Ischemia and Reperfusion Flashcards
oxygen paradox
too much of a good thing: oxygen-derived free radical formation (reactive oxygen species (ROS))
Calcium paradox
Large influx of calcium into the cell
pH paradox
pH moves from acidic to normal – potentiates many of the changes
Inflammation causes
neutrophil activation
When Are Oxygen Free Radicals Generated?
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
What Factors Determine The Amount of Oxygen Free Radicals Produced?
Severity of ischemic injury Activation and recruitment of neutrophils
to myocardium
Level of O2 in the cardioplegic solution
Presence of endogenous scavengers and inhibitors
what Changes Are Caused By Oxygen Free Radicals?
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
How Do Oxygen Free Radicals Cause Injury?
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
What is the Mitochondrial Permeability Transition Pore?
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
How Can We “Attack” The Oxygen Free Radical Problem?
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
What Changes Are Caused By Myocyte Calcium Influx?
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
What Changes Are Caused By Myocyte Calcium Influx? 2
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
What Starts The Activation of Neutrophils?
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
Neutrophil Products
hypoclorous acid platelet activating factor oxygen-derived free radicals cytokines proteases
What Causes Myocardial Edema?
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
How Can We Target The Perpetrators During Bypass?
Cardioplegia
Ability to modify conditions of reperfusion and the composition of the solution
Conditions
hydrodynamics temperature route
Composition
pH metabolic substrate hypocalcemia oxygen pharmaceuticals
How Do We Target The Perpetrators During Off-Pump Cases?
IV administration
NO cardioplegia NO hypothermia MINIMAL cardiac work-load reduction
What Clinical Results Do We See As a Result of RPI?
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
What Clinical Results Do We See As a Result of RPI? 2
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`
When Can Myocardial Injury Occur?
Three phases
Before bypass (think “lines”) During cardioplegic arrest (think XC ON) During reperfusion (think XC off)
Phase One
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
Phase Two
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
Phase Three
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
4 main objectives of cardioplegia
immediate/sustained electromechanical arrest
rapid/sustained homogenous myocardial cooling
maintenance of therapeutic additives in effective concentrations
periodic washout of metabolic inhibitors
goals of myocardial protection
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?
