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EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA

EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA. Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning and Research U.P. College of Medicine. Disclosures.

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EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA

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  1. EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning and Research U.P. College of Medicine

  2. Disclosures • Currently a Professor at the College of Medicine, University of the Philippines, Manila • Active Pulmonary Consultant at Manila Doctors’ Hospital and Associate Active Consultant at Makati Medical Center • Has done studies, and given lectures in relation to these studies, for Astra Zeneca, Glaxo Smith Kline, Eli Lilly, Pfizer, United Laboratories, Pharmacia, Pfizer, Bayer, and Otsuka; these have no bearing on the lecture on High Altitude Diseases

  3. DO WE NEED TO KNOW HIGH ALTITUDE DISEASE? High altitude data: • 140M people reside at altitudes >2500m • There are telescopes at >5000m and mines at >4500m • 30 to 50,000 workers in the Tibet railroad project worked at >4000m • Skiers and mountain trekkers go to 3000m mostly, some to >8000m West, JB. Annals Intern Med, 2004, 141:789-900

  4. Can anyone climb Mt. Everest? Up to 2004, Himalayan database showed that: • Mt. Everest summit was reached 2251 times • 130 of these ascents were without supplemental oxygen

  5. Who really was the first Filipino to reach the summit of Mt. Everest? • Leo Oracion • Erwin Emata • Romy Garduce • Dale Abenojar

  6. HOW HIGH IS HIGH-ALTITUDE ? • High altitude: 1500-3000m above sea level • Very high altitude: 3000-5000m • Extreme altitude: above 5000m • For sea level visitors, 4600-4900m = highest acceptable level for permanent habitation • For high altitude residents, 5800-6000m = highest so far recorded Tibetan plateau & Himalayan valleys (8848m) Andes (6962m) Ethiopian highlands (4620m)

  7. Mt. Apo Mindanao 2954m Mt. Pulog Luzon 2922 Mt. Halcon Mindoro 2582 Mayon Volcano Luzon 2462 Mt. Katanglad Mindanao 2938 Kanlaon Mountain Negros 2430 Mt. Madiaas Panay 2117 Mt. Mantaling Palawan 2085

  8. LECTURE OUTLINE • Review of basic physiological principles of respiration as they relate to changes in pressure and temperature • Animal and human adaptations to high altitude • What happens when acclimatization fails ? • Acute mountain sickness • High altitude pulmonary edema • High altitude cerebral edema

  9. External Respiration

  10. Atmospheric composition at sea level GAS PERCENT NITROGEN 78.08 OXYGEN 20.95 ARGON 0.94 CARBON DIOXIDE 0.03 HYDROGEN 0.01 NEON 0.0018 HELIUM 0.0005

  11. Atmospheric Pressure declines with altitude Sea level: 1 atm = 14.7 lbs/inch2 (psi) 18,000 ft (5,486 m): 0.5 atm = 7.35 psi

  12. Atmosphere - 8863 m Mount Everest Pressure reduced to 1/2 atm Reduction in Pressure And O2 - 4860 m Human Settlement, Tibet 0.1 atm reduction every 1km 2954 m Mt. Apo Sea Level = 1 atm Hydrosphere 13 atm -130 m Increase in Pressure And Gas Solubility 370 atm -3700 m average depth of oceans 1 atm increase every ~10 m -10860 m Mariana Trench 1086 atm

  13. Baguio City Mt. Apo Pressure differences are enormous, leading to differences in oxygen supply for air-breathers

  14. Adaptations to high altitude High altitude mammals: More pigment in blood High affinity hemoglobin Birds: (1) Cross-current flow of air and blood allowing higher O2 concentration in blood than in exhaled air (2) Tolerate low CO2 in blood (Alkalosis) (3) Normal blood flow to the brain at low blood PCO2 (4) Total respiratory volume is 3X that of mammals

  15. Evolution of hemoglobin function • Highland Camelids (llama, vicuña, alpaca) display lower P50 (higher affinity) than lowland Asian/African camels • Amino acid substitutions in -globin chains which reduce the effect of DPG binding • A small number of substitutions are sufficient to adapt the functional properties of hemoglobin to severely hypoxic conditions

  16. Adaptation vs Acclimation/Acclimatization 1) Short Term Acclimation Mountain climbers who are able to maintain normal blood pH at low oxygen 2) Developmental Acclimation A person reared at high altitude: larger lung volume Higher concentration of red blood cells 3) Adaptation Llamas: Blood with high Oxygen affinities

  17. High Altitude: Humans Developmental Acclimation (Mountain People) • Larger lung volumes • 40% higher ventilation rate in populations at 4500m (≠ maladapted hyperventilation) • Increase number of blood cells (5 million/mm3 --> 8 million/mm3 at 4000m) • Increase myoglobin concentration in muscles • Effect on Enzymatic pathways not understood • Increase in number of muscle capillaries and mitochondria • Whether Adaptive differences occur in Humans is not known

  18. High Altitude: Humans • Highest permanent settlement: 5000m mining camp in Andes RESPONSE TO LOW O2: • Hyperventilation leading to low PCO2 • Chronic Hypoxia

  19. High Altitude: Humans Acclimation (or Acclimatization) • Change in response of respiratory center (in hypothalamus) • Adjust bicarbonate concentration in blood to maintain normal blood pH at low PO2 (and low PCO2 that arises from hyperventilation)

  20. ACCLIMATIZATION • Process by which people gradually adjust to high altitude • Determines survival and performance at high altitude • Series of physiological changes • O2 delivery • hypoxic tolerance +++ • Acclimatization depends on • severity of the high-altitude hypoxic stress • rate of onset of the hypoxia • individual’s physiological response to hypoxia

  21. High Altitude: Humans • Hyperventilation (negative feedback) (1) In response to low O2, ventilation increases (2) But then this reduces PCO2 (3) pH increases, reducing normal stimulation in the respiratory center (4) Reduces ventilation (5) Decrease oxygen supply (6) More increased ventilation to gain O2 • Hypoxia:Brain damage after 4-6 minutes of oxygen deprivation

  22. Heart and Pulmonary Circulation at High Altitude Penaloza, D and vier Arias-Stella J. Circulation. 2007;115:1132-1146.)

  23. Decreased PCO2 VENTILATORY ACCLIMATIZATION • Hypoxic ventilatory response =  VE • Starts within the 1st few hours of exposure  1500m • Mechanism Ascent to altitude Hypoxia Carotid body stimulation Respiratory centres stimulation Increased ventilation Improved hypoxia CO2 + H2O H2CO3HCO3- + H+

  24. ADJUSMENT OF RESPIRATORY ALKALOSIS •  alkaline bicarbonate excretion in the urine but slow process ! • Progressive increase in the sensitivity of the carotid bodies • After several hr to days at altitude (interval of ventilatory acclimatization): cerebrospinal fluid pH adjustment to the respiratory alkalosis new steady state

  25. VENTILATORY RESPONSE TO EXERCISE • Varies with hypoxia ventilatory response (HVR) at rest at sea level • Larger ventilatory response  climbing performance • but, at extreme altitude, larger work of breathing altitude  trade-off Schoene et al., 1984

  26. LUNG DIFFUSION • Definition Process by which O2 moves from the alveolar gas into the pulmonary capillary blood, and CO2 moves in the reverse direction • High altitude  O2 diffusion, because of • a lower driving pressure for O2 from the air to the blood • a lower affinity of Hb for O2 on the steep portion of the O2/Hb curve •  and inadequate time for equilibration

  27. CONSEQUENCE  O2 DIFFUSION •  arterial O2 saturation West et al., 1983 Wagner et al, Mt. Everest II project,1995

  28. VA/Q HETEROGENEITY • Varies from zero to infinity • Zero : perfusion but no ventilation • O2 and CO2 tensions in arterial blood, equal those of mixed venous blood because there is no gas exchange in the capillaries • Infinity:ventilation but no perfusion • no modification of inspired air takes place due to over-ventilation or under-perfusion

  29. VA/Q HETEROGENEITY • At rest • At high altitude • interstitial edema  heterogeneity +++ O2 - Inhaled air is not evenly distributed to alveoli - Composition of gases is not uniform throughout lungs - Different areas of the lungs have different perfusion - Differences are less in recumbent position

  30. Penaloza, D and vier Arias-Stella J. Circulation. 2007;115:1132-1146.)

  31. MIGET evaluation of Ventilation-perfusion relationships during induced polycythemia (with no pulmonary hypertension) Balgos A, Willford D, West JB. J Appl Physiol, 65(4): 1686-1692, 1988

  32. Maximal oxygen consumption at high altitude • 85% of sea level values, at 3000m; 60% at 5000m, and only 20% at 8000m • Ascribed to reduction in mitochondrial PO2 • Could also be due to central inhibition from brain • Most likely not due to pulmonary hypertension • Elite mountaineers tend to have an insertion variant of angiotensin-converting enzyme gene West, JB. Annals Intern Med, 2004, 141:789-900

  33. Effects on Mental performance • Most people working at >4000m experience increased arithmetic error, reduced attention span, and increased mental fatigue • Visual sensitivity (night vision) decreased at 2000m, and up to 50% at 5000m • Molecular and cellular mechanisms of these effects of hypoxia are poorly understood • Suggested mechanisms: altered ion homeostasis, changes in calcium metabolism, alterations in neurotransmitter metab., and impaired synapse function West, JB. Annals Intern Med, 2004, 141:789-900

  34. Effects on Sleep • Sleep impairment common and most distressing: frequent awakenings, unpleasant dreams, do not feel refreshed on waking up in the morning • Periodic breathing,which occurs at >4000m is most likely an important causative factor • Possible reasons for periodic breathing: instability of of control system for hypoxic drive, or response to CO2, as well as low levels of PaO2 after apneic episodes West, JB. Annals Intern Med, 2004, 141:789-900

  35. WHEN ACCLIMATIZATION FAILS • Altitude syndromes • Acute mountain sickness (AMS): the least-threatening and most common • High altitude pulmonary edema • High altitude cerebral edema • All these syndromes have • several features in common • respond to descent or oxygen potentially lethal form of AMS

  36. ACUTE MOUNTAIN SICKNESS • Major symptoms • Headache • Fatigue • Dizziness • Anorexia • Dyspnea (but tricky!) • Incidence and severity depend on • Rate of ascent • Altitude attained • Length of time at altitude • Degree of physical exertion • Individual’s physiological susceptibility • Treatment hardly needed • Only a problem if progression of symptoms to those of • HAPE • HACE

  37. HIGH ALTITUDE PULMONARY EDEMA (HAPE) • Noticed only after 24-48hr and occurs after the 2nd night • Occurs in otherwise healthy people without known cardiac or pulmonary disease • 1:50 climbers on McKinley succumb to HAPE (Hackett et al., 1990) • Occurs when people go rapidly to high altitude • Extravasation of fluid from the intra- to extravascular space in the lung

  38. WHY DOES HAPE OCCUR ? • Hypothesis 1. Pulmonary hypertension • Strong relationship between the development of HAPE in people with • Mild pulmonary hypertension at rest • Accentuated pulmonary vascular response to hypoxia or exercise • But pulmonary hypertension alone is not enough to result in HAPE(Sartori et al., 2002) • There is strong evidence that HAPE is due to patchy capillary damage due to pulmonary hypertension (West JB, 2004)

  39. WHY DOES HAPE OCCUR ? • Hypothesis 2. Pulmonary endothelium barrier fragility • Pulmonary endothelium barrier susceptible to • Mechanical stress  Stretching of the endothelium  gaps  passage of proteins and red blood cells • Inflammation  Mediators release  permeability  gaps  passage of proteins, red blood cells and inflammatory mediators • Questions: • inflammation = 1st culprit • High pressure alone enough to result in extra vascular leak ?

  40. INFLAMMATION IN HAPE ? • Schoene et al., 1986, 1998 • [Leukotrienes] (marker of inflammation) very high in BAL in subjects acutely ill with HAPE • But is inflammation present at the start or as a result of HAPE ? • Swenson et al., 2002 • RBC and proteins present in BAL in people at onset of HAPE • But no inflammatory markers present Inflammation probably not the causative factor Swenson et al., 2002

  41. HYPOXIC PULMONARY VASOCONSTRICTION • The stress failure theory (West et Mathieu-Costello, 1998, 99) Alveolar hypoxia Hypoxic pulmonary vasoconstriction (uneven)  capillary pressure (some capillaries) • VA/Q heterogeneity Damage to capillary wall (stress failure) Exposed basement membrane EDEMA Inflammatory mediators West, JB. Annals Intern Med, 2004, 141:789-900

  42. EXERCISE +/- O2 MORE HYPOXEMIA EXERCISE-INDUCED HYPOXEMIA Alveolar hypoxia Hypoxic pulmonary vasoconstriction (uneven)  capillary pressure (some capillaries) • VA/Q heterogeneity Damage to capillary wall (stress failure) Exposed basement membrane EDEMA Inflammatory mediators results in about ½ endurance athletes (Powers et al., 1988)

  43. INTEGRITY OF PULMONARY BLOOD-GAS BARRIER IN ATHLETES • Hopkins et al., 1997 • BAL in 6 athletes after a 7min exercise at maximal intensity • Post exercise: • RBC • Total protein • Albumin • Leukotrienes B4 • Hopkins et al., 1998 • 1h at 70% VO2max  no signs of alteration • Impairment of the integrity of blood-gas barrier only at extreme level of exercise in elite athletes > control subjects at rest

  44. Circular break of the epithelium Full break of the blood-gas barrier Costello et al., 1992 Red cell moving out of the capillary lumen (c) into an alveolus (a) West et al., 1995

  45. WHY DOES HAPE OCCUR ? • Hypothesis 3. Perturbation of alveolar fluid clearance • Role of fluid in extravascular space depends on: • Its accumulation • Efficiency of its rate of clearance • Hypoxia  Na,K-ATPase activity (Dada et al., 2003)

  46. PREVENTION OF HAPE • Don't climb at high altitude!!!! • Undergo hypoxic ventilation test to determine natural fitness for high altitude • If not fit, undergo training, and plan for slow ascent (At altitudes above 3000 m individuals should climb no more than 300 m per day with a rest day every third day) • Avoid strenuous physical exertion • Anyone suffering symptoms of acute mountain sickness should stop, and if symptoms do not resolve within 24 hours descend at least 500 m.

  47. TREATMENT OF HAPE • Get the patient down in lower altitude as fast and as low as possible • Give O2 or hyperbaria • Apply expiratory positive airways pressure • With a respiratory valve device • Or by pursed lips breathing • Treat like any other case of pulmonary edema; in some cases, antibiotics may be needed

  48. SPECIFIC TREATMENT OF HAPE • Acetazolamide, oral 125-250 mg 2x/day • Dexamethasone, oral. I.M. or I.V. 2 mg q 6hrs or 4 mg q 12 hrs. • Nifedipine, oral 20-30 mg long-acting, q 12 hrs. • Tadalafil oral 50 mg. 2x/day • Sildenafil 50 mg q 8 hrs • Salmeterol inhaled 125mg 2x/day

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