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