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  1. 1. REPERFUSION INJURY Frank Nami, M.D. Saint Barnabas Medical Center
  2. 2. Ischemia and Reperfusion <ul><li>Ischemic tissue will ultimately progress to cellular death if restoration of blood flow does not occur in a timely manner. </li></ul><ul><li>Restoration of blood flow and oxygenation to ischemic tissues can result in a paradoxical enhancement of tissue injury. </li></ul>
  3. 3. Reperfusion Injury <ul><li>Often more severe than damage incurred during the ischemic period itself. </li></ul><ul><li>Characterized by cellular edema, intracellular Ca 2+ overload with subsequent activation of Ca 2+ - dependent autolytic enzymes, disruption of lipid membranes, and perturbations in mitochondrial structure and function. </li></ul>
  4. 4. Reperfusion Injury <ul><li>Great relevance to the practice of surgery: </li></ul><ul><li>Vascular Surgery </li></ul><ul><li>Cardiac Surgery </li></ul><ul><li>Transplant Surgery </li></ul><ul><li>Restoration of blood flow to the ischemic limb, heart or transplanted organ. </li></ul>
  5. 5. Mediators of Reperfusion Injury <ul><li>Endothelial Cell </li></ul><ul><li>Oxygen Free Radicals </li></ul><ul><li>Polymorphonuclear Cells (PMNs) </li></ul>
  6. 6. Endothelial Cell <ul><li>Thin monolayer of cells, resting on a basement membrane, surface area 5000 m 2 but comprises only 1% of total body weight. </li></ul><ul><li>Exerts influence over blood vessel tone, permeability, cell adhesion, coagulation, and growth by regulating the production of a battery of molecules and cell surface proteins. </li></ul>
  7. 7. Endothelial Cell-Mediated Vasomotor Tone <ul><li>Vasodilation - Prostacyclin (PGI 2 ) via cyclooxygenase pathway, activates adenylate cyclase and protein kinase A, also inhibits platelet aggregation by increasing cAMP - promotes microcirculatory flow. </li></ul>
  8. 8. Endothelial Cell-Mediated Vasomotor Tone <ul><li>Vasodilation - Nitric Oxide (NO) also inhibits platelet aggregation, decreases vascular smooth muscle cell proliferation. Produced from L-arginine and oxygen in endothelial cytosol. </li></ul><ul><li>Deficiency of NO synthesis reported in study of human volunteers with hypertension. </li></ul>
  9. 9. Endothelial Cell-Mediated Vasomotor Tone <ul><li>Patients with diabetes, atherosclerosis, hypercholesterolemia, or cigarette smoking also exhibit deficient NO synthesis. </li></ul><ul><li>Adenosine - also a vasodilator, inhibits platelet and neutrophil aggregation. </li></ul>
  10. 10. Endothelial Cell-Mediated Vasomotor Tone <ul><li>Vasoconstriction - Thromboxane A 2 (TXA 2 ) via thromboxane synthase, opposes prostacyclin and produces platelet adherence. </li></ul><ul><li>Endothelin-1, most potent vasoconstrictor known, counteracts NO. </li></ul>
  11. 11. Endothelial Cell-Mediated Cell Adhesion <ul><li>Mediators formed during reperfusion induce endothelial cells to express intercellular adhesion molecules (ICAM 1 and 2), endothelial leukocyte adhesion molecule (ELAM) and selectins. </li></ul><ul><li>These receptors bind the CD11/CD18 complex on activated, facilitating PMN adherence to and migration across endothelium. </li></ul>
  12. 12. Endothelial Cell <ul><li>Secretes an abundance of soluble factors which promote vasoconstriction, platelet aggregation, PMN plugging of capillaries, and increased vascular permeability. </li></ul><ul><li>Factors include: Platelet aggregating factor (PAF), LTB 4 , TXA 2 and endothelin. </li></ul>
  13. 13. Endothelial Cell <ul><li>End result : perfusion of the microcirculation is severely compromised, which manifests as the classic “no-reflow” phenomenon of reperfusion injury. </li></ul>
  14. 14. Oxygen Free Radicals <ul><li>Three different molecules to be aware of: </li></ul><ul><li>Superoxide anion O 2 - </li></ul><ul><li>Hydrogen peroxide H 2 O 2 </li></ul><ul><li>Hydroxyl radical . OH </li></ul>
  15. 15. Oxygen Free Radicals <ul><li>Reperfusion stimulates xanthine oxidase which is activated in ischemic endothelial cells to generate superoxide radicals. </li></ul><ul><li>PMNs also generate oxygen free radicals. </li></ul>
  16. 16. Oxygen Free Radicals <ul><li>These toxic moieties are rapidly generated at the onset of reperfusion and cause widespread damage to cellular macromolecules. </li></ul><ul><li>Peroxidation of lipid membranes, protein degradation, nucleic acid damage, cytochrome inactivation and neutralization of nitric oxide. </li></ul>
  17. 17. Oxygen Free Radicals <ul><li>Most damaging effect is on lipid membranes, impairs normal fluidity and permeability of cell membranes leading to cellular edema, massive Ca 2+ and Na + overload and cell lysis. </li></ul>
  18. 18. Oxygen Free Radicals <ul><li>Oxygen free radical scavengers and antioxidants have been shown both experimentally and clinically to ameliorate reperfusion injury. </li></ul>
  19. 19. Oxygen Free Radicals <ul><li>Natural protective enzyme systems to reduce free radical damage include superoxide dismutase, catalase, and glutathione peroxidase. </li></ul><ul><li>Most important endogenous antioxidant is glutathione. N-acetylcysteine is an artificial glutathione precursor. </li></ul>
  20. 20. Activated PMNs <ul><li>Inflict damage to reperfused endothelial and parenchymal cells. </li></ul><ul><li>Release a host of destructive proteolytic enzymes, including elastase, collagenase, gelatinase, lysozyme, and cathepsin G. </li></ul>
  21. 21. Activated PMNs <ul><li>Source of oxygen free radicals by virtue of a superoxide generating NAD oxidase. </li></ul><ul><li>Produce hypochlorous acid by activity of myeloperoxidase. </li></ul>
  22. 22. Reduction of Reperfusion Injury <ul><li>Allopurinol - inhibitor of xanthine oxidase has been shown to have protective effects. </li></ul><ul><li>Desferrioxamine - an iron chelator, removes an essential cofactor for the generation of hydroxyl radical. </li></ul>
  23. 23. Reduction of Reperfusion Injury <ul><li>Vitamin E - prevents neutrophil accumulation and attenuates tissue damage in ischemic-reperfused human skeletal muscle. </li></ul><ul><li>N-acetylcysteine - pretreatment 30 minutes before infrarenal aortic clamping may help prevent reperfusion injury. </li></ul>
  24. 24. Ischemia, Reperfusion Injury and Compartment Syndrome <ul><li>Elevated pressure within a confined tissue space. </li></ul><ul><li>High energy injuries. </li></ul><ul><li>Pain out of proportion to injury. </li></ul><ul><li>Most commonly occurs in the leg. </li></ul>
  25. 25. Ischemia, Reperfusion Injury and Compartment Syndrome <ul><li>Four compartments in leg: </li></ul><ul><li>Anterior: anterior tibial artery, deep peroneal nerve, extensor muscles of toes and foot </li></ul><ul><li>Lateral: superficial peroneal nerve, peroneal brevis and longis muscle </li></ul>
  26. 26. Ischemia, Reperfusion Injury and Compartment Syndrome <ul><li>Deep posterior: tibial nerve, posterior tibial artery, peroneal artery, deep toe and foot flexor muscles </li></ul><ul><li>Superficial posterior: superficial foot flexor muscles </li></ul><ul><li>Examining leg, document sensation at first web space (deep peroneal nerve), dorsum of foot (superficial peroneal nerve) and plantar surface of foot (tibial nerve) </li></ul>
  27. 27. Ischemia, Reperfusion Injury and Compartment Syndrome <ul><li>Pressure threshold at which fasciotomy is indicated has been debated. </li></ul><ul><li>30-40 mm Hg </li></ul><ul><li>Can use arterial pressure transducer, IV tubing, 3 way stopcock, 20 ml syringe, a 16Ga needle. </li></ul><ul><li>Four compartments should be measured </li></ul>