EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA
Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCPAgatep 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
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
DO WE NEED TO KNOW HIGH ALTITUDE DISEASE?
Up to 2004, Himalayan database showed that:
• Mt. Everest summit was reached 2251 times• 130 of these ascents were without supplemental oxygen
Can anyone climb Mt. Everest?
Who really was the first Filipino to reachthe 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• 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)
2085PalawanMt. Mantaling
2117PanayMt. Madiaas
2430NegrosKanlaon Mountain
2938MindanaoMt. Katanglad
2462LuzonMayon Volcano
2582MindoroMt. Halcon
2922LuzonMt. Pulog
2954mMindanaoMt. Apo
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 PERCENTNITROGEN 78.08
OXYGEN 20.95
ARGON 0.94
CARBON DIOXIDE 0.03
HYDROGEN 0.01
NEON 0.0018
HELIUM 0.0005
Atmospheric Pressure Atmospheric Pressure declines with altitudedeclines with altitude
Sea levelSea level: 1 atm = 14.7 lbs/inch: 1 atm = 14.7 lbs/inch2 2 (psi)(psi)18,000 ft (5,486 m18,000 ft (5,486 m): 0.5 atm = 7.35 psi): 0.5 atm = 7.35 psi
2954 m Mt. Apo
Pressure reduced to 1/2 atm
1 atm increase every ~10 m
0.1 atm reduction every 1km
Sea Level = 1 atm
13 atm
370 atm -3700 m average depth of oceans
1086 atm -10860 m Mariana Trench
-130 m
- 8863 m Mount Everest
- 4860 m Human Settlement, Tibet
Reduction in Pressure
And O2
Increase in PressureAnd Gas Solubility
Atmosphere
Hydrosphere
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
Pressure differences are enormous, leading to differences in oxygen supply for air-breathers
Mt. Apo
Baguio City
Adaptations to high altitude
High altitude mammals: More pigment in bloodHigh 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 Adaptation vs Acclimation/Acclimatization
1) Short Term Acclimation1) Short Term AcclimationMountain climbers who are able to maintain normal Mountain climbers who are able to maintain normal
blood pH at low oxygenblood pH at low oxygen
2) Developmental Acclimation2) Developmental AcclimationA person reared at high altitude: larger lung volumeA person reared at high altitude: larger lung volumeHigher concentration of red blood cellsHigher concentration of red blood cells
3) Adaptation3) AdaptationLlamas: Blood with high Oxygen affinities Llamas: Blood with high Oxygen affinities
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: High Altitude: HumansHumans
• Highest permanent settlement: 5000m mining camp in Andes
RESPONSE TO LOW ORESPONSE TO LOW O22::
• 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)
• 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
ACCLIMATIZATION
High Altitude: HumansHigh Altitude: Humans
• HyperventilationHyperventilation (negative feedback) (negative feedback)
(1) In response to low O(1) In response to low O22, ventilation increases , ventilation increases
(2) But then this reduces (2) But then this reduces PPCOCO22
(3) pH increases, reducing normal stimulation in (3) pH increases, reducing normal stimulation in the respiratory centerthe respiratory center
(4) Reduces ventilation(4) Reduces ventilation
(5) Decrease oxygen supply(5) Decrease oxygen supply
(6) More increased ventilation to gain O(6) More increased ventilation to gain O22
• HypoxiaHypoxia:: Brain damage after 4-6 minutes of oxygen Brain damage after 4-6 minutes of oxygen deprivationdeprivation
Heart and Pulmonary Circulation at High Altitude
Penaloza, D and vier Arias-Stella J. Circulation. 2007;115:1132-1146.)
• Hypoxic ventilatory response = VE
• Starts within the 1st few hours of exposure 1500m
• Mechanism
VENTILATORY ACCLIMATIZATION
Ascent to altitude
Hypoxia
Carotid body stimulation
Respiratory centres stimulation
Increased ventilation
Improved hypoxia
Decreased PCO2
CO2 + H2O H2CO3 HCO3- + H+
• 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
ADJUSMENT OF RESPIRATORY ALKALOSIS
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
• DefinitionProcess 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
West et al., 1983
CONSEQUENCE O2 DIFFUSION
arterial O2 saturation
Wagner et al, Mt. Everest II project,1995
• 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
VA/Q HETEROGENEITY
• At high altitude– interstitial edema heterogeneity +++
VA/Q HETEROGENEITY
O2
• At rest
- 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.)
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
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
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 – High altitude cerebral edema
• All these syndromes have – several features in common – respond to descent or oxygen
potentially lethal form of AMS
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
• 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
• The stress failure theory (West et Mathieu-Costello, 1998, 99)Alveolar hypoxia
capillary pressure (some capillaries)
Hypoxic pulmonary vasoconstriction (uneven)
Damage to capillary wall (stress failure)
EDEMAExposed basement
membrane
Inflammatory mediators
VA/Q heterogeneity
West, JB. Annals Intern Med, 2004, 141:789-900
EXERCISE-INDUCED HYPOXEMIA
Alveolar hypoxia
capillary pressure (some capillaries)
Hypoxic pulmonary vasoconstriction (uneven)
Damage to capillary wall (stress failure)
EDEMAExposed basement
membrane
Inflammatory mediators
VA/Q heterogeneity
EXERCISE +/-
MORE HYPOXEMIAO2 results in about ½ endurance
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
• 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
West et al., 1995
Costello et al., 1992
Full break of the blood-gas barrier
Circular break of the epithelium
Red cell moving out of the capillary lumen (c) into an alveolus (a)
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 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
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 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
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
• 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
SummarySummary
• 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
SummarySummary
RECOMMENDED REFERENCESBOOK• Ward et al. High altitude medicine and physiology. 3rd edition.
Arnold. 2000ARTICLES
• 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
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