High Altitude Pulmonary Edema: Diagnosis, Management, and Preventive Strategies

Author: Linda Sanders, MD (EM Resident Physician, Temple University Hospital)

Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Case:

A 32 year-old man with no significant past medical history is part of a trekking group to Mount Everest Base Camp. The patient is a lowlander from the Northeastern US and is a social drinker, nonsmoker, and active triathlete. He has been trekking for 10 days starting at 9000 ft. with a graded ascent and has had a recent gain in altitude of approximately 450 meters over the course of 24 hours. At approximately 16,000 ft. (4900m) the patient starts to trail behind the rest of the group. He reports moderate dyspnea on exertion with chest tightness. At 17,000 ft. the patient begins coughing.

After 8 hours of trekking the individual arrives at Everest Base Camp ER (17,600 ft.) where his pulse oximetry is found to be 60% with a heart rate of 115. The patient appears well at rest but has a rapid respiratory rate of approximately 28. There is no thermometer to record a temperature and the blood pressure is not taken. As the patient returns to the teahouse at 17,000 ft. he develops worsening shortness of breath now at rest with associated cough. You wonder if the patient needs a helicopter evacuation for immediate descent.

Introduction

High Altitude Pulmonary Edema (HAPE) is a form of noncardiogenic pulmonary edema that occurs secondary to hypoxia and is characterized by dyspnea and cough at altitude. It typically occurs at elevations above 2500m (8000 ft.) but can develop as low as 2000m. The incidence of High Altitude Pulmonary Edema (HAPE) among unacclimatized travelers to altitude is largely dependent on genetic susceptibility, the rate of ascent, and the final altitude achieved. In those with no prior history of HAPE who ascend to 4500m the incidence is relatively low, ranging from 0.01-0.2%.1,5 However, for ascents greater than 5500m the incidence is closer to 6 to 15%. 2-5 Furthermore, if the individual has a prior history of HAPE and ascends rapidly above 4500m the recurrence rate is as high as 60%.3 HAPE has the highest associated mortality of any altitude related illness, estimated at 11-50%.2, 6- 7

Pathophysiology

HAPE is the result of a pathologic response by the pulmonary vasculature to hypoxia.

Although the fraction of inspired oxygen (FiO2) remains 21% at altitude, low barometric pressures decrease the partial pressure of inspired oxygen.

The alveolar gas equation helps demonstrate this:

PiO2 = FiO2 x (PB – 47mmHg) – 1.2 (PaCO2)

PB = barometric pressure

Sea level barometric pressures are 760mmHg, while at the altitude of Everest Base Camp (EBC) for instance, the PB drops to just under 400mmHg. Thus, if one assumes a physiologic PaCO2 of 40mmHg, the PiO2 at EBC is about half. This converts to a PaO2 of just 27mmHg at EBC compared to 100mmHg at sea level.

Fortunately with lower PaCO2 levels, there is a corresponding increase in the PiO2. Thus, the body’s adaptation to this hypoxia is hyperventilation, referred to as the hypoxic ventilatory response (HVR). If however, there is a blunted HVR due to a genetically poor ventilator drive or depressed drive secondary to sedatives, the individual will be exposed to increasing levels of hypoxia.6,8

Exposure to this degree of prolonged hypoxia at altitude results in a vasoconstrictor response of the pulmonary vasculature. The pulmonary vasoconstriction in HAPE is non-uniform, resulting in increased pulmonary increased perfusion of some alveoli and decreased perfusion in others. This regional over-perfusion results in increased pressures in those alveoli resulting in increased capillary permeability of the smaller arterioles and consequently pulmonary edema. There also seems to be some degree of weakened capacity for the alveolar fluid to be resorbed. This has been theorized to be secondary to reduced activity of the epithelial sodium channels in genetically susceptible individuals.6,8

Risk Factors

The primary risk factors for the development of HAPE are a rapid rate of ascent to altitudes above 2500m, a higher final altitude reached, and genetic susceptibility. Physical fitness does not have a protective effect against the development of HAPE or other forms of altitude illness.9,17 Even well acclimatized mountaineers can develop HAPE during a sudden push to summit.6

The pathophysiology of HAPE is closely tied to an inadequate hypoxic ventilatory response resulting in hypoventilation; thus, medications inducing decreased respiratory drive increase the risk of developing HAPE. Physical exertion is also known to worsen HAPE likely secondary to worsening hypoxia. Underlying medical conditions which cause worsening hypoxia similarly may predispose one to HAPE. These include upper respiratory infection, patent foramen ovale, and in children specifically, congenital cardiac abnormalities.6-7  

Clinical Presentation

HAPE is characterized as occurring in two forms. One of which occurs in highlanders who visit low altitudes and then upon return to altitude experience re-entry HAPE and the other is among unacclimatized lowlanders.1 HAPE typically occurs after two to five days at altitudes above 2500m.6 If dyspnea and cough begin after 5 days at the same altitude, other differential diagnoses are more likely.

Early signs and symptoms include decreased exercise tolerance compared to fellow travellers, dyspnea on exertion, longer than usual recovery time when resting, and a dry cough. As symptoms progress patients may develop cyanosis and crackles on exam. Orthopnea is thought to be fairly uncommon. Individuals may also develop concurrent HACE due to severe hypoxemia; thus it’s important to monitor for ataxia and altered mental status.6 In autopsy findings of over 20 persons who died of HAPE, 50% had HACE. A retrospective study found the incidence of HACE to be closer to 14% in those diagnosed with HAPE.4,6,10

Diagnosis

Diagnostic tests are often limited in high altitude settings, thus the Lake Louise Criteria were developed for establishing the clinical diagnosis of HAPE.11 These include the following:

The setting of high altitude, plus 2 signs and 2 symptoms:

Symptoms (at least 2 of the following):

  • chest tightness
  • cough
  • dyspnea at rest
  • markedly decreased exercise tolerance

Signs (at least 2 of the following):

  • central cyanosis
  • pulmonary crackles or wheezes
  • tachycardia
  • tachypnea

If pulse oximetry is available it can be used to support the diagnosis. The oxygen saturation in HAPE subjects has been demonstrated to range from 40-70% as compared to healthy controls whose average pulse oximetry reading was 92%.4,6

Portable ultrasounds have allowed for examination of the lungs, which often demonstrate B-lines. If further diagnostic testing is available a chest x-ray typically shows patchy infiltrates without cardiomegaly. Repeat xrays generally clear in one to two days of descent.6 EKGs may demonstrate sinus tachycardia and right axis deviation. Echocardiograms have been used to estimate pulmonary artery pressures (PAP) in these patients and have found elevated PAP ranging from 36-51mmHg.6,12-14

Differential

Differential diagnoses for HAPE should include pneumonia, bronchitis, asthma, pulmonary embolism, and myocardial infarction.6

Management

The mainstay of treatment for an individual with HAPE is descent. Early HAPE may respond to a descent of only 500m.1 In such cases individuals may consider gradual re-ascent two to three days later. The mode of descent may include helicopter evacuation in severe cases, but individuals with mild to moderate HAPE often descend on foot. In such cases it is important to minimize exertion as this is known to exacerbate the illness due to worsened hypoxemia. It is recommended that in such cases individuals minimize load and descend without a pack. Additionally the patient should be kept warm as cold stress will worsen their condition.1,6,18

If supplemental oxygen is available, high flow oxygen at 2 to 4 liters per minute with a goal oxygen saturation of > 90% will decrease pulmonary artery pressures and improve the patient’s tachypnea over the course of 24 to 48 hours.15

In cases where descent is not possible or may be delayed, the calcium channel blocker nifedipine is the drug of choice. Extended release nifedipine, 30mg given every 12 hours, has been demonstrated to improve clinical symptoms.16,18 However, nifedipine provides no added benefit if oxygen and descent are available options.19 Phosphodiesterase inhibitors similarly act to dilate the pulmonary vasculature and have a role in HAPE prophylaxis but have not been formally evaluated as treatment.

If the patient’s condition is severe in remote situations where descent is not immediately possible, the patient may be placed in a portable hyperbaric bag also known as a Gamow bag, which can simulate descent up to 2800m (9000 ft), though only 500m may be necessary. This device is easy to use and has been successfully employed for HAPE by first responders.24

In some cases concomitant infection as well as other forms of altitude illness may co-occur. One should also have a high suspicion for Acute Mountain Sickness (AMS) and High Altitude Cerebral Edema (HACE) in any patient with HAPE.6 

Prevention

The key to HAPE prevention is a gradual ascent. It is recommended that above 3000m, trekkers not ascend greater than 300 to 500 meters per day and should incorporate a rest day every 3 to 4 days for acclimatization, especially after large gains in altitude.18 Sleeping altitude is particularly important and should not increase by more than 500m per day.20 Because hyperventilation is the main adaptive response to hypoxemia at altitude, it is important to avoid any sedating agents which may blunt the respiratory drive.

For individuals with a prior history of HAPE, nifedipine is suggested as prophylaxis when ascending to altitudes above 2500m. This is supported by a randomized controlled trial (RCT) which demonstrated decreased incidence of HAPE along with lower pulmonary artery pressures and improve oxygen saturation in HAPE susceptible patients as well as prior nonrandomized trials which demonstrated reduced incidence of HAPE.16,18,21

Phosphodiesterase inhibitors have demonstrated efficacy for HAPE prophylaxis in susceptible individuals as well, though the evidence is limited. There have been two RCTs demonstrating some benefit, although sildenafil notably exacerbated AMS symptoms.22,23 At this time, PDE-5 inhibitors are not recommended for prophylaxis as single agents, but rather in combination with nifedipine.18,22 The same study demonstrated a reduction in HAPE incidence with prophylactic dexamethasone which may act by increasing the activity of nitric oxide synthase resulting in pulmonary vasodilation.22

Acetazolamide has no demonstrated role in HAPE prevention but reduces the incidence of HACE and AMS and assists with acclimatization by inducing hyperventilation to compensate for a metabolic acidosis induced by the diuresis of bicarbonate. The recommended dose is 125mg twice a day.18 

Summary/Bottom Line

  • HAPE is a clinical diagnosis based on the patient’s signs and symptoms using the Lake Louise Criteria. Objective data are rarely initially available but may be used to support the diagnosis.
  • Descent and supplemental oxygen are the mainstays of treatment for HAPE.
  • Nifedipine and a Gamow Bag are reasonable alternatives if these options are not immediately available.
  • Those with prior episodes of HAPE are at a high risk of recurrence when at altitude and should use nifedipine alone or in combination with a phosphodiesterase inhibitor for prophylaxis along with a gradual rate of ascent.

References/Further Reading

  1. Korzeniewski K., Nitsch-Osuch A., Guzek A., and Juszczak D. High altitude pulmonary edema in mountain climbers. Respir Physiol Neurobiol 2015; 209: pp. 33-38.
  2. Bärtsch P., and Swenson E.R. Acute high-altitude illnesses. New Engl J Med 2013; 368: pp. 2294-2302.
  3. Bärtsch P., Maggiorini M., Maribäurl H., and Vock P., Swenson E.R. Pulmonary extravascular fluid accumulation in climbers. Lancet 2002; 360: pp. 571-572.
  4. Hultgren H.N., Honigman B., Theis K., and Nicholas D. High-altitude pulmonary edema at a ski resort. West J Med 1996;164 (3): pp. 222-227.
  5. Hultgren H.N., and Marticorena E.A. High altitude pulmonary edema. Epidemiologic observations in Peru. Chest 1978; 74(4): pp. 372-376.
  6. Hackett P.H. High-altitude medicine. Auerbach PS, ed. Wilderness Medicine. 6th Ed. Philadelphia, PA: Mosby; 2012. 2-43.
  7. Jones B.E., Stokes S., McKenzie S., and Nilles E.J. Management of HAPE in the Himalaya: a review of 56 cases presenting at Pheriche Medical Aid Post (4240m). Wilderness Environ Med 2013 March; 24(1): pp. 32-36.
  8. Bhaghi S., Srivastava S., and Singh S.B. High-altitude Pulmonary Edema: Review. J Occup Health 2014; 56: pp. 235-243.
  9. Honigman B., Read M., Lezotte D., and Roach C. Sea-level physical activity and acute mountain sickness at moderate altitude. West J Med 1995; 163(2): pp. 117-121.
  10. Hackett P.H., and Roach R.C. High altitude cerebral edema. High Alt Med Biol 2004; 5(2): pp.136-146.
  11. Roach R.C., Bärtsch P., Hackett P.H., Oelz O. Lake Louise acute mountain sickness coring system. In: Sutton JR, Coates G, Houston CH, (Eds.) Hypoxia and Molecular Medicine. Queen City Press, Burlington, VT, 1993 pp. 272-274.
  12. Maggiorini M., Mélot C., Pierre S., et al. High altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 2001; 103: pp. 2078-2083.
  13. Kronenberg R.G., Safar P., Wright F., et al: Pulmonary artery pressure and alveolar gas exchange in men during acclimatization to 12,470 ft. J Clin Invest 1971; 50: pp. 827-837.
  14. Roy B.S., Guleria J.S., Khanna P.K., et al: Haemodynamic studies in high altitude pulmonary edema. Br Heart J 1969; 31: pp. 52-58.
  15. Maggiorini, M. Prevention and Treatment of High-Altitude Pulmonary Edema. Prog in Cardiovasc Dis 2014; 52: pp. 500-506.
  16. Oelz O., Ritter M., Jenni R., Maggiorini M., et al. Nifedipine for high altitude pulmonary oedema. Lancet 1989, Nov 25: pp. 1241.
  17. Milledge J.S., Beeley J.M., Broome J., et al. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J 1991;4: pp. 1000-3.
  18. Luks, A.M. et al. Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2014 Update. Wilderness Environ Med 2014; 25: pp. S4-S14.
  19. Deshwal R., Iqbal M., and Basnet S. Nifedipine for the treatment of high altitude pulmonary edema. Wilderness Environ Med 2012; 23(1): pp. 7-10.
  20. Bärtsch P, Mairbaurl H, Swenson ER, et al: High altitude pulmonary oedema. Swiss Med Wkly 2003 Jul 12;133: pp. 377-384.
  21. Bärtsch P., Maggiorini M., Ritter M. et al. Prevention of High-Altitude Pulmonary Edema by Nifedipine. New Engl J Med 1991, 325(8): 1284-1289.
  22. Maggiorini M., Brunner-La Rocca H.P., Peth S., et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: A randomized trial. Ann Intern Med 2006;145:497-506.
  23. Bates et al. Sildenafil Citrate for the Prevention of High Altitude Hypoxic Pulmonary Hypertension: Double Blind, Randomized, Placebo-Controlled Trial. High Altit Med Biol 2011; 12(3): 207-214
  24. Freeman K., Shalit M., and Stroh G. Use of the Gamow Bag by EMT-Basic Park Rangers for Treatment of High-Altitude Pulmonary Edema and High-Altitude Cerebral Edema. Wilderness Environ Med 2004; 15: pp. 198-201.

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