Ischemia and Reperfusion

Question 1

oxygen paradox

Answer 1

too much of a good thing: oxygen-derived free
radical formation (reactive oxygen species (ROS))

Question 2

Calcium paradox

Answer 2

Large influx of calcium into the cell

Question 3

pH paradox

Answer 3

pH moves from acidic to normal – potentiates many of the changes

Question 4

Inflammation causes

Answer 4

neutrophil activation

Question 5

When Are Oxygen Free Radicals Generated?

Answer 5

Myocardial ischemia favors oxygen free radical generation
 Tissue stores of endogenous antioxidants
depleted during ischemia  superoxide dismutase
 catalase  glutathione  glutathione peroxidase
 Oxygen not available until reperfusion after clamp off
Greatest risk (i.e. greatest production) occurs when oxygen returned to myocardium

Question 6

What Factors Determine The Amount of Oxygen Free Radicals Produced?

Answer 6

Severity of ischemic injury  Activation and recruitment of neutrophils
to myocardium
 Level of O2 in the cardioplegic solution
 Presence of endogenous scavengers and inhibitors

Question 7

what Changes Are Caused By Oxygen Free Radicals?

Answer 7

Peroxidation of lipid components of myocellular membranes
 steal electrons from lipid membranes  Impairment of vascular endothelial function
 produces vasoactive & antiinflammatory autocoids autocoids: act like local hormones, act near site of synthesis, short acting
 Results:  postischemic dysfunction  dysrhythmias  morphologic injury  necrosis

Question 8

How Do Oxygen Free Radicals Cause Injury?

Answer 8

Induce opening of mitochondrial permeability transition pore
 Act as neutrophil chemoattractants  Mediate dysfunction of sarcoplasmic reticulum  Contribute to intracellular calcium overload  Damage cell membrane by lipid peroxidation  Induce enzyme denaturation  Cause direct oxidative damage to DNA

Question 9

What is the Mitochondrial Permeability Transition Pore?

Answer 9

Nonselective channel (protein) of inner mitochondrial membrane
 When open increases permeability of molecules <1500 Daltons
 When open oxidative phosphorylation is uncoupled
 Results in ATP and cell death  Closed during ischemia / open during
 Opens in response to mitochondrial calcium overload, oxidative stress, restoration of physiologic pH, and ATP depletion

Question 10

How Can We “Attack” The Oxygen Free Radical Problem?

Answer 10

Administer pharmacological agents that inhibit the formation of oxygen free radicals
 Anesthetic agents, Anti arrhythmics may eliminate hydroxyl radicals, Vit C ->peroxides
 Administer pharmacological agents that scavenge / remove oxygen free radicals
 Mannitol, N-acetylcysteine, etc (page 182-183 Gravlee)
 Administer anti-neutrophil agents  Decrease ischemia-reperfusion injury

Question 11

What Changes Are Caused By Myocyte Calcium Influx?

Answer 11

Depletion of high-energy phosphate stores  Energy stores needed for ATP production
 Accumulation in mitochondria kills ability to produce ATP
 Inability to produce ATP affects:
 Ability of cell to contract
 Ability of cell to move calcium out of the cell or back into the SR
 Activation of catalytic enzymes  Increase cellular damage

Question 12

What Changes Are Caused By Myocyte Calcium Influx? 2

Answer 12

Alteration of excitation-contraction coupling of actin-myosin-troponin
 Calcium into the cell causes the contraction sequence
 Calcium not removed  Stone heart syndrome
 Calcium can enter by multiple pathways

Question 13

What Starts The Activation of Neutrophils?

Answer 13

Receptor molecules will be activated / exposed  Start attachment process to the endothelium
 Three types of receptor molecules  selectins (P, L, E)
 Initial binding processes with endothelial wall
 beta2 integrins (CD11/CD18 complex)  Mediate firmer contact with wall
 immunoglobulin superfamily (ICAM-1)  Mediates final surface adherence
 Once bound – Diapedesis - blood goes thru capillaries
P-selectin (endothelial cells) triggered by proinflammatory mediators
 oxygen-derived free radicals  Hydrogen Peroxide etc
 thrombin  complement components  histamine
 Neutrophil recruitment triggered by similar proinflammatory mediators

Question 14

Neutrophil Products

Answer 14

hypoclorous acid
platelet activating factor
oxygen-derived free radicals
cytokines
 proteases

Question 15

What Causes Myocardial Edema?

Answer 15

Increasedintracellularosmoticpressure  accumulation metabolic end-products of anaerobic glycolysis, lipolysis, ATP
hydrolysis
 Disruption of electrical potential across cell membrane  sodium / chloride accumulate inside the cell – attract water
 Increasedmicrovascularpermeability
 Increasedinterstitialosmoticpressure
 Highcardioplegiadeliverypressure
 Hypothermia induced changes to sodium-potassium pump
 Results  increasedmicrovasculatureresistance  increased diffusion distance to myofibril

Question 16

How Can We Target The Perpetrators During Bypass?

Answer 16

Cardioplegia
 Ability to modify conditions of reperfusion and the composition of the solution
Conditions
hydrodynamics temperature route
Composition
pH metabolic substrate hypocalcemia oxygen pharmaceuticals

Question 17

How Do We Target The Perpetrators During Off-Pump Cases?

Answer 17

IV administration

 NO cardioplegia  NO hypothermia  MINIMAL cardiac work-load reduction

Question 18

What Clinical Results Do We See As a Result of RPI?

Answer 18

Dysrhythmias  PVC’s, fibrillation, non-spontaneous return of sinus rhythm,
dysrhythmia persistence  Systolic dysfunction
 contractile function / stroke volume  View by TEE or measure a Cardiac Output
 Diastolic dysfunction (compliance / relaxation)
 impaired filling

Question 19

What Clinical Results Do We See As a Result of RPI? 2

Answer 19

Myocardial necrosis  Endothelial dysfunction
 No reflow phenomenon
 Post ischemic tissue edema
 Interstitial hemorrhage
 Active vasoconstriction from loss of endothelium derived vasodilators
 Release of neutrophil derived vasoconstrictors  Capillary plugging by adhering neutrophils`

Question 20

When Can Myocardial Injury Occur?

Answer 20

Three phases

 Before bypass (think “lines”)  During cardioplegic arrest (think XC ON)  During reperfusion (think XC off)

Question 21

Phase One

Answer 21

Pre-bypass / before delivery of cardioplegia – “prebypass window”
 Period of unprotected ischemia
 coronary artery or other disease process
 hypotension due to dysrhythmia and/or cardiogenic shock
 coronary spasm

Question 22

Phase Two

Answer 22

 Cross-clamp applied / cardioplegia delivered  Period of protected ischemia
 unresolved coronary stenosis  obstruction within vascular graft (kink, tight anastomosis,
emboli)
 maldistribution of cardioplegia
 inadequate cardioplegia delivery (inadequate pressure or volume, inappropriate composition)
 between infusions of intermittent cardioplegia  unintentional interruption of continuous cardioplegia

Question 23

Phase Three

Answer 23

 Reperfusion


After cross-clamp removed
 earlyphase:<4hours
 late phase: 4 to 6 hours
 resolution of hypotension / dysrhythmia restores blood flow
 cardioplegia infused at high pressures or with improper composition
 coronary blood flow restored with unmodified blood after clamp removal
Ischemic injury also possible
 hypotension post clamp release (think “neo”)  during weaning/termination CPB (do not distend)  vascular graft thrombosis or mechanical obstruction  Dysrhythmias (watch EKG)  vasospasm of grafted vessel

Question 24

4 main objectives of cardioplegia

Answer 24

immediate/sustained electromechanical arrest
rapid/sustained homogenous myocardial cooling
maintenance of therapeutic additives in effective concentrations
periodic washout of metabolic inhibitors

Question 25

goals of myocardial protection

Answer 25

decrease oxygen demand
no activity to increase perfusion
minimize ischemia by controlling temperature and decompressing heart
control reperfusion by pharmological additives and target RPI perpetrators
off pump procedure?