1. 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 1

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. 140M people reside at altitudes >2500m
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: 3

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 4

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

6. HOW HIGH IS HIGH-ALTITUDE ?
High altitude: m above sea level
Very high altitude: m
Extreme altitude: above 5000m
For sea level visitors, m = highest acceptable level for permanent habitation
For high altitude residents, m = highest so far recorded
Tibetan plateau & Himalayan valleys (8848m)
Andes (6962m)
Highest peak of Ethiopia : Ras Dashau
Highest peak of Central Andes of Chile/Argentina : Aconcagua,
Ethiopian highlands (4620m) 6

8. 2085 Palawan Mt. Mantaling 2117 Panay Mt. Madiaas 2430 Negros
Kanlaon Mountain
2938
Mindanao
Mt. Katanglad
2462
Luzon
Mayon Volcano
2582
Mindoro
Mt. Halcon
2922
Mt. Pulog
2954m
Mt. Apo 8

9. 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
At high altitude, respiration extracts utilizes a high proportion of the overall energy expenditure. In spite of a slight decrease in the work of breathing resulting from the lower density of the ambient air at high altitude, much greater volumes of air are necessary to supply enough oxygen to the body from atmospheric air, in which the level of oxygen is reduced. Delivery of oxygen is further impaired by a diffusion limitation of oxygen from the air to the blood, which increases with altitude. At extreme altitudes, a disabling sense of dyspnea is compounded by cerebral hypoxia, which may further limit exercise. Climbers to these heights have reported taking as many as 10 breaths per step as the rate of ascent progressively and tortuously slows. Reinhold Messner wrote of his first ascent of Mount Everest (8828m, barometric pressure 33.3kPa) without supplemental oxygen that ‘I am nothing more than a single narrow, gasping lung, floating over the mists and summits’. Thus, we come back to the lung as the primary and essential organ for human function and survival at high altitude without which the first step up could not be taken. 9

10. External Respiration 10

11. Atmospheric composition at sea level
GAS PERCENT
NITROGEN
OXYGEN
ARGON
CARBON DIOXIDE
HYDROGEN
NEON
HELIUM 11

12. 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

13. Atmosphere Hydrosphere Reduction in Pressure And O2
m Mount Everest
Pressure reduced to 1/2 atm
Reduction
in Pressure
And O2
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
m Mariana Trench 13

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

15. 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

16. 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

17. 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

18. 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

19. High Altitude: Humans
Highest permanent settlement: 5000m mining camp in Andes
RESPONSE TO LOW O2:
Hyperventilation leading to low PCO2
Chronic Hypoxia 19

20. 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

21. 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

22. High Altitude: Humans (1) In response to low O2, ventilation increases
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

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

24. VENTILATORY ACCLIMATIZATION
Hypoxic ventilatory response =  VE
Starts within the 1st few hours of exposure  1500m
Mechanism
Ascent to altitude
Hypoxia
Decreased PCO2
Carotid body stimulation
On arrival at altitude, increased carotid body activity attempts to increase ventilation, and thereby to raise the arterial oxygen pressure back to the sea level value. However, this presents the body with a dilemma. An increase in breathing causes an increased excretion of carbon dioxide in the exhaled air. When CO2 is in body tissues, it creates an acid aqueous solution, and when it is lost in exhaled air, the body fluids, including blood, become more alkaline, thus altering the acid-base balance in the body. The dilemma is that ventilation is regulated not only to keep oxygen pressure constant, but also for acid- base balance. CO2 regulates breathing in the opposite direction from oxygen. Thus when the CO2 pressure (i.e., the degree of acidity somewhere within the respiratory centre) rises, ventilation rises, and when it falls, ventilation falls. On arrival at high altitude, any increase in ventilation caused by the low oxygen environment will lead to a fall in CO2 pressure, which causes alkalosis and acts to oppose the increased ventilation. Therefore, the dilemma on arrival is that the body cannot maintain constancy in both oxygen pressure and acid-base balance. Human beings require many hours and even days to regain proper balance.
Respiratory centres stimulation
Increased ventilation
CO2 + H2O  H2CO3  HCO3- + H+
Improved hypoxia 24

25. 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
One method for rebalancing is for the kidneys to increase alkaline bicarbonate excretion in the urine, which compensates for the respiratory loss of acidity, thus helping to restore the body's acid-base balance toward the sea-level values. The renal excretion of bicarbonate is a relatively slow process. For example, on going from sea level to 4,300 m (14,110 ft), acclimatization requires from seven to ten days (figure 37.3). This action of the kidneys, which reduces the alkaline inhibition of ventilation, was once thought to be the major reason for the slow increase in ventilation following ascent, but more recent research assigns a dominant role to a progressive increase in the sensitivity of the hypoxic sensing ability of the carotid bodies during the early hours to days following ascent to altitude. This is the interval of ventilatory acclimatization. The acclimatization process allows, in effect, ventilation to rise in response to low arterial oxygen pressure even though the CO2 pressure is falling. As the ventilation rises and pressure falls with acclimatization at altitude, there is a resultant and concomitant rise in oxygen pressure within the lung alveoli and the arterial blood. 25

26. 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
Although the actual increase in the sensitivity of the carotid body to hypoxemia during the course of acclimation is not fully understood, it appears that each individual’s HVR, as measured at sea level, is roughly proportional to the ventilatory response to exercise at high altitude (Schoene et al., 1984; Schoene et al., 1990). In other words, subjects with a low HVR at rest measured at sea level have a relatively more blunted ventilatory response to exercise at high altitude than those with a high HVR, and vice versa. A large ventilatory response to exercise conveys a greater respiratory alkalosis and higher arterial oxygen saturation and may confer a better climbing performance at very high altitudes (Schoene et al., 1984) (Fig.2). However, individuals with very large HVRs may incur a greater work of breathing at extreme altitude. Thus, there may be a trade-off between increased arterial blood oxygenation and the increased work of breathing in these individuals.
Schoene et al., 1984 26

27. LUNG DIFFUSION Definition High altitude   O2 diffusion, because of
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
High altitude imposes a diffusion limitation of oxygen from the air to the blood (Fig.6). This diffusion limitation is secondary to several factors: (i) a lower driving pressure for oxygen from the air to the blood, (ii) a lower affinity of hemoglobin for oxygen on the steep portion of the oxygen/hemoglobin curve, and (iii) a decreased and inadequate time for equilibration of oxygen as the red blood cell traverses the pulmonary capillary. As mentioned above, the decreased alveolar partial pressure of oxygen at high altitude is in part minimized by ongoing ventilatory acclimation. This response to acclimation, however, is never adequate to overcome the ambient hypobaria. But, because of the large volume of gas that is required to supply an adequate quantity of oxygen, especially during the high metabolic demands of exercise, the lung is well designed to minimize the diffusion limitation in that the alveolar–capillary interface provides a large surface area for gas exchange that is instantly adaptable (West and Mathieu-Costello, 1992). Oxygen flux depends on the demand for oxygen, and the greater the ratio of diffusion capacity to perfusion the more successful is the loading of oxygen to the blood. 27

28. CONSEQUENCE  O2 DIFFUSION
 arterial O2 saturation
Arterial oxygen saturation thus decreases with exercise at high altitude, as has been documented in a number of human studies in both field and laboratory settings (Gale et al., 1985; Torre-Bueno et al., 1985; Wagner et al., 1986; Wagner et al., 1987; West et al., 1983) (Fig.7). Using sophisticated evaluations of gas exchange (the multiple inert gas elimination technique, MIGET), investigators have been able to apportion the decline in arterial oxygen saturation by looking at ventilation/perfusion relationships as well as diffusion characteristics (Fig.8). During acute hypobaric hypoxia to simulate an altitude of 4700m, Gale et al. (Gale et al., 1985), Torre-Bueno et al. (Torre-Bueno et al., 1985) and Wagner et al. (Wagner et al., 1986) showed both a ventilation/perfusion inequality and a diffusion limitation in the lung, both of which accounted for worsening hypoxemia with increasing work loads at higher altitudes. In Operation Everest II, the assimilated ascent to 8828m (PO2, approximately 33.3kPa) demonstrated that the ventilation/perfusion heterogeneity persisted to a modest degree while the diffusion limitation of oxygen became greater with increasing altitude (Wagner et al., 1987) (Fig.8). The increase in diffusion limitation was thought to be secondary to the marked decrease in driving pressure for oxygen from the air to the blood at these extreme simulated altitudes.
West et al., 1983
Wagner et al, Mt. Everest II project,1995 28

29. 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

30. VA/Q HETEROGENEITY O2 At rest At high altitude interstitial edema
The ventilation/perfusion heterogeneity was attributed to interstitial edema from high intervascular pressures, which correlated with the increase in pulmonary artery pressures. Much controversy exists regarding the effect on gas exchange of increased intervascular pressures during exercise at high altitude. During acute hypoxia, extravasation of fluid from the intra- to the extravascular space has been documented both at high altitude and at sea level in human and equine experiments (Hopkins et al., 1997; Pascoe et al., 1981; Seaman et al., 1995; Whitwell and Greet, 1984). 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

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

32. 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
0.56
1.66
40-49 45
1.05
2.20
50-59 55
1,22
2.87
60-69 65
1.97
3.44
70-79 75
2.72
3.96
Balgos A, Willford D, West JB. J Appl Physiol, 65(4): , 1988

34. 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:

35. 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:

36. 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:

37. 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 37

38. 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 38

39. 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 39

40. 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) 40

41. 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 ? 41

42. 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 42

43. 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: 43

44. EXERCISE-INDUCED HYPOXEMIA
MORE HYPOXEMIA O2
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) 44

45. 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
We tested the hypothesis that, in elite human athletes, the high capillary pressure that occurs during severe exercise alters the structure and function of the blood-gas barrier. We performed bronchoalveolar lavage (BAL) in six healthy athletes, who had a history suggestive of lung bleeding, 1 h after a 7-min cycling race simulation and four normal sedentary control subjects who did not exercise before BAL. The athletes had higher (p < 0.05) concentrations of red blood cells (0.51 x 10(5) versus 0.01 x 10(5).ml-1), total protein (128.0 versus micrograms/ml), albumin (65.6 versus 53.0 micrograms/ml), and leukotriene B4 (LTB4) (243 versus 0 pg/ml) in BAL fluid than control subjects. The proportion of neutrophils was similar in athletes and control subjects but the proportion of lymphocytes in BAL fluid was reduced (p < 0.05). There were no differences in levels of surfactant apoprotein A, tumor necrosis factor bioactivity, lipopolysaccharide, or interleukin-8 (IL-8) between groups. These results show that brief intense exercise in athletes with a history suggestive of lung bleeding alters blood-gas barrier function resulting in higher concentrations of red cells and protein in BAL fluid. The lack of activation of proinflammatory pathways (except LTB4) in the airspaces supports the hypothesis that the mechanism for altered blood- gas barrier function is mechanical stress. 45

46. 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 46

47. 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)
Twenty years ago, pioneering studies by Matthay et al. (3) revealed that alveolar fluid resorption in adult animals was not affected by manipulating Starling forces but via active transport of sodium (Na+) from the alveolar airspaces, across the alveolar epithelium, and into the pulmonary circulation. This creates an osmotic gradient that is responsible for the clearance of lung edema from the alveolar spaces (4–6). As depicted in Figure 1, Na+ uptake occurs on the apical surface of alveolar epithelial cells (AECs), predominantly through amiloride- sensitive Na+ channels (6, 7). (Amiloride is a specific Na+ channel inhibitor.) Subsequently, Na+ is actively extruded from the basolateral surface into the lung interstitium by the sodium potassium-adenosine triphosphatase (Na,K-ATPase); water follows because of the osmotic gradient (2, 8, 9). Experiments in human lungs, in situ animal models, and isolated rat lungs have demonstrated that lung liquid clearance is prevented by hypothermia—probably by inhibition of active metabolic processes for solute transport (10)—and inhibited by both amiloride and ouabain, a Na,K-ATPase inhibitor (8, 11, 12).
The Na,K-ATPase is a plasma membrane enzyme that maintains electrochemical Na+ and K+ gradients across the plasma membrane by pumping Na+ out of the cell and K+ into the cell against their respective concentration gradients in an adenosine 5'-triphosphate-dependent process. 47

48. 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.

49. 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 49

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

51. Hepatic Insufficiency
Medication
Renal Insufficiency
Hepatic Insufficiency
Pregnancy
Other Issues
Acetazolamide
Avoid if GFR <10 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
May increase FBS in diabetics; avoid in PUD or GO-bleed risk patients
Nifedipine
Best to avoid; if use necessary, 10 mg B.I.D.
Caution PUD or GO-bleed risk or gastroesoph varices patients
Tadalafil
5mg if GFR mL/min. Max 10 mg; <5 if GFR < 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
Salmeterol
Insufficient data; best to avoid
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:

52. 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
Sildenafil
Salmeterol
Avoid chloroquine due to increased risk of QT- interval prolongation and ventricular arrhythmia. Other agents safe to use
Luks and Swenson, Chest, 2008; 133:

53. 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 53

54. 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

55. 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

56. 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. 1997;155(3):
West JB et al. Pathogenesis of high-altitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J. 1995;8(4):523-9.
Schoene. Unraveling the mechanism of high altitude pulmonary edema. High Alt Med Biol. 2004;5(2):
West, JB. The Physiologic Basis of High Altitude Diseases. Annals Intern Med, 2004, 141:
Luks and Swenson, Chest, 2008; 133:
Martin, et al. Variattion in human performance in the hypoxi mountain environment. Exp Physiol, 2010; 953: 56