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
• 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
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
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
Who really was the first Filipino to reach
the summit of Mt. Everest?
•Leo Oracion
•Erwin Emata
•Romy Garduce
•Dale Abenojar
HOW HIGH IS HIGH-ALTITUDE ?
•
•
••
High altitude: 1500-3000m above sea level
Very high altitude: 3000-5000m
For sea altitude:
level visitors,
Extreme
above 5000m
Andes
4600-4900m =
(6962m)
highest acceptable
level for permanent
habitation
Tibetan plateau
& Himalayan
valleys (8848m)
• For high altitude
residents, 58006000m = highest so
far recorded
Ethiopian highlands (4620m)
Mt. Apo
Mindanao
2954m
Mt. Pulog
Luzon
2922
Mt. Halcon
Mindoro
2582
Mayon
Luzon
Volcano
Mt. Katanglad Mindanao
2462
Kanlaon
Mountain
Mt. Madiaas
Negros
2430
Panay
2117
Mt. Mantaling Palawan
2938
2085
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
External Respiration
Atmospheric composition at sea
level
GAS
NITROGEN
OXYGEN
ARGON
CARBON DIOXIDE
HYDROGEN
NEON
HELIUM
PERCENT
78.08
20.95
0.94
0.03
0.01
0.0018
0.0005
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
Atmosphere
Reduction
in Pressure
And O2
- 8863 m Mount Everest
Pressure reduced
to 1/2 atm
0.1 atm reduction every 1km
- 4860 m Human
Settlement, Tibet
2954 m Mt. Apo
Sea Level = 1 atm
Hydrosphere
Increase in
Pressure
And Gas
Solubility
13 atm
370 atm
-130 m
-3700 m average
depth of oceans
1 atm increase every ~10 m
1086 atm
-10860 m Mariana Trench
Baguio City
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Pressure differences are
enormous, leading to
differences in oxygen supply for
air-breathers
Mt. Apo
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
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
Adaptation vs Acclimation/Acclimatization
1) Short Term Acclimation
Mountain climbers who are able to maintain normal
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
blood
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
High Altitude:
Humans
• Highest permanent settlement: 5000m mining camp
in Andes
RESPONSE TO LOW O2:
• Hyperventilation leading to low PCO2
• Chronic Hypoxia
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)
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
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
Heart and Pulmonary Circulation at
High Altitude
Penaloza, D and vier Arias-Stella J. Circulation. 2007;115:1132-1146.)
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
Respiratory centres stimulation
Increased ventilation
CO2 + H2O H2CO3 HCO3- + H+
Improved hypoxia
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
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
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
CONSEQUENCE  O2 DIFFUSION
 arterial O2 saturation
West et al., 1983
Wagner et al, Mt. Everest II project,1995
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 overventilation or under-perfusion
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
Penaloza, D and vier Arias-Stella J. Circulation. 2007;115:1132-1146.)
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
0.47+0.20
0.56
1.79+0.14
1.66
40-49
45
0.49+0.09
1.05
1.40+0.52
2.20
50-59
55
0.48+0.08
1,22
1.53+0.26
2.87
60-69
65
0.46+0.04
1.97
1.10+0.52
3.44
70-79
75
0.44+0.10
2.72
0.84+0.58
3.96
Balgos A, Willford D, West JB. J Appl Physiol, 65(4): 1686-1692, 1988
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
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
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
WHEN ACCLIMATIZATION FAILS
• Altitude syndromes
– Acute mountain sickness (AMS): the least-threatening
and most common
– High altitude pulmonary edema
potentially lethal
form of AMS
– High altitude cerebral edema
• All these syndromes have
– several features in common
– respond to descent or oxygen
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
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
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)
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 ?
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
HYPOXIC PULMONARY
VASOCONSTRICTION
hypoxia
• The stress failure Alveolar
theory (West
et Mathieu-Costello, 1998, 99)
Hypoxic pulmonary vasoconstriction (uneven)
VA/Q heterogeneity
 capillary pressure (some
capillaries)
Damage to capillary wall (stress failure)
EDEMA
Exposed basement
membrane
Inflammatory mediators
West, JB. Annals Intern Med, 2004, 141:789-900
EXERCISE-INDUCED
HYPOXEMIA
EXERCISE
+/-
Alveolar hypoxia
Hypoxic pulmonary vasoconstriction (uneven)
VA/Q heterogeneity
 capillary pressure (some
capillaries)
Damage to capillary wall (stress failure)
EDEMA
Exposed basement
membrane
Inflammatory mediators
O2
in about ½ endurance
MORE HYPOXEMIAresults
athletes (Powers et al., 1988)
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
> control subjects at rest
• 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
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
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)
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.
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
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
Medication
Acetazolamide
Renal
Insufficiency
Avoid if GFR <10
Hepatic
Insufficiency
Pregnancy
Other Issues
Contraindicated
Category C
Avoid if w/ concurrent longterm aspirin; cuation with sulfa
allergy; avoid concurrent Kwasting diuretics and
ophthalmjic CAI
mL/min, metab
acidosis, hypoK,
hypercalcemia, &
hyperphosphatemia
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; <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
Same dose adj as
Tadalafil
Decrease dose;
start with 25 mg;
avoid use if with g-e
varices
Category B
No C.I.; No dose
adjustments
Insufficient data;
best to avoid
Category C
Sildenafil
Salmeterol
with other meds affecting
cP450; avoid concurrent
nitrates and B-blockers
Incr. Risk of GERD; caution
with other meds affecting
cP450; avoid concurrent
nitrates and B-blockers
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
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
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
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
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
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):1090-4.
• 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):125-35.
•
West, JB. The Physiologic Basis of High Altitude Diseases. Annals Intern
Med, 2004, 141:789-900
•
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