High-altitude pulmonary edema: Pathophysiology and clinical review

SPECIAL CONTRIBUTION edema, pulmonary, high altitude

High-Altitude Pulmonary Edema: Pathophysiology and Clinical Review

High-altitude pulmonary edema (HAPE) affects young, healthy climbers in an unpredictable fashion. It is potentially fatal, and its underlying pathophysiology is not thoroughly understood. The history and clinlcal presentation of HAPE, as Well as the known underlying pathophysiology, are reviewed. For instance, in HAPE there is an association with blunted respiratory drives to hypoxia and accentuated hypoxic pulmonary vasoconstriction. Recent data show that HAPE is a high permeability leak of protein into the alveolar space associated with an influx of alveolar macrophages. These data have been obtained recently by fiberoptic bronchoscopy iI~ the field setting Of Mt McKinley at 4,400 m. The approach to recognition and treatment that involves primarily descent and~or oxygen is discussed. [Schoene RB: High-altitude pulmonary edema: Pathophysiology and clinical review. Ann Emerg Med September 1987;16:987-992.]

I N T R O D U C T I O N High-altitude pulmonary edema (HAPE) occurs in 1% to 2% of climbers

who a t tempt to cl imb Mt McKinley (6,192 m). Climbers ascend from sea level at varying rates over one to four weeks. Prior to 1982, a number of deaths resulted from HAPE; but since that t ime, there have been no reported deaths from HAPE or other al t i tude illnesses on Mt McKinleY. The incidence of the disorder has not decreased, but the remarkable fact that there have been no recent fatalities can be at tr ibuted to increased awareness and recognition of the disease, as well as the presence of the Denali Medical Research Hut at 4,400 m on the West Buttress route. This facili ty has been instrumen- tal in diagnosing, treating, and advising al t i tude illness vic t ims (Figure 1).

There are still many reported deaths from HAPE from mounta in ranges around the world; and almost all of them could have been avoided by recognition of the early signs and Symptoms of HAPE. This t reatable disease, which affects young heal thy climbers, skiers, and trekkers, need not be fatal. This article reviews the history, clinical presentation, pathophysiolog34, and treatment of HAPE.

HISTORY HAPE was ne t recognized as an al t i tude il lness per se for many centuries.

The earliest; best description was by Ravenhill, a medical officer for a mining company in the Andes.] In 1913, he described three individuals wi th severe cardiopulmonary symptoms; two died and the third recovered on descent. Most of the symptoms were compatible wi th either congestive heart failure "of high alt i tude" and/or pneumonia and were treated as such, despite the fact that most of the vic t ims were young and heal thy individuals. It was not until the 1960s that HAPE became recognized as a noncardiogenic form of pulmonary edema clearly re la ted to acute exposure to high al t i tude. Dr Charles Houston reported the first case of HAPE in the English l i terature in a cross-country skier. 2 Work by Hultgren and others clearly defined HAPE as a clinical en t i ty related to h igh-al t i tude exposure and not due to cardiac failure.3, 4 Several excellent reviews are available.S,6

CLINICAL PRESENTATION HAPE generally occurs in the setting of rapid ascent to 3,000 to 4,000 m.

Most of the vic t ims are young and physical ly active. Illness is most common

Robert B Schoene, MD Seattle, Washington

From the Pulmonary Function and Exercise Laboratory, Harborview Medical Center, Seattle, Washington.

Received for publication February 23, 1987. Revision received April 22, 1987. Accepted for publication May 4, 1987.

Presented at the UAEM/IRIEM Research Symposium on Environmental Emergencies in Clearwater Beach, Florida, February 1987.

Address for reprints: Robert B Schoene, MD, Pulmonary Function Laboratory, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104.

16:9 September 1987 Annals of Emergency Medicine 987/99

PULMONARY EDEMA Schoene

FIGURE 1. The Denali Medical Re- search Project high-altitude research station at 4,400 m on Mt McKinley, where studies on high-altitude illnesses have taken place since 1982. Mt Foraker is in the background.

within the first two to four days of ascent, but there are an increas ing number of reports of HAPE having occurred at very high altitudes (more than 6,000 m) after the individual had been previously acclimatized to lower altitudes. This change in pattern of presentation may be secondary to the inc reas ing n u m b e r of aggress ive climbers who are a t tempting rapid "alpine" ascents of high peal<s.

Fatigue, dyspnea at rest, marked decrease in exerc i se to le rance , dry cough, and difficulty sleeping are early symptoms of the disease. They may be preceded by symptoms of acute mounta in sickness, including head- ache and anorexia. If the individual rests at this point in the ascent, symptoms may decrease or abate in one to three days and the individual may be able to ascend further However, the symptoms may progress to severe dyspnea at rest, cough with pink and frothy sputum, orthopnea, confusion, lethargy, ataxia, and coma. These later symptoms may be secondary to high altitude cerebral edema {HACE) and/or worsening hypoxemia. If the symptoms progress to this stage and are not recognized and treated, death soon fol- lows.

The physical examination usually reveals a slightly confused, dyspneic patient with a low-grade fever, cya- nosis, tachycardia, and tachypnea. Rales or "crackles" on chest ausculta- tion often begin in the area of the right middle lobe, but usually spread diffusely.

Chest radiograph shows a normal cardiac silhouette with diffuse patchy infiltrates in both lung fields (Figure 2). The ECG may demonstrate only sinus tachycardia or may possibly in- dicate right heart strain. Pulmonary function tests show decreased vital ca- pacity and peak expiratory flow rates. Insight into the mechanism of these findings emanates from earlier studies, which have shown that even in asymptomatic sojourners to high altitude, pulmonary dysfunction compatible with interstit ial lung water may be present.7-n If this dysfunction does not resolve, then worsening of

TABLE. Bronchoalveolar lavage at high altitude

Total WBC (x105/mL)

Polymorphonuclear leukocyte (%)

Alveolar macrophage (%)

Total protein (mg/dL)

Controls AMS n = 4 n = 4

0.7 + 0.6 0.9 -+ 0.4

2.8 +- 1.5 2.4 + 1.7

93.8 -+ 5.2 93.8 -+ 3.4

12.0 -+ 3.4 10.4 -+ 8.3

HAPE n = 8

3.5 _+ 2.0

25.4 _+ 20.0

67.4 _+ 28.1

616.0 + 329.1

gas exchange with evolving and overt alveolar edema may ensue.

PATHOPHYSIOLOGY Autopsy studies of victims of HAPE

are limited but show diffuse, patchy alveolar flooding with hyaline mem- branes and varying amounts of inflam- matory cells. Some autopsies show bronchopneumonia and fibrin deposi- tion in the pulmonary microvascula- ture. 12-'4 It is not clear how many of these changes were concomitant findings that may have predisposed the victims to death, or were perimortem changes.

The pathophysiologic events that lead to HAPE are not absolutely deter- mined. A schema for the underlying pathophysiologic events that lead to pulmonary edema at high altitude is shown (Figure 3). Failure to produce a reliable animal model of the disease

has made investigation quite difficult. The common underlying denomina-

tor of alti tude exposure is alveolar hypoxia secondary to the decreased barometric pressure at high altitude. This factor is present in all sojourners to altitude, but in some individuals it may trip a sequence of events that leads to an increase in lung water There are several features that may be permissive and contribute to the evo- lu t ion of HAPE. For ins tance , al- though alveolar hypoxia is common in all individuals at high altitude, there is wide variation in the response of ventilation, which is mediated largely by the carotid body. Persons who have a lower response and subsequently hy- poventilate have a lower alveolar partial pressure of oxygen and a higher partial pressure of carbon dioxide. Subsequently, the hypoxic pulmonary vascular response leads to an increase

100/988 Annals of Emergency Medicine 16:9 September 1987

FIGURE 2. Chest radiograph in a sub- ject with high-altitude pulmonary edema showing di'ffuse bilateral infiltrates and normal cardiac silhouette (courtesy Peter H Hackett, MD).

viduals who suffered or had previously suffered from HAPE. None of them demonstrated increased wedge pressures or evidence of left ventricular failure. Subsequent studies 26-29 suggested that individuals susceptible to HAPE had a disproportionately greater p u l m o n a r y vascu la r r e sponse to hypoxia than did controls. A study by Hackett et a130 added further evidence to the role of "shear forces" in the pulmonary vascular bed by documenting that individuals with congenital uni- lateral absence of the pulmonary artery developed HAPE at modest al- t i tudes . Therefore , the hypox ic pulmonary vasoconstrictive response may be one of the permissive, rather than causative, factors that lead to the development of HAPE.

in pulmonary artery pressure. The greater the degree of alveolar hypoxia, the greater the increase in pulmonary vascular response. Relative hypercapnia may inhibit normal diuresis that occurs on ascent to high altitude. Ex- ercise at high altitude leads to increased cardiac output, which further stresses a constricted pulmonary vascular bed. The pulmonary vasculature may then be subjected to "shear forces" that lead to loss of integrity of the endothelium to fluid and protein fluxes,

This s c h e m a is s u p p o r t e d by clinical evidence. Individuals who are more prone to altitude illnesses have a blunted vent i la tory response to hypoxia, la-17 Those with an intact or more brisk ven t i l a to ry response on ascent may minimize the alveolar hypoxia and subsequent hypoxic pulmonary vasoconstrictive response. A

recent study from Mt McKinley found that individuals with and after recov- ery from HAPE had extremely blunted ventilatory responses to hypoxia, 18 which predisposed these individuals to the development of HAPE. Ad- ditionally, a l though the data are not consistent, a number of studies show fluid retention on ascent to high al t i tude in individuals wi th both acute mounta in sickness and HAPE.13,t7,19-24 This fluid retention has been associated with relative hypercapnia and with a blunted ventilatory response on ascent.

The potential relationship between hypoxic pulmonary vasoconstriction and the development of HAPE are ele- gantly reviewed by Reeves et al, 22 Lockhard and Saiag, ~3 and Reeves and Grover.24 Investigations 25-27 have doc- umented an increased pulmonary vascular response to hypoxia in indi-

PROTEIN PERMEABILITY A number of theories have evolved

as to the mechanism and nature of the alveolar leak. One school suggested that HAPE represented hydrostatic leak, in which increased pulmonary vascular pressures from altitude and an increase in cardiac output caused increases in intravascular pressures. Therefore, low-protein fluid leaked as a transudate into the pulmonary inter- stitium and then into the alveolar air spaces. The other school thought that HAPE was a result of the loss of integrity of the pulmonary vasculature to fluid and protein. This so-called "per- meabil i ty leak" would produce alveolar fluid high in protein content.

A recent study by Schoene et al convincingly resolved the issue of whe ther HAPE is a permeabi l i ty leak.g1 In this and a subsequent study, 32 the authors performed bronchoalveolar lavage by fiberoptic bronchoscopy at a research laboratory at 4,400 m near the West Buttress of Nit McKinley. The fluid was analyzed for cells, protein, mediators of inflamma- tion, and vascular reactivity. The results demonstrated that the fluid was very high in protein content, even higher than in patients with adult respiratory distress syndrome (ARDS), and laden with cells, which were primarily alveolar macrophages (Table). The proteins were of very high mo- lecular weight; the biochemical medi-

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FIGURE 3. Possible schema of physiologic events leading to HAPE.

ators included markers of in f lamma- t i o n s u c h as c o m p l e m e n t (C5a) , leukotr iene B4, and markers of vascular react ivi ty such as thromboxane B 2. Al l of the subjects w i th severe HAPE recovered wi th oxygen therapy and descent. Six of the eight vic t ims r ecove red enough to c l i m b to the summi t wi th in ten to 14 days.

The findings of this s tudy strongly suggest tha t HAPE is a leak in the t rue p e r m e a b i l i t y sense. HAPE vic- t ims recover quickly, if treated, as gas exchange and card iopulmonary func- t ion return to normal in a relatively short period of time. This is dist inct ly different f rom pa t i en t s w i t h ARDS, w h o also have a h igh p e r m e a b i l i t y leak, but may require mon ths to recover integri ty of their pulmonary ar- chitecture. These findings suggest that the mechanisms and subsequent out- come between HAPE and ARDS are quite different.

RECOGNITION Excep t in e x t r a o r d i n a r y c i r c u m -

stances when weather or environmental cond i t ions forbid evacua t ion or descent , no person should die f rom HAPE. The signs and symptoms out- lined in the previous section offer the rescuer reasonable warning to recog- nize HAPE in its early stages. Climb- ers, trekkers, or adventurers who go to high al t i tude mus t be aware of the early clinical signs and symptoms. Inor- dinate shortness of breath and cough should make one suspect HAPE.

TREATMENT The bes t t he rapeu t i c s t ra tegy for

HAPE is prevention. Accl imat iza t ion to high al t i tude is a very complex pro- cess that requires patience. Slow, grad- ua l a c c l i m a t i z a t i o n shou ld p r even t most cases of HAPE. Above 3,000 m, gain in sleeping al t i tude should be no more than 300 m per day. Another al- ternative is to cl imb higher during the day, but return to a lower al t i tude to sleep at night . •Unfor tunate ly , w i t h easy access to high altitude, rapid ascent is t h e rule rather than the excep- tion.

Once the disease develops, the best t reatment is descent. Even a modest descent of 500 to 1,000 m may make the impor tant difference between im- p r o v e m e n t and dea th . However , in some situations, it is not possib!e to

102/990

Hypoxia +

Relative hypoventilation

Antidiuresis

1' Alveolar hypoxia +

1' Relative hypercapnia

/ I

L Overperfusion of pulmonary vasculature

Accentuated pulmonary hypertension

/

HAPE

descend. The alternatives become rest and/or supp lementa l oxygen, prefer- ably w i th a m a s k tha t a l lows con- t ro l led pos i t ive end-exp i r a to ry pressure. When available, oxygen is a very effective t reatment .

T h e c o n t i n u o u s p o s i t i v e a i r w a y pressure (CPAP) mask may stabi l ize the v i c t i m when evacua t ion or descent is not possible. The rationale for using the device in HAPE vict ims is based on the s imilar i ty of HAPE with o t h e r f o r m s of d i f fuse p u l m o n a r y e d e m a w i t h h y p o x e m i a in w h i c h pos i t i ve p r e s s u r e i m p r o v e s gas exchange.

An increase in end-expiratory pressure presumably opens atelectat ic al- veoli and improves vent i la t ion-perfusion match. Two studies33, 34 showed that the CPAP mask was effective in

Annals of Emergency Medicine

i m p r o v i n g v e n t i l a t i o n - p e r f u s i o n match and oxygenation in HAPE. The results of one study are shown (Figure 4). This technique should be regarded merely as a temporizing measure unti l evacuation or descent can be effected.

Because of the low inc idence" of HAPE and the r emo te loca t ions in which most cases occur, good studies of drug efficacy for prevention or treatment of HAPE are lacking. Acetazol- amide, which has been shown to be qu i t e e f fec t ive in p r e v e n t i n g acu te mounta in sickness, may be helpful in preventing HAPE, but there are not yet solid data to support this conten- tion. It is possible that acetazolamide, a r e sp i r a to ry s t imulan t and mi ld d i - uret ic , m a y be effect ive in t r ea t ing HAPE once i t is s t a r ted , bu t he re !again there are no data. Drugs such a s

16:9 September 1987

Oximeter Reading

(%)

65

60

55

50

3 0

PAC02 25 (torr) 20

15

14

13

(L/min, BTPS) I 2

I I

25

Respiratory 20 Rate

(breaths/min) 15 I0

q

2

Heart Rate (beats/min)

I10

I00

90

80

b

2

I I I

0 5 I0

CPAP (cm H20) 4

m o r p h i n e , f u r o s e m i d e , or n i t r o - glycerin have been proposed for treating HAPE. Their potent actions miti- gate agains t field use. D e x a m e t h a - sone, which is very effective in treating acute m o u n t a i n s ickness , may also be useful in preventing or treating HAPE, but no studies are yet available.

CLINICAL COMPARISON All forms of pulmonary edema re-

sult in gas exchange abnormal i t ies , primarily increased right-to-left intra-

16:9 September 1987

pulmonary shunt, which worsens hypoxemia. As permeability pulmonary edemas, HAPE, ARDS, and neuro- genic pu lmonary edema (NPE) have high protein contents in the alveolar fluid, with HAPE having the highest con ten t measured thus far.32, 33 The cellular response in the alveolar fluid varies widely. HAPE shows primarily alveolar macrophages, whi le ARDS has a great influx of neutrophils. 3~ It is not known whether the presence of these specific cell types plays a role in the development of HAPE, or whether

Annals of Emergency Medicine

FIGURE 4. Effec t o f C P A P on m e a - s u r e d v a r i a b l e s a t r e s t i n s u b j e c t s w i t h H A P E . N u m b e r u n d e r d a t a p o i n t s is n u m b e r of sub jec t s , a < P = .05 f r o m n o r m a i s ; b < P = .005 f r o m n o r m a l & c < P = .05 f r o m CPAP 0 c m H20.33

they are merely a response to the ini- tial injury. The high neutrophi l content in ARDS suggests an intense in- f l a m m a t o r y response , w h i c h m a y re su l t in d e s t r u c t i o n of l u n g par- enchyma. This theory fits the clinical observation that patients with HAPE recover quickly and fully, while vic- t ims of ARDS may take months to resolve, with residual pu lmonary dysfunction. In this respect, HAPE has characteristics similar to NPE, which appears and resolves quickly. Accentu- ated p u l m o n a r y hyper t ens ion mediated by elevated catecholamines may occur in NPE as well as in HAPE.

SUMMARY HAPE is a potentially fatal disease

that occurs in young and otherwise healthy people who ascend to high altitude. Recognition of the early signs and symptoms is the most important step to avoid catastrophe. Once HAPE has occurred, descent or oxygen is manda to ry to al leviate the adverse physiologic effects of hypoxia. Positive p ressure masks , w h i c h are l ight - weight and portable, may be an effective t empor iz ing measure un t i l descent can be undertaken.

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3. Hultgren HN, Grover RF, and Hartley LH: Abnormal circulatory responses to high altitude in subjects with a previous history of high altitude pulmonary edema. Circulation 1971; 44:759-770.

4. Hultgren HN: High altitude pulmonary edema, in Staub NC (ed): Lung Water and Sol- ute Exchange. New York, Marcel Dekker Pub- lishers, 1978, p 437-469.

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Clinical efficacy and effect on ventilation. JAMA 1982;248:328-332.

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19. Hackett PH: Mountain Sickness: Preven- tion, Recognition. and Treatment. New York, The American Alpine Club, 1978.

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pulmonary edema of altitude: Clinical and physiologic observations. Circulation 1962;25: 929-937.

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28. Hultgren HN, Lopez CE, Lundberg E, et al: Physiologic studies of pulmonary edema at high altitude. Circulation 1964;29:393-408.

29. Viswanathan R, Subramanian S, Radha TG: Effect of hypoxia on regional lung perfusion by scanning. Respiration 1979;37:142-147.

30. Hackett PH, Creagh CE, Graver RF, et al: High altitude pulmonary edema in persons without the right pulmonary artery. N Engl J Med 1980;302:1070-1073.

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32. Schoene RB, Swenson ER, Pizza C, et ah High altitude pulmonary edema: Comparison with other forms of lung injury. Am Rev Respir Dis 1986~133:A269.

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High-altitude pulmonary edema: Pathophysiology and clinical review