American Heart Journal October, 1965, Volume 70, Number J-

Editorial

High-altitude pulmonary edema

Inder Sin& M.B. (Rangoon), F.R.C.P.E., F.R.C.P. (Glasg.), F.A.M.S.* New Delhi, India

U ntil 1960, when Houstoni recorded his case in the English literature,

high-altitude pulmonary edema was lit- tle known outside the Peruvian Andes. Hurtado, however, first reported it in 1937, in a South American Indian who became acutely ill after returning from sea level during one of his several trips between Casapalca at 13,665 feet and Lima. Since then, 83 cases in all have been reported by Lundberg,3 Lizarraga,4 Bardalez,5 Alza- nlora-Castro,6 Hultgren and associates,7-y Stewart,‘O and Fred and associates.11 The Himalayan fighting of 1963 brought this disorder to India,12 and more than 450 cases have been recorded.

Predisposing causes

Probably no age is exempt. ;\‘Iany of the cases previously recorded were in children and young adults, and the oldest patient was 42 years of age. The Indian cases were in men between 18 and 53 years of age.

Local residents and plainsmen who have stayed at an altitude above 11,000 feet for more than 8 months are not prone to attacks of high-altitude pulmonary edema. But if they return to high altitude after staying a few days at lea level, they are unusually susceptible to it. After they have stayed away at sea level for 6 to 12 months,

the increased susceptibility disappears. They are then only as prone as the un- acclimatized plainsmen to develop high- altitude pulmonary edema.

The vulnerable altitude varies from country to country and apparently depends on the snow line. It is about 8,000 feet in the continental United States, 11,000 feet in the Himalayas, and 12,000 feet in the Peruvian Andes.

An individual’s chances of developing pulmonary edema diminish rapidly after the third day of his arrival at high altitude and become remote after the tenth day. Reinductees are prone to develop it earlier than others. The time lag between arrival and onset in such cases in the Peruvian Andes was 9 to 36 hours.

Rapidity of arrival from a low to a higher altitude predisposes one to high- altitude pulmonary edema. It is not un- usual to see pulmonary edema develop in an individual who has traveled by air. A less fast journey but one associated with physical exertion may do likewise. Pul- monary edema is not entirely confined to individuals moving beyond the vulnerable heights. Some cases may occur in persons on the way down from a high to a lower altitude. In such individuals, and in those who develop pulmonary edema after more

Received for publication April 12. 1965. *Address: Office of the Director General, Armed Forces Medical Services, Ministry of Defence. D.H.Q.P.O., New

Delhi 11, India.

435

t ban a IO-da). stal, at high altitude, ph;si- WI exertion and exposure to cold are un- portant contributing causes. In some indi- viduals, hoLyever, the protective reserve is OIll\~ marginal, and pulmonary edema develops even at rest. In fresh inductees, severe physical exertion on arrival at high altitude makes them as susceptible to high-altitude pulmonary edema as the reinductees, and the incidence in both is then the same.

Clinical features

Characteristically, high-altitude pulmo- nary edema begins with progressive cough and dyspnea. Cyanosis appears on the face and extremities, and Ales are heard in the chest. There is no symmetry about the Ales. They first appear on one or both sides in the interscapular area and spread to the upper zones. Both pulse and respiratory rates are increased. Tachycardia, however, is comparatively milder than dyspnea. In the early stages the lung bases are usuall~~ spared and the patient responds rapid])- to oxygen therapy or evacuation to altitudes below 4,500 feet.

In fulminating cases the patient feels choked, and wheezes are heard all around. I Ie rapidly becomes moribund, and hemor- rhagic pleural effusions ma)’ occur on one or both sides before death.

The onset may be less spectacular. In an individual afflicted with acute mountain sickness, increasing malaise, dyspnea, or a dq- cough are indications of impending pulmonary edema. In some cases, pre- monitory malaise, weakness, pain in the calf muscles, headache, insomnia, anxiety, an d excitement are followed by dyspnea and dry cough, with or without palpita- tion, before a full-fledged picture of pul- monary edema becomes manifest. Dyspnea at night, at rest, on slight exertion for 1 to 3 days during w:hich the man continues to be active, may appear to be insignifi- cant until pulmonary edema truly sets in. There ma)- be frequency of micturition and oliguria.

Sometimes, cerebral symptoms dominate the picture. Giddiness, hallucinations, and lack of interest in surroundings lead to unconsciousness and pulmonary manifesta- tions within a day or two.

LYhen the course is prolonged to 3 or 4

da>rs or more, clinical evidence of right ven- tricular failure, such as distended neck VcYllS, enlarged and tender liver, and peripheral edema, may be found.

Early interscapular involvement and spread to the upper zones and absence of toxemia distinguish pulmonaq~ edema from infection of the lungs. High fever, leuko- cytosis, and increased blood sedimentation rate are usually absent. :\loderate fever and leukocytosis occur puri pnss~ \\,ith pulmonary edema and run the same course hvhen the individual is treated \vith oxygen or evacuated to sea level. No antibiotics are required, unless infection becomes superadded.

Chest x-ray films show pulmonaq. densi- ties, usually first confined to the middle and upper zones, more predominant on the right than on the left side. In cases of slo\v onset, interlobal septal lines, indicative of interstitial edema, ma>. be seen. 111

severe cases, especially when prolonged over 2 or 3 days, all zones ma), be involved, and there may be pleura1 effusion on one or both sides. In addition, there is fullness of the hilar blood vessels, and the pul- monary artery is often, and sometimes grossly, enlarged. The rest of the configura- tion of the heart is not changed, unless there is associated right ventricular fail- ure, in Lvhich case it becomes globular. On evacuation of the patient to sea level, the pulmonary densities disappear in 6 to 48 hours but regression of the pul- monary artery may take 2 to 6 weeks.

The electrocardiograms show evidence of right axis deviation, clockwise rotation, T inverstion in Leads Vl-\‘s/‘Vi, prominent R in Leads aVR, VI, and \‘:,R/VqR, and peaked P in severe cases. One or more of these changes may be present in milder cases. Evidence of myocardial ischemia without injury may be present in limb leads. JIost of these changes reflect the degree of pulmonaqr hypertension, con- comitantly present with pulmonary edema, and, like the radiologic findings, take 2 to 6 Lveeks to disappear. As the inverted ‘I naves revert, they ma~r become abnormalI> high in most of the V leads and remain so for some time before becoming normal.

In hemodynamic studies of convales- cents, the pulmonary blood volume is found to be increasedI and remains so for 3 to 24

lveeks after evacuation of the patient to sea level.

Necropsy findings

The macroscopic findings are charac- teristic of pulmonary edema, comparable in distribution with the cIinica1 or radiologic findings. The right side of the heart is distended with blood, and the left side is empty. All viscera are congested.

RIicroscopically, there is enormous dis- tention of the pulmonary blood vessels as far as the capillaries. Scattered foci of hemorrhages are seen in the alveoli, as well as in the pleura. A remarkable feature is the extensive plugging of alveolar capil- laries with sludged red blood cells. These plugs of sludged red blood cells are also seen in some of the thin-walled veins. There is fibrinous exudate in the alveoli, some of which may be lined by a hyaline membrane akin to that seen in hyaline membrane disease. There are focal areas of atelectasis, and it is noteworthy that maximum capil- lary sludging is seen in these foci. With the PTAH stain,14 homogeneous or indis- tinctly laminated hyaline thrombi are seen in alveolar capillaries and some branches of the pulmonary artery. Similar fibrin thrombi are found in the kidney, plugging the glomerular and peritubular arteries, and also in the sinusoids of the liver.

Pathogenesis

Hemodynamic studies made within 12 to 72 hours of the episode in 5 cases have not revealed any evidence of left ventricular failure in high-altitude pulmonary edema. The left atria1 and the pulmonary venous pressures were normal.gJ1 Therefore, for pulmonary edema to be precipitated, hypoxic vasoconstriction must occur pri- marily or predominantly at the pulmonary venular level. Pulmonary edema would then be confined to areas of increased capillary pressure where the abundant transudate overloads the pulmonary lym- phatics and escapes into the alveoli: hence, the patchy densities seen in chest x-ray films. In experimental subjects there is a preferential lower-zone vasoconstric- tion of greater or lesser magnitude in re- sponse to induced alveolar hypoxia.‘” In the remaining zones the blood flow is increased. The patchy densities noted

radiologically in high-altitude pulmonary. edema are identical in distribution and intensity to the increased areas of blood flow noted in these experiments.

The underlying mechanism of these vas- cular changes is not clear. But any explana- tion must take into account the fact that pulmonary edema does not occur immed- iately on arrival at high altitude, but only, after a delay of several hours. This rules out the direct effect of hypoxia, or its indirect effect via the aortic and carotid reflexes, on the pulmonary circulation. It is interesting to note that lesions in the preoptic region result in lung hemorrhage and edema only after 1 to 24 hours.16 It is possible that the effects of hypoxia in high-altitude pulmonary edema are mediated via the hypothalamus. If this should be the case, there will then be con- striction of the venous reservoirs, and an excess volume of blood will be dumped into the pulmonary circuit, and pulmonary- edema may occur.

The hypothalamus may be triggered into action by low arterial oxygen saturation or by constriction of cerebral blood vessels induced by a low CO2 partial pressure (PCO2). There is, however, a third possi- bility. The fact that the majority of individuals with high-altitude pulmonary edema also suffer from acute mountain sickness may be significant. Symptoms of acute mountain sickness are aggravated by orally administered sodium bicarbo- naten and appear to be due to respiratory alkalosis. Alkalosis induced by hyperventi- lation continues to increase in the early stages of acclimatization” and persists for weeks and months before renal excretion of bicarbonate eventually restores the blood pH to norma1.‘8-2’ Alkalosis makes hemoglobin desaturation more difficult and tends to promote tissue anoxia,“? which may not only adversely affect the hy.- pothalamic mechanism but also predispose locally to pulmonary venous spasm, This may well account for the predisposition to pulmonary edema not earlier than 9 hours after arrival at high altitude and during the subsequent stay of several weeks ;it high altitude.

When acclimatized individuals move to sea level, there is a considerable destruction of red blond cells within 3 or 4 d;i?~ I,II~

438 Sing12

the plasma volume increases at the same time.7 Arrival at high altitude is followed within a day by a decrease in plasma volume.?” Before an adequate decrease occurs, however, the reinductee is high11 susceptible to pulmonarv edema within the first few hours of arrival at high alti- tude.

Physical exertion, particularly in snow, precipitates pulmonary edema by increas- ing the flow of blood and the activity of the right ventricle, and by aggravating hypoxia with all of its consequent!>, adverse effects at various levels.

In the Peruvian Andes, the incidence of pultnonary edema is high during the month of January, when the weather is especial!) favorable for the formation of ozone. ‘4nd concentrations of ozone which are not in themselves sufficient to produce irritation and edema of the lungs diminish the uptake of oxygen.“4 This and other local environ- mental factors, such as hydrogen sulfide, and heated or very cold air, may possibly account for restricted pockets of high- altitude pulmonary edema at almost identi- cal altitudes.

Several factors may be responsible for the associated pulmonary hypertension. Passive pulmonary hypertension is near!> always present, resulting from increased capillary pressure. Active pulmonary hJ~- pertension may occur as the result of powerful reflex vasoconstriction of the arterioles and venules due to hypoxic stimulation of the carotid and aortic bodies.25 The effect may be facilitated b> increased sensitivity of the single muscle cells present in the walls of the arterioles and venulesZ6 to low oxygen tensions, b, local release of catecholamines,27 and prob- ably by failure of the hypoxic lung to in- activate serotonin.

The persistence of pulmonary hyper- tension for weeks after pulmonary edema has subsided is an indication, however, that the changes induced in the pulmonary circulation are not entirely functional. The sludging of cells and the fibrin thrombi in the alveolar capillaries and venules add an organic element to the picture. These findings suggest that exposure to hypoxic stress causes a breakdown of the fibrino- lytic enzyme system, and the equilibrium

hetlveen fibrin formation and dissolution is upset.

Treatment

The vast majority of individuals afflicted with pulmonary edema respond either to oxygen therapy given locally or to evacua- tion to sea level. This happens in spite of the fact that inhalation of 100 per cent oxygen by the BLB mask may not correct completely the arterial hemoglobin de- saturation even in healthy individualszY The response, if it is to occur, is always quick. Lack of response nlav be due either to functional hypoventilation or to the presence of organic changes, such as ob- struction of blood vessels, atelectasis, and alveolar fibrin membranes. On acute ex- posure of the patient to louver ambient oxygen tension the carotid and aortic chemorereptors are stimulated and ve11- tilation is increased. The resulting fall in I’COZ, however, depresses the pH of the cerebrospinal fluid, which, in turn, reduces the neural activity of the medullarq, respira- tor). pII receptors. The effect of carotid and aortic chetnoreceptor stimulation is, therefore, partially neutralized ; and, as long as the pH of the cerebrospinal fluid is not restored to normal, an increase in ventilation does not occur to the full ex- tent.29 In addition, alkalosis decreases the intensity of the anoxic stimulus of the carotid and aortic chemoreceptors. When functional hypoventilation is present due to the altered cerebrospinal fluid pII, oxygen administered by intermittent posi- tive pressure respiration is helpful. \h’hen, however, organic changes ;tre present, hyperbaric oxygen is possibly- needed.

Patients suffering from high-altitude pulmonary edema tolerate morphine \\,ell, and it can be used with impunit>- to alla> anxiet>- and restlessness. Alan>, patients make remarkable improvement after its use. The beneficial effect of morphine ap pears to be due to a redistribution of blood to the periphery. The pulmonary blood volume is thereby loweredI and pulmonary edema is relieved. Atropine, aminophylline, and digoxin, which normall\- lower the central venous pressure, are probably useful adjuvants.

Keinductees with increased blood vol-

High-altitude pulmonary edemn 439

ume who develop high-altitude pulmonary edema during the first 3 days of arrival before the blood volume begins to fall may benefit from rapidly acting diuretics, such as Frusemide or ethacrynic acid.

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17. Nielsen, M., and Smith, H.: Studies on regula- tion of respiration in acute hypoxia. With ap- pendix on respiratory control during prolonged hypoxia, Acta Physiol. Scandinav. 24:293, 19.52.

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