
(response to Na-nitroprusside, nitroglycerin)• Beta-adrenergic cyclic adenosine
monophosphate – mediated vasorelaxation (response to isuprel)
Myocardium before Reperfusion
• Energy depletion state
• High energy phosphate to cellular repair
• Washout adenosine, inosine, hypoxanthine & xanthine
• Breakdown of purine base derived from AMP
~~ Reperfusion (O2 supply) produce superoxide, hydrogen peroxide ion O2 radical combine to
Fe production of hydroxyl ion myocardial damage
Re-oxygenation Injury in Pediatric CPB
• Re-oxygenation injury is a real source of postoperative cardiac and pulmonary dysfunction
• White blood cells play an integral role in the production of oxygen-free radicals that are responsible for the damage
• This injury can be modified and possibly ameliorated by changes in the intra-operative management of cardiopulmonary bypass
Limiting Re-oxygenation Injury in Pediatric CPB
Bypass Protocol 1. Wash & leucodepleted blood prime 2. In-line arterial filter 3. Initiate bypass using normoxic management(PaO2 80-100nnHg) & FiO2 is increased slowly over 20 minutes to maintain a PaO2 of 100-150mmHg
Pathogenesis of Reperfusion Injury
1. Activated neutrophils
Oxygen free radicals, namely, superoxide
anions, hydroxyl radicals, hypochlorous acid
2. Platelet-activating factor is also involved
in the activation of platelets and neutrophils
in the inflammatory process & is synthesized
during tissue reperfusion.
Injury after Ischemia & Reperfusion
• 1st component of myocardial injury induced by biochemical changes mediated by ischemia.
ATP depletion, ATP catabolite, acidosis, influx of Na, Ca, activation of phospholipase, proteolytic enzyme & complements
• 2nd component of myocardial injury is reperfusion phenomena by production of oxygen free radicals.
1. ATP catabolism providing xanthine oxidase substrates 2. Neutrophil-complement activation 3. Phospholipase-arachidonic acid pathway intermediates 4. Electron transport in mitochondria 5. Autooxidation of catecholamine 6. Others not yet identified
Characteristics of Reperfusion Injury
• Extracellular calcium movement to the
intracellular, especially in the mitochondria
• Explosive cell swelling with reduction of
postischemic blood flow & reduced ventricular
compliance
• Inability to use delivered oxygen
Role of Neutrophils after IschemicReperfusion
Under condition of hypoxemia or ischemia, coronary vascular endothelium expresses sites that bind neutrophils on reperfusion. Once bound, the neutrophil may be activated by several pathways.
1) Superoxide production by xanthine oxidase 2) Complement activation 3) Leukotriene production
Deleterious Effects of Activated Neutrophil
1. Direct myocardial injury
NADPH oxidase on the surface of neutrophil produces superoxide
anions, hydroxyl radicals, and hypochlorous acid.
2. Mechanical obstruction of capillaries
It prevents reperfusion to the distal area of myocardium.
3. Depress calcium transport and calcium stimulated magnesium
dependent ATP activity.
4. Lipid peroxidation of cellular membrane
It disrupts cellular homeostasis, resulting edema.
5. Oxidation of arachidonic acid
Liberation of leucotrienes, prostaglandins, and thromboxanes
Endothelial Damage Process
• Oxygen free radicals through formation of xanthine oxidase in the endothelium
• Complement activation -- PMNL -- O2
free radical
• Release of adenosine diphosphate or formation of thromboxanthine
• Platelet induced endothelial injury
Roles of NO in Myocardial Ischemia-Reperfusion Injury
1. Beneficial effects
1) Decreased leukocyte accumulation
2) Inhibition of platelet aggregation
3) Neutralization of superoxide radicals
2. Deleterious effects
: Production of peroxynitrite, free radicals
both direct & indirect cytotoxic properties
Oxygen Derived Free Radicals
• Inhibitor of free radical generation
Allopurinol• Free radical scavenging enzymes
Reduce the release of lipid peroxidation
Superoxide dismutase & catalase• Iron chelating agent
Slowing the rate of reaction by decreasing the
availability of metacatalyst
Deferoxamine
Oxygen Free Radical Production
• Oxygen free radicals directly alter tissue structure and cell membrane through lipid peroxidation & inactivation of membrane band enzyme.
1. Sources of oxygen free radicals Xanthine metabolism, arachidonic acid metabolism,
catecholamine oxidation, & electron transport in mitochodria,
neutrophil activation in ECF
2. Cell types Myocytes, endothelial cell, monocyte, polymorphonuclear
leucocyte are responsible for O2 free radical production
during reperfusion.
Mechanisms of Preconditioning - induced Protection
1. Reduced glycogen content prior to sustained
ischemic period
2. Adenosine receptor stimulation
3. Slower metabolism because of ischemia
4. Protein kinase C stimulation
5. Calcitonin gene-related peptide from cardiac
sensory nerves
Potential Mechanisms of Ischemic Preconditioning
1. Activation of A1 adenosine receptors
2. Activation or opening of ATP-sensitive
K- channels & subsequent cardioplegic effect
3. Induction of heat-shock proteins
4. Preservation of cellular ATP levels by
slowing the rate of ATP depletion
Chemical Principles Inducing Cardiac Arrest
• Myocardial depletion of calcium
• Myocardial depletion of sodium
• Elevation of extracellular sodium
• Elevation of extracellular magnesium
• Infusion of local anesthetic agents
• Infusion of calcium & antagonistics
Function of Cardioplegic Protection
1. Electromechanical arrest
2. Function of temperature effect
3. Function of oxygen content
4. Substrate enhancement
5. Buffering capacity
Cardioplegic Solution ; Additives (I)
• Potassium Depolarize the myocardial cell, producing sustained diastole
• Magnesium Depress the inherent rhythmicity of pacemaker cell and myocardial contractility (magnesium block the inward flow of sodium into the cells
and compete with calcium at activation site of ATP)
• Calcium
Actively associated with excitation contraction (uptake of calcium is ATP dependant) Following excitataion, calcium in ECF with sodium moved into the cell and released calcium in the sarcoplasmic reticulum cause sarcomere shorting by complex of calcium and tropin-tropomyosin - after then decrease of
cytosolic calcium level, begin to diastole - active calcium pumping to ECF
Cardioplegic Solution ; Additives (II)
• Local anesthetic agents Act upon cell membrane by blocking sodium, slow calcium channel, and calcium channels of sarcoplasmic reticulum
• Hypothermia• Substrate enhancement• Membrane stabilizer - controversial• Calcium channel blockers• Beta-blockers• Secondary additives Glucose, pH, osmolarity
• Cardioplegic distribution• Asanguineous versus sanguineous
Advantages of Blood in Cardioplegia
• Particulate rheologic action which promote perfusion of coronary artery and distribution
• Buffering capacity of Hb
• Increased onconicity prevent edema
• Ability of blood to provide a physiologic calcium concentration
• Ability of RBC to provide enzyme active in the removal of O2 – free radical
Advantages of Blood Cardioplegia
• Excellent buffering capacity
• Increase tissue perfusion
• Lower coronary perfusion pressure & less edema
• Oxygen carrying capacity
• Less leftward shift of oxyhemoglobin dissociation
with decreasing tempertature
Terminal Warm Blood Cardioplegia
1. Lower the oxygen demands by keeping the heart in an arrested state, when utilization capacity is impaired.
2. Allow the heart to channel energy resources toward the ionic & cellular homeostasis, while optimizing the metabolic rate.
Adverse Effects of Cold Blood Cardioplegia
1. Elevated levels of ADP & impairment of mitrochondrial
respiration & oxidative phosphorylation
2. Inhibits citrate synthetase, a key rate-limiting enzyme in
Krebs cycle vital to maintenance of aerobic metabolism
3. Myocardial depression of glucose, lactate, and fatty acid
oxidation
4. Increased coronary vascular resistance, which could
negatively influence myocyte perfusion
5. Potentiate ventricular fibrillation after removal of x-clamp