EXTREME PHYSIOLOGY

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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
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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

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DO WE NEED TO KNOW HIGH ALTITUDE DISEASE?

• High altitude data
• 140M people reside at altitudes gt2500m
• There are telescopes at gt5000m and
• mines at gt4500m
• 30 to 50,000 workers in the Tibet
• railroad project worked at gt4000m
• Skiers and mountain trekkers go to
• 3000m mostly, some to gt8000m

West, JB. Annals Intern Med, 2004, 141789-900
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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

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Who really was the first Filipino to reach the
summit of Mt. Everest?

• Leo Oracion
• Erwin Emata
• Romy Garduce
• Dale Abenojar

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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)
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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

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External Respiration
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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

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• 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
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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
1086 atm
-10860 m Mariana Trench
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Baguio City
Mt. Apo
Pressure differences are enormous, leading to
differences in oxygen supply for air-breathers
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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

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• 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

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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
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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 --gt 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

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High Altitude Humans

• Highest permanent settlement 5000m mining camp
  in Andes
• RESPONSE TO LOW O2
• Hyperventilation leading to low PCO2
• Chronic Hypoxia

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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)

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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
• individuals physiological response to hypoxia

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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

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Heart and Pulmonary Circulation at High Altitude
Penaloza, D and vier Arias-Stella J. Circulation.
20071151132-1146.)
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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  H2CO3  HCO3- H
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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

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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
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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

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CONSEQUENCE ? O2 DIFFUSION

• ? arterial O2 saturation

West et al., 1983
Wagner et al, Mt. Everest II project,1995
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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

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VA/Q HETEROGENEITY

• At high altitude
• interstitial edema
• ? heterogeneity

• At rest

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
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Penaloza, D and vier Arias-Stella J. Circulation.
20071151132-1146.)
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MIGET evaluation of Ventilation-perfusion
relationships during induced polycythemia (with
no pulmonary hypertension)
Hct Range Hct Midpoint Log SD Perfusion Mean Perfusion Log SD Ventilation Mean Ventilation
30-39 35 0.470.20 0.56 1.790.14 1.66
40-49 45 0.490.09 1.05 1.400.52 2.20
50-59 55 0.480.08 1,22 1.530.26 2.87
60-69 65 0.460.04 1.97 1.100.52 3.44
70-79 75 0.440.10 2.72 0.840.58 3.96
Balgos A, Willford D, West JB. J Appl Physiol,
65(4) 1686-1692, 1988
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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, 141789-900
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Effects on Mental performance

• Most people working at gt4000m 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, 141789-900
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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 gt4000m 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, 141789-900
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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
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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
• Individuals physiological susceptibility

• Treatment hardly needed
• Only a problem if progression of symptoms to
  those of
• HAPE
• HACE

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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
• 150 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

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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)

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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 ?

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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
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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, 141789-900
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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)
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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

gt control subjects at rest
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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
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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)

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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.

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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

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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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Medication Renal Insufficiency Hepatic Insufficiency Pregnancy Other Issues
Acetazolamide Avoid if GFR lt10 mL/min, metab acidosis, hypoK, hypercalcemia, hyperphosphatemia Contraindicated Category C Avoid if w/ concurrent long-term aspirin cuation with sulfa allergy avoid concurrent K-wasting diuretics and ophthalmjic CAI
Dexamethasone No C.I. No dose adjustments No C.I. No dose adjustments Category C May increase FBS in diabetics avoid in PUD or GO-bleed risk patients
Nifedipine No C.I. No dose adjustments Best to avoid if use necessary, 10 mg B.I.D. Category C Caution PUD or GO-bleed risk or gastroesoph varices patients
Tadalafil 5mg if GFR 30-50 mL/min. Max 10 mg lt5 if GFR lt 30mL/min. Child's Class A B 10mg/dL Child's class C don't use Category B Incr. Risk of GERD caution with other meds affecting cP450 avoid concurrent nitrates and B-blockers
Sildenafil Same dose adj as Tadalafil Decrease dose start with 25 mg avoid use if with g-e varices Category B Incr. Risk of GERD caution with other meds affecting cP450 avoid concurrent nitrates and B-blockers
Salmeterol No C.I. No dose adjustments Insufficient data best to avoid Category C Potential for adverse reaction in pts w/ CAD prone to arrhythmia avoid concurrent beta-blockers, monoamine oxidase inhibitors, or tricyclic antidepressants
Luks and Swenson, Chest, 2008 133 744-755
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Medication Malaria Traveler's Diarrhea
Acetazolamide No known interactions with prophylaxis med, but could increase serum quinine concentration No interactions with fluroquinolones or macrolides
Dexamethasone No known interactions with prophylaxis or treatment meds Potential increased risk of tendon injury
Nifedipine No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin safe to use azithromycin and fluroquinolones
Tadalafil No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin safe to use azithromycin and fluroquinolones
Sildenafil No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin safe to use azithromycin and fluroquinolones
Salmeterol Avoid chloroquine due to increased risk of QT- interval prolongation and ventricular arrhythmia. Other agents safe to use Avoid clarithromycin safe to use azithromycin and fluroquinolones
Luks and Swenson, Chest, 2008 133 744-755
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KEY POINTS

• High altitude stressful environment for the
  lungs
• At extreme altitudes lung primary and
  essential organ for human function and survival
• HAPE potentially lethal form of AMS
• Extravasation of fluid from the intra- to
  extravascular space in the lung
• Main mechanism involved
• pulmonary hypoxic vasoconstriction
• Capillary stress failure
• Exercise-induced hypoxemia at sea level shows a
  similar pattern

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Summary

• Respiration is directly tied to metabolism, and
  physical and physiologic principles
• High Pressure and Altitude pose problems for
  Respiration, which reach the limits of normal
  physiology
• Different animals, including man, respond to high
  altitude through adaptation and/or
  acclimatization Gene regulation of Hemoglobin
  evolves more quickly than structural changes
• Acute ascent to high altitude poses clinical
  problems that could lead to various forms of
  acute mountain sickness (AMS) which, like HAPE,
  may be fatal
• Prevention and early recognition of symptoms of
  HAPE important, for prompt treatment

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Summary

• Best treatment is prevention
• Specific treatment modalities helpful, but not
  always successful
• Best treatment is descent from high altitude.
• Other supportive treatment similar to any
  capillary leak pulmonary edema is often necessary

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RECOMMENDED REFERENCES

• BOOK
• Ward et al. High altitude medicine and
  physiology. 3rd edition. Arnold. 2000
• ARTICLES
• Hopkins et al. Intense exercise impairs the
  integrity of the pulmonary blood-gas barrier in
  elite athletes. Am J Respir Crit Care Med.
  1997155(3)1090-4.
• West JB et al. Pathogenesis of high-altitude
  pulmonary oedema direct evidence of stress
  failure of pulmonary capillaries. Eur Respir J.
  19958(4)523-9.
• Schoene. Unraveling the mechanism of high
  altitude pulmonary edema. High Alt Med Biol.
  20045(2)125-35.
• West, JB. The Physiologic Basis of High Altitude
  Diseases. Annals Intern Med, 2004, 141789-900
• Luks and Swenson, Chest, 2008 133 744-755
• Martin, et al. Variattion in human performance in
  the hypoxi mountain environment. Exp Physiol,
  2010 953 463-470