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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