High-Altitude Pulmonary Oedema

Original Editor - Kapil Narale

Top Contributors - Kapil Narale and Kim Jackson  

Introduction

High Altitude Pulmonary Oedema (HAPE) is the pulmonary form of high altitude illness. The primary factors that contribute to HAPE include altitude, speed and mode of ascent, and individual variability.

HAPE usually develops 2-5 days after a person ascends to altitudes above 2500-3000m. It hardly occurs at an altitude below 2500-3000m, and after 1 week of acclimatisation at a given altitude. As mentioned on the Acclimatisation page, this is considered 'moderate altitude', where mountain sickness can occur, and acclimatisation would be essential for athletic performance.

There are two different scenarios in which HAPE can occur. The first involves individuals who live at high altitude, and are returning from a journey at low altitude, while the second scenario involves individuals who live at low elevation or sea level and are rapidly ascending altitude.

The first type can be elicited with returning to HAPE conditions, and indicated as pulmonary oedema with electrocardiographic (ECG) signs of right-ventricular overload. This was reported in Peru. The type with unacclimatised individuals was reported in the Rocky Mountains. It is seen that both types may share the same pathophysiology.

Epidemiology

HAPE can occur in healthy individuals. It most commonly occurs in mountain climbers and trekkers, and can be experienced by 1 in every 2 climbers rapidly ascending >300m/day and reaching an altitude of higher than 4000m. Since it is a life-threatening condition, it is best to have individuals at risk identified, especially if it is their first time ascending altitude.

In this population, when the ascent to an altitude of 4559m, takes 3 or more days, the prevalence of HAPE is <0.2%. However, when an ascent to the same altitude is completed within 22 hours, the incidence increases to 7% in individuals without radiographically proven HAPE, and increases to 62% in individuals with radiographically proven HAPE. If there is a quick ascent in individuals who already are at risk of HAPE, the incidence rises to ~60%.

The incidence of HAPE also increases from 2.5-15.5% when an altitude of 5500m is ascended by airlift, rather than trekking, and having gradual exposure to changing conditions over 4-6 days.

HAPE can also occur at lower elevations ranging from 2500-3000m, which can be found in the Japanese Alps and North America. There is an estimated incidence of 0.01-0.1% in visitors of the ski resorts in the Rocky Mountains of Colorado. Re-entry HAPE (the first scenario) is seen to occur in the Rocky Mountains, which is also seen to occur in the Andes. It is common in vulnerable families, and commonly affects children. There is a <0.2% incidence of HAPE in an Alpine mountaineering population. Among trekkers in the Himalayas and in the Alps, the incidence of HAPE for climbers ascending about 600m/day is about 4%.

It is interesting to note that HAPE has been found to occur at Alpine resorts at elevations of 1400 to 2400m, which have areas for skiing up to 3200m. Individuals who my be more prone to HAPE at these elevations may have had previous or unknown underlying conditions. It is possible that affected individuals may have had diastolic heart failure rather than HAPE caused by hypertensive heart disease.

In addition, Women are seen to be more prone to HAPE than Men.

It is seen that HAPE has a lower rate of occurrence compared to AMS.

Risks

Low hypoxic ventilatory response can be correlated with a risk of HAPE, as reported in various studies. In addition, there is a correlation between the risk of HAPE and a reduced vital capacity or functional residual capacity.

Right Heart Catheter Studies

As noted in hemodynamic measurements, HAPE occurs following increased pulmonary pressure. It was found that mean pulmonary artery pressure increased to 38mmHg after a hemodynamic evaluation of HAPE prone individuals after a rapid ascent of 4559m within 24 hours. In individuals who developed pulmonary oedema, mean pulmonary artery pressure was 42mmHg.

However, these studies have shown that left ventricular filling pressure, right atrial pressure, and cardiac output, are normal. Therefore, a significant indicator of this condition is that the hemodynamic measurements in HAPE can signify the development of pulmonary hypertension subsequent to rapid exposure to high altitude. The use of pulmonary vasodilators can help prevent or treat HAPE.

Pathophysiology

It is known that HAPE is physiologically caused by an increased pulmonary hypoxic vasoconstriction, thus producing an abnormally high pulmonary artery pressure. The significance of the high pressure in individuals with HAPE can be denoted by increased pulmonary vasoconstrictive response in those at risk of HAPE at acute hypoxia, or with exercise in normal conditions.

Exaggerated Pulmonary Pressure

Cardiac catheterisation of untreated cases of HAPE at high altitude displayed mean pulmonary artery pressures of 60 mmHg (with a range of 33–117 mmHg), as it is seen that wedge pressures are normal. Systolic pulmonary artery pressure, estimated via ECG, displayed results between 50 and 80 mmHg for subjects with HAPE, and 30–50 mm Hg for healthy controls.

A marked increase in pulmonary artery pressure is important for the onset of HAPE. This pressure increase leads to the development of HAPE.

An example at Capanna Margherita (4559m), right heart catheterisation showed that the abnormal rise in pulmonary artery pressure in individuals who are prone to developing HAPE occur with a capillary pressure that is increased to above 20mmHg in individuals that develop HAPE. This helps explain that Pulmonary capillary hypertension is critical in the pathophysiology of HAPE.

High-Permeability type of Oedema

Broncho-alveolar lavage (BAL) carried out in individuals at risk of HAPE within a day subsequent to ascending to 4559m showed an increased red blood cell count and concentration of serum-derived protein in BAL fluid. The number of red blood cells/μl and the albumin concentration was higher in individuals who had HAPE at the time of BAL, compared to individuals who experienced HAPE over the next 24 hours. HAPE in an initial stage is seen as a high-pressure mediated permeability type of pulmonary oedema.

Mechanisms Accounting for Increased Capillary Pressure

It is possible that individuals who are at risk of HAPE have an increased pulmonary capillary hypertension. There are two possible explanations. One reason is through homogenous hypoxic vasoconstriction, which causes regional overperfusion of capillaries where there are areas of low arterial vasoconstriction. This results in scattered pulmonary oedema, containing large amounts protein and red blood cells. Another reason explains that hypoxic constriction can occur at the smallest leaky arterioles and/or venules.

In either case, an increase in pulmonary blood flow during exercise raises pulmonary capillary pressure, caused by venous resistance.

Inflammation

There is a higher level of red blood cell count, with serum-derived protein concentration in BAL fluid, in individuals who have HAPE and those who developed HAPE after 24 hours, when BAL was performed within the same day. Although it is possible that there may be a possible inflammatory leak, there is no difference between individuals resistant to or prone to HAPE. Active salt and water reabsorption occur, while gathering the protein leaked in the initial stages of HAPE occurs, which is seen when alveolar protein concentration is greater than the plasma protein concentration in HAPE.

Due to these reasons, in more advanced cases of HAPE, inflammation may occur and contribute to increased pulmonary capillary permeability.

HAPE can be seen as a hydrostatic type of pulmonary oedema. The pathophysiology can be explained with increased hypoxic pulmonary vasoconstriction of small arteries and veins. This would lead to an overdistension of the vessel walls, which would open cellular junctions. This may cause stress failure of the alveolo-capillary membrane. With this, the secondary occurrence would be noted by the signs of inflammation found in the BAL fluid of patients with advanced HAPE.

It is seen that an increase in the permeability of the alveolar-capillary membrane decreases the pressure needed to result in oedema. Thus, with increased permeability, HAPE may occur in individuals with a normal hypoxic pulmonary vascular response.

Therefore, the development of HAPE can occur at distinctly low altitudes if an individual has an upper respiratory tract infection prior to a journey in the French Alps and vigorous exercise between 2000-3000m. Other reasons could include diastolic heart failure in hypertension, and/or an undiagnosed pathology as an underlying factor of HAPE, which can include silent pulmonary embolism, which can occur from prolonged travel.

Alveolar Fluid Clearance

It is possible that an improper clearing of fluid from the alveoli can lead to the pathophysiology of HAPE. It is seen that hypoxia decreases the transepithelial sodium transport. This accounts for the reduced fluid clearance from the alveoli of hypoxic rats at an FiO₂ of 0.08. Mice that are somewhat lacking of apical (alveolar-facing) epithelial sodium channel display an increased accumulation of lung water in hypoxia.

Congenital Anomalies

It is possible that HAPE can be experienced at altitudes below 3000m, which can occur due to congenital anomalies. This would be caused by congenital anomalies of the large pulmonary arteries and pulmonary embolism. This helps explain the increase in pulmonary artery pressure with exposure to high altitude, which can occur from the deficiency of the pulmonary vascular bed cross-sectional area.

Small lungs relative to a person's body size can also make someone prone to HAPE.

Individuals with congenital cardiac shunts and/or pre-existing pulmonary hypertension may be prone to HAPE at moderate altitude. High altitude hypoxemia may be aggravated by right–left shunt across a patent foramen ovale, and may lead to HAPE. For this reason, if an individual develops HAPE at an altitude less than 3000m, an assessment should be done with electrocardiogram (ECG) to rule out pulmonary hypertension and/or a congenital anomaly.

Exercise

Increasing pulmonary pressure, thus the risk of HAPE can be caused by vigorous exercise. It is seen that vigorous exercise can cause subclinical permeability oedema with high concentrations of red blood cells and protein, which can remain for a few days at high altitude. This can be caused by imbalanced spread of blood flow within the pulmonary vascular bed and/or heightened pulmonary vascular pressures. In normoxia and hypoxia, vigorous exercise can cause pulmonary blood flow and pulmonary vascular pressures to greatly increase. This increase in vascular pressure would be associated with the increased left atrial pressure. Thus, the increase in pulmonary vascular resistance would be less significant.

In adults at risk of HAPE, exercise increases pulmonary artery pressure and pulmonary artery occluded pressure (wedge pressure) greater than in individuals resistant to HAPE. This may be due to a dysfunctional left ventricular filling due to the dilation of the right ventricle and bulging of the septum toward the left side.

Signs & Symptoms

In many cases, HAPE is preceded by symptoms of Acute Mountain Sickness (AMS). It is possible, though, that HAPE may occur without experiencing symptoms of AMS, as shown in a study with differing AMS scores in adults with HAPE at 4559m. In severe cases, above 4559m, arterial PO₂ may be reduced below 35mmHg.

Primary symptoms of HAPE include extreme fatigue, dyspnoea on slight exertion, chest tightness, cough, and reduced exercise performance. As the pulmonary oedema condition advances, the cough can worsen, dyspnoea at rest and orthopnoea may result. Further progression may be indicated by gurgling in the chest, haemoptysis, and pink frothy sputum.

Clinical features can include cyanosis, tachypnoea, tachycardia, and an increased body temperature though below 38.5 degrees. Rales can be noticed, and would specifically be located over the middle lung fields.

The degree of pulmonary oedema seen on a chest x-ray may outweigh the findings that can be noticed on auscultation.

In serious and progressed cases, there may be signs of cerebral oedema associated with the pulmonary oedema, such as ataxia or reduced levels of consciousness.

Subclinical HAPE may occur, but cause none to minimal symptoms, which can be ignored. It is possible that people may have subclinical pleural oedema in the lung, which can vaguely represent oedema, and resolve on its own, even with the individuals at high altitude.

There are demonstrated drastic Arterial Blood Gas (ABG) values of HAPE at 4559m of elevation. Mean arterial PO₂ was 23 ± 3 (SD) mmHg, with controls at 40 ± 5 mmHg, and arterial oxygen saturation was 48 ± 8%, with controls at 78 ± 7%. In early stages of HAPE at this altitude, 30 mmHg for PO₂ and 70% for SaO₂ can be observed.

Individuals at risk of HAPE can also have a marked increased pulmonary artery pressure, mean pressures of 35 mmHg and 55mmHg, which is followed by pulmonary oedema. This would also be true when exercising in hypoxic conditions. Increased pulmonary capillary pressure and protein, and red blood cell rich oedema fluid, without primary signs of inflammation may also lead to HAPE.

The risk of HAPE can be increased during or subsequent to infections.

Individuals at risk of HAPE have an abnormal increase of pulmonary artery systolic pressure in hypoxia and exercise in normoxic conditions, a reduced hypoxic ventilatory response, and a reduced lung volume.

Chest x-ray

In early conditions of HAPE, patchy peripheral distribution of oedema is seen radiographically. In more advanced cases, and during recovery, the radiographic image is more homogenous and diffuse. Differing radiographic imaging within two cases in the same person shows that structural abnormalities may not represent consistency in oedema location.

Surgical Findings

Autopsies did not reveal left ventricular failure, but did show that there are distended pulmonary arteries and diffuse pulmonary oedema with bloody foamy fluid which is present in the airways. In many cases, hyaline membranes can be found, as well as arteriolar thrombi, pulmonary haemorrhages, or infarcts.

Treatment & Prevention

If a person experiences HAPE, improvement of oxygenation would be the primary treatment. Bed-rest can also be used for treatment purposes.

When a person is at ascent, there may be limited medical facilities or supplies available. If there is access to a medical facility, the person's arterial oxygen level (SpO₂) should be maintained above 90%, preferably using a low-flow oxygen mask (2-4L.min). The person's symptoms can be relieved within a few hours, and the clinical symptoms can be relieved within 2-3 days. If there are more severe cases, with cerebral oedema present, the individual would need to be taken a lower altitude, and hospitalised.

Without any medical facilities available, immediately descending to a lower elevation would be indicated. As mentioned, improvement in oxygenation would be recommended, or using a hyperbaric chamber.

However, if neither of these options are viable, and a slow ascent is not possible, treatment with prophylaxis and nifedipine would be recommended until descent becomes an available option.

Nifedipine is an inhibitor of hypoxic pulmonary vasoconstriction. The dosage of the nifedipine (and prophylaxis) includes 60mg of a slow-release formula, which should start being administered upon ascent and concluded on the 3rd or 4th day after reaching the final altitude if the individual is remaining there for some time, after descent to an altitude below 3000m, or an altitude where the individual is acclimatised. Nifedipine helps to avoid HAPE, however it is not effective with helping to prevent acute mountain sickness.

In Himalayan mountaineers, mortality has been estimated at 50% if descent or another treatment is not available. Without descent or the availability of supplemental oxygen, portable hyperbaric chambers and nifedipine treatment (20mg slow release formula every 6 hours) should be implemented until descent is possible. Olez et al (1989) mention that with the administration of 20mg of nifedipine every 6 hours over 34 hours, mountaineers with HAPE at 4559m displayed a relief of symptoms with an improvement in gas exchange and radiographic clearance. Maggiorinic mentioned that 20mg of the slow-release formula of nifedipine taken every 8 hours, commencing 24 hours prior to ascent to an altitude of 4559m, and continued until descent, reduced the incidence of HAPE from 63% to 10%.

Another prevention method would be with using prophylaxis and dexamethasone. This prevents HAPE in individuals at risk when taken 1 day before ascent and continued while ascending and while at 4559m. Dexamethasone was seen to dampen the increase in pulmonary artery pressure at high altitude.

Due to the increased arterial pressure causing HAPE, pharmacological medications lowering pulmonary artery pressure can improve gas exchange in HAPE.

Treatments that decrease pulmonary artery pressure are effective.

Prevention

Individuals who are susceptible to HAPE can avoid the risk of such a condition if ascent is gradual, with an average ascent of 300-350m per day when at an altitude greater than 2500m. This is especially important for individual at greater risk.

It was found that mountaineers who have developed HAPE more than once with rapid ascent in the Alps can have the condition prevented. Altitudes of up to 7000m can be reached by these individuals, without experiencing medical issues, if they ascend only 350-400m per day when they are above 2000m, or with a gradual ascent.

If mountaineers are experiencing altitude sickness, and want to prevent the occurrence of life-threatening illnesses, they would be advised to stop their ascent and monitor their symptoms for a day. If the symptoms do not improve, they should descend from that altitude.

If an individual has a history of HAPE, vigorous exercise should be avoided during the initial days of exposure to altitude, since exercise induced circulatory changes can worsen or cause pulmonary oedema. This would especially include individuals who are experiencing symptoms of altitude sickness with rapid ascent to altitudes of 3500-4000m. The risk of HAPE can also be increased with or after infection.

Statistics of HAPE susceptibility

General screening of HAPE in individuals trekking to high altitudes cannot necessarily be recommended, especially in individuals who have uncertain altitude tolerance. The most effective methods for such screening consists of PASP assessment at rest subsequent to 2h of hypoxic exposure at an FiO₂ of 0.12 or during normoxic exercise.

The factors that rule in the general screening to be ineffective include the low prevalence of HAPE in mountaineers at 4,500 m, which is 0.2–6.0%, and the prevalence of 9–10% of an abnormal PASP response to hypoxia in healthy subjects. With specificities and sensitivities of between 77% and 94% for rest hypoxia and exercise normoxia, respectively, screening in a mass randomised population will result in more false-positive than true-positive HAPE-susceptible individuals.

Despite this, testing may be useful in some situations, especially in a person who had a previous episode of HAPE who wants to return to mountain climbing. A PASP value <40 mmHg would rule out susceptibility to HAPE, with a negative predictive value 97%, as a greater hypoxic pulmonary vascular response would be less certain (positive predictive value of 56%). If PASP is >40 mmHg, with a history compatible with HAPE, it is possible that the individual would be more susceptible to HAPE.

Conclusion

Regardless of the deemed risk or susceptibility to HAPE, the following rules and guidelines should be followed to prevent severe-AMS and HAPE in mountainous regions:

• Do not ascend to a higher sleeping altitude when symptoms of AMS are present
• Descent should be undertaken if these symptoms do not improve with a day of rest
• if the symptoms indicate early-HAPE, immediate descent should be undertaken

In addition, a study by Bartsch et al (1999), showed 2 cases which demonstrate that HAPE may even occur in individuals with low to no susceptibility, especially if they go high enough and fast enough. In one case, in which the individual did not survive, the ascent occurred over 9 days to an altitude of 7200m. In another case individuals who showed they were tolerant to an altitude above 8000m, with many previous exposures, experienced HAPE after climbing 8400m over 14 days.