Complications in Long-Term Hypoxia

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Complications in Long-Term Hypoxia

• Intern ???
• 2002/02/17

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Hypoxia

• A lack of oxygen at the tissue level of the body
  due to a decreased partial pressure of oxygen in
  the inspired air
• Normally 1000 mls/minute (550 mls/min/m2) of
  oxygen is transported from the lungs to the
  periphery by the circulation
• Only 25 of this is utilized in a resting person.

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Cyanosis

• Bluish color of the skin and mucous membranes
  resulting from an increased quantity of reduced
  hemoglobin
• Lips, nail beds, ears, and malar eminences
• 3.45.0 g/dl of reduced hemoglobin in the
  systemic circulation
• You cant see cyanosis until the O2 saturation is
  in the mid-80 or less

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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

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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)

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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

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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

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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)

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Hypoxic-ischemic encephalopathy

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

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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

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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

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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

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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

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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

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Pathogenesis of Ischemic-associated Thrombosis

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

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Hypoxia-induced PH

• alveolar hypoxia involves most of the lung and is
  prolonged --gt 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

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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

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Chronic-intermittent hypoxia induced hypertension

• chronic-intermittent hypoxia (as obstructive
  sleep apnea syndrome --gt activation of the
  sympathetic nervous system (included cortical and
  brainstem components) --gt hypertension

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Other organs under hypoxic environment

• More acute hypoxic damages than chronic damages
• Kidney
• Liver
• Intestine
• Pancreas

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Reference

• Harrisons 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