Complications in Long-Term Hypoxia

1. Complications in Long-Term Hypoxia Intern ??? 2002/02/17

3. Cyanosis Bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin Lips, nail beds, ears, and malar eminences 3.4~5.0 g/dl of reduced hemoglobin in the systemic circulation You can�t see cyanosis until the O2 saturation is in the mid-80% or less

4. Hypoxic Injury To Cells (1) REVERSIBLE changes: impaired aerobic respiration (mitochondria) decreased ATP (energy) anerobic glycolysis glycogen depletion accumulation of lactic acid (intracellular acidosis) with associated nuclear chromatin clumping

5. Hypoxic Injury To Cells (2) IRREVERSIBLE changes: vacuolization of mitochondria swelling of lysosomes damage to plasma membranes loss of phospholipids (decreased synthesis and increased degradation). cytoskeletal alterations (damage to cytoskeletal-membrane connections, effects of cell swelling, activation of proteases) effects of free radicals (toxic oxygen radicals or toxic oxygen species, produced by PMN's) lipid breakdown products (free fatty acids and other with a detergent effect on cell membrane)

6. Hypoxic Injury To Cells (3) influx of Ca++ into the cell and mitochondria with inhibition of cellular enzymes denaturation of proteins and coagulation of cells (coagulative necrosis) cell components are degraded by inflammatory processes, with associated further enzyme leakages and release of inflammatory mediators final breakdown product of dead cells include free fatty acids which attract Ca++ with formation of soaps

7. Causes of Hypoxia Anemic Hypoxia Carbon Monoxide Intoxication Respiratory Hypoxia Hypoxia Secondary to High Altitude Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting Circulatory Hypoxia Specific Organ Hypoxia Increased O2 Requirements Improper Oxygen Utilization

8. Effects of Hypoxia Changes in the central nervous system, particularly the higher centers Impaired judgment, motor incoordination Fatigue, drowsiness, apathy, inattentiveness, delayed reaction time, and reduced work capacity Death usually results from respiratory failure (Brainstem hypoxia)

9. Hypoxic-ischemic encephalopathy Impaired judgment, inattentiveness, motor incoordination, and, at times, euphoria Circulatory arrest --> consciousness is lost within seconds Circulation is restored within 3 to 5 min --> full recovery may occur (eg. Neonatal asphyxia) Hypoxia-ischemia lasts beyond 3 to 5 min --> some degree of permanent cerebral damage Hypoxia v.s. Hypoxic-ischemia

10. Hypoxic-ischemic encephalopathy �Delayed injury� ( may continue for days to weeks): 6-24 hours after the initial injury, a new phase of neuronal destruction sets in, characterized by apoptosis Mild hypothermia: 2-6 degrees C for 3-72 h after reoxygenation/reperfusion has been shown to reduce brain damage by 25-80%

11. Pulmonary Hypertension (PH) A common companion of many congenital disease (CHD) The determining factor in assessing the advisability of operation ( Pulmonary Resistance v.s. Systemic Resistance) Eisenmenger syndrome: right-to-left shunts Heart-lung transplantation

12. Erythrocytosis Increased erythropoietin production Compensated vs. decompensated Phlebotomy for recurrent hyperviscosity symptoms Iron-depleted erythrocytosis progressive symptoms after recurrent phlebotomy are usually due to iron depletion with hypochromic microcytosis

13. Hyperviscosity Phlebotomy, when required for symptoms of hyperviscosity not due to dehydration or iron deficiency, is a simple outpatient removal of 500 mL of blood over 45 min with isovolumetric replacement with isotonic saline (5% dextrose if congestive heart failure exists) Iron repletion must be done gradually

14. Abnormal Hemostasis Increased blood volume and engorged capillaries Abnormalities in platelet function Abnormalities of the extrinsic and intrinsic coagulation system Oral contraceptives are contraindicated for cyanotic women

15. Pathogenesis of Ischemic-associated Thrombosis transcription factor early growth response-1 (Egr-1) --> de novo transcription/translation of tissue facto in mononuclear phagocytes and smooth muscle cells --> vascular fibrin deposition. Concomitant suppression of fibrinolysis by hypoxia-mediated upregulation of plasminogen activator inhibitor-1

16. Hypoxia-induced PH alveolar hypoxia involves most of the lung and is prolonged --> any usefulness of acute hypoxic pulmonary vasoconstriction is offset by a rise in pulmonary arterial pressure. structural changes in small peripheral pulmonary arteries: increased wall thickness of muscular arteries, the appearance of new muscle in normally non-muscular arteries. Eg. COPD, populations living at high attitude Genetic susceptability HIF (Hypoxia inducible factor)-1 Endothelin-1 Angiotensin II

17. Oxidant tissue injury in hypoxic PH Increase of radical production induced by lung tissue hypoxia Hypoxia ? alveolar macrophages ? hydrogen peroxide Nitric oxide; serum concentration of nitrotyrosine (radical product of nitric oxide and superoxide interaction) Radicals ? metabolism of vascular wall matrix proteins ? vascular remodeling ? Thickened and less compliant peripheral pulmonary vasculature

18. Chronic-intermittent hypoxia induced hypertension chronic-intermittent hypoxia (as obstructive sleep apnea syndrome --> activation of the sympathetic nervous system (included cortical and brainstem components) --> hypertension

19. Other organs under hypoxic environment More acute hypoxic damages than chronic damages Kidney Liver Intestine Pancreas

20. Reference Harrison�s Principles of Internal Medicine, 15th ed. Morrell et al.: Genetic and molecular mechanisms of pulmonary hypertension. Clinical Medicine 1(2): pp 138-145 Yan, Shi-Fang et al.: Hypoxia/Hypoxemia-Induced Activation of the Procoagulant Pathways and the Pathogenesis of Ischemia-Associated Thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology.: 19(9) Sep. 1999 pp 2029-2035 Anonymous: Keeping a cool head, post-hypoxic hypothermia--an old idea revisited. Acta Paediatrica.: 86(10):1029-33, 1997 Oct Frank et al.: A possible role of the oxidant tissue injury in the development of hypoxic pulmonary hypertension. Physiological Research. 49(5):493-501, 2000