Continuing Education Activity

High-altitude pulmonary edema is a largely preventable condition. Lack of knowledge about the prevention, recognition, and treatment of this disease demonstrates why high-altitude pulmonary edema is the leading cause of death associated with high altitudes. This activity illustrates the etiology, epidemiology, pathophysiology, presentation, evaluation, and management of high-altitude pulmonary edema. This activity highlights the role of the interprofessional team in preventing, recognizing, and managing this condition.

Objectives:

• Describe the underlying pathophysiology of high-altitude pulmonary edema.
• Summarize the clinical presentation of a patient presenting with high-altitude pulmonary edema.
• Explain the management strategies for high-altitude pulmonary edema.
• Outline some interventions that clinicians can use to prevent and treat high-altitude pulmonary edema and improve patient outcomes.

Introduction

Every year, millions of outdoor enthusiasts visit high-altitude destinations. Many of these individuals are unaware or underprepared for the potential medical risks involved with their travels. Healthcare professionals must be cognizant of the potential complications of these high-altitude activities and prepared to provide education and treatment to these patients.[1]

High-altitude illnesses are commonly observed at altitudes greater than 2500 meters (8200 feet). The more severe forms of altitude illness, such as those affecting the cerebral and cardiopulmonary systems, present at moderately high altitudes due to the ease of travel with a rapid ascent to popular destinations such as ski resorts. Prompt recognition and initiation of treatment significantly reduce morbidity and mortality in these patients.[2]

The most studied form of pulmonary insult at altitude, high-altitude pulmonary edema (HAPE), is also the most common cause of high-altitude-related death.[3] HAPE is largely preventable with proper acclimatization and gradual ascent. If recognized early and treated promptly, HAPE has a good prognosis, with most patients making a quick, full recovery. HAPE is characterized by respiratory compromise leading to respiratory distress and failure secondary to noncardiogenic pulmonary edema. Although underlying medical comorbidities can predispose patients to develop HAPE, many affected patients are young, healthy individuals.

Etiology

High-altitude pulmonary edema is classically associated with a rapid ascent that does not allow time to acclimatize to altitude—individual susceptibility, environmental factors, and underlying medical comorbidities all influence one’s likelihood of developing HAPE.

HAPE is more common in males and those who use alcohol, sleeping pills, or other substances that cause respiratory depression. Individuals with a history of HAPE are at an increased susceptibility in the future, with recurrence rates up to 60% in some studies.[4][5]

A rapid rate of ascent is a strong predisposing factor in the development of HAPE. This is noted both in individuals who arrive abruptly at a high altitude, such as air travel to a high-altitude resort, as well as those who reach altitude via trekking. Higher altitudes, colder environments, and destinations requiring a higher degree of physical exertion all correlate with a higher incidence of developing HAPE.[6]

Underlying medical conditions also predispose individuals to the development of HAPE. High-risk conditions include pulmonary hypertension, restrictive/obstructive lung disease, and congenital cardiac abnormalities.[7] Those with a patent foramen ovale (PFO) seem disproportionately affected by HAPE.[8] Other cardiac structural abnormalities that lead to left-to-right shuts (atrial septal defects, ventricular septal defects, and patent ductus arteriosus) also predispose to the development of HAPE.[9] Those with a congenitally absent right pulmonary artery are at a very high risk of developing HAPE.[6]

Although not fully understood, genetics play a role in one’s susceptibility to the development of HAPE. Patients at risk of HAPE have reduced nitric oxide and increased endothelin during periods of hypoxia when compared to less sensitive counterparts.[7] HAPE-sensitive patients also have a diminished capacity to transport sodium and water across the epithelial layers, leading to decreased alveolar fluid reabsorption and subsequent difficulty regulating edema.[10] Studies continue to investigate the genetics behind the nitric oxide pathway, nitric oxide synthase, angiotensin-converting enzyme, and renin-angiotensin-aldosterone pathways.[11][12][6]

Epidemiology

The cardiovascular and cerebral effects of altitude are most pronounced at higher altitudes. Generally, high altitude is defined as 1500 to 3500 meters (4,921 to 11,483 feet), very high altitude as 3500 to 5500 meters (11,483 to 18,045 feet), and extreme altitude as greater than 5500 meters (18,045 feet).[13]

Altitude-related illnesses are most common at altitudes greater than 2500 meters (8200 feet), and more severe forms of illness would be uncommon at less than 3000 meters.[14] The overall incidence is variable due to confounding factors such as the rate of ascent and time to acclimatize.[15] At moderately high-altitude resorts in Colorado, incidence can reach one in 10,000 travelers. With extreme altitudes, such as attempting to summit Denali (6200 meters), this increases to 2 to 3% of climbers. Indian Army soldiers deployed to 5500 meters had a 15% incidence attributed to rapid ascent to extreme altitude.[3][6][5]

The incidence of HAPE strongly correlates with the abruptness of the ascent. In an ascent of 4500 meters over four days, there is a 0.2% incidence of HAPE. This incidence increases to 6% incidence with a one to two-day ascent.[5]

Pathophysiology

The hallmark of HAPE is the presence of noncardiogenic pulmonary edema leading to worsening respiratory distress and failure. The pathophysiology behind this phenomenon is complex and multifactorial. The proposed mechanism involves hypoxia at altitude leading to pulmonary vasoconstriction, subsequent pulmonary hypertension, capillary over perfusion, leak, and edema.[15]

When a portion of the lung is suffering from poor ventilation (e.g., lobar pneumonia), regional vasoconstriction occurs, shunting the blood to the better-perfused regions of the lung to ensure adequate oxygenation. This phenomenon, known as the hypoxic pulmonary vasoconstrictor response (HPVR), optimizes adequate gas exchange to prevent systemic hypoxia.[15][16] High altitude environments can cause global hypoxia secondary to the decreased partial pressure of oxygen at these altitudes. The body’s response to this hypoxia is diffuse pulmonary vasoconstriction.[17] With the constriction of these pulmonary vessels throughout the lung, resultant pulmonary artery hypertension occurs.[18][19] Pulmonary hypertension is present in all patients diagnosed with HAPE, although not all patients with pulmonary hypertension will necessarily progress to HAPE.

Increased pulmonary artery pressures occur in an unequal distribution throughout the lung, leading to focal capillary beds with increased capillary pressures, over perfusion, and subsequent edema secondary to capillary leak. This over perfusion and capillary leak in an unequal distribution may explain the patchy distribution of edema noted on imaging.

As the capillary leak progresses, worsening disruption of the epithelial cell membranes leads to increasing edema. Autopsy findings have noted lung weights of two to four times normal. Alveolar hemorrhage is common, as are pulmonary infarcts. Edema samples on bronchoalveolar lavage and autopsy have proteinaceous debris with plasma and red blood cells, microthrombi, but an absence of neutrophils and bacteria.[17]

History and Physical

In the wilderness setting, high-altitude pulmonary edema is primarily a clinical diagnosis, and thus a thorough history and physical are paramount. Most cases of HAPE present during the first two to four days of ascent. Symptoms usually begin on the second night at altitude. Initial symptoms may be insidious and easily dismissed as secondary to increased exertion. A non-productive cough, mild dyspnea on exertion, decreased capacity for exercise tolerance with a more extended recovery period can all occur.[20]

If early HAPE goes unrecognized, symptoms will progress to increasing weakness and fatigue, mild cyanosis, and the development of tachypnea and tachycardia. The hallmark of HAPE is dyspnea at rest, which often increases at night. At this stage, with increasing respiratory distress, most will recognize the clinical significance of their symptoms and the need to seek treatment. Only in the late stages of HAPE will the patient’s cough produce pink, frothy sputum.[6]

In about 50% of cases of HAPE, patients suffer from symptoms of acute mountain sickness (AMS) such as headaches, nausea and vomiting, insomnia, or dizziness.  Approximately 14% of HAPE cases have concurrent high-altitude cerebral edema (HACE), with mental status changes such as ataxia, confusion, with progression to coma in severe cases.[6]

Hypoxia, often profound, is the most consistent finding in HAPE patients. On physical exam, this manifests as respiratory distress with an increased work of breathing. Tachypnea, tachycardia, cyanosis, and rales are common on pulmonary auscultation. Patients can uncommonly have elevated temperatures to 38.5 C (101.3 F). HAPE must be kept high on the differential for all patients at altitude who present with hypoxia and altered mental status, regardless of subjective respiratory complaints.[5]

Evaluation

A thorough history and examination with vital sign measurements are sufficient to establish a diagnosis of high-altitude pulmonary edema. No specific laboratory or radiographic findings are required for diagnosis, though they can support and offer additional clinical indicators of disease process.

Radiologic findings on X-ray for HAPE include pulmonary infiltrates in an unequal, patchy distribution, unilateral or bilateral. The right middle lobe is most commonly affected. The degree of infiltrates correlates with severity.[21] Consistent with noncardiogenic edema, HAPE patients do not have cardiomegaly. Serial radiographs often show rapid improvement, correlating with a patient’s clinical improvement as they descend and receive therapy.

Pulmonary ultrasound reveals comet tails or B-lines. The comet tail scoring system designed for use in cardiogenic pulmonary edema is also effective for altitude-related pulmonary edema. The sonographic artifact results from edema causing interference that reflects the ultrasound beam.[22]

Echocardiographic findings in HAPE include increased pulmonary artery pressures and, in severe cases, right heart strain. 

No laboratory testing will definitively diagnose HAPE. Arterial blood gas (ABG) usually shows hypoxemia and respiratory alkalosis. A mild leukocytosis in HAPE patients is common but nonspecific. Brain natriuretic peptide (BNP) testing may reveal a mild to moderate elevation.[23] Troponin may be mildly elevated, especially in the setting of right heart strain. 

Treatment / Management

Treatment of high-altitude pulmonary edema depends on illness severity, resources, and rescue logistics in austere environments. Descent and supplemental oxygen are the mainstays of therapy.[4] Patients with mild to moderate HAPE show rapid improvement of symptoms with a decent of even 500-1000 meters.[2] However, wilderness conditions may complicate descent and the patient’s diminished exercise tolerance or potential inability to ambulate.

Supplemental oxygen therapy should be initiated immediately upon suspicion of HAPE to relieve hypoxia, decrease the hypoxic pulmonary vasoconstrictor response, and provide symptom improvement. Goal oxygen saturations should be 90% or greater.[2] If available, hyperbaric oxygen therapy should be considered if available, with some rescue units having portable inflatable chambers for scene therapy if immediate descent is unrealistic.[15][14] Colder temperatures and continued exertion will further worsen HAPE due to increases in pulmonary artery pressures (PAP); therefore, efforts should ensure patients are warmed and resting unless making efforts to descend.

In a hospital setting, oxygen remains the most effective therapy for patients with HAPE. Supplemental oxygen immediately improves hypoxia, reduces pulmonary vasoconstriction, relieves shunting, and demonstrates symptomatic relief with an improvement of the patient’s work of breathing, tachypnea, and tachycardia. In severe cases of HAPE, patients may benefit from continuous positive airway pressure (CPAP) or expiratory positive airway pressures (EPAP).[2]

Medications have a limited role in managing HAPE, as descent and oxygen therapy are highly effective. Medications have a role in situations in which descent and oxygen therapy are not feasible or as adjuvants in severe cases to decrease pulmonary artery pressures. Nifedipine, a calcium channel blocker, can provide a small reduction of pulmonary vascular pressure and pulmonary vascular resistance. The common dosing of nifedipine for HAPE is 30 mg every 12 hours.[15] Phosphodiesterase-5 inhibitors such as sildenafil and tadalafil have been utilized as prophylaxis for HAPE and may offer some benefit by increasing the amount of nitric oxide, which serves as a pulmonary vasodilator.[24] Prophylactic dosing of sildenafil is 50 mg every 8 hours and tadalafil 10 mg every 12 hours. There is insufficient data to recommend a treatment dose. Dexamethasone should be considered to treat concomitant high-altitude cerebral edema but has little use in isolation for HAPE. Other medications, such as diuretics, nitrates, or morphine, have been studied previously but are no longer recommended for the treatment of HAPE.[2] The potential benefits of these medications are far inferior to oxygen and descent.[6][14]

Patients with mild symptoms that resolve fully with descent can begin a slow reascent after 2 or 3 days of rest at a lower altitude. Cases of HAPE at moderately high-altitude resorts may require only rest and administration of low flow supplemental oxygen for 2-3 days duration if the patient elects not to descend and the health care team is familiar and comfortable with management.

Differential Diagnosis

Although altitude-related illnesses are a common cause of patient decompensation at altitude, exacerbations of underlying chronic conditions must be kept in the differential diagnosis. Exacerbations of pulmonary artery hypertension, congestive heart failure, peripheral edema, symptomatic valvular heart disease, dysrhythmias, and acute pneumonia/bronchitis may occur at any altitude and must be considered in a hypoxic and/or dyspneic patient.[2]

High-altitude illnesses such as HAPE may occur in isolation or concurrently with other altitude illnesses. A clinician must perform a thorough history and assessment to evaluate for other altitude illnesses such as high-altitude cerebral edema (HACE), acute mountain sickness, high-altitude headache, high-altitude syncope, and high-altitude bronchitis/cough.[14] Patients have an increased incidence of thrombosis at high altitudes, which can lead to acute cerebral vascular accidents and pulmonary emboli. Immunosuppression has been described at altitude, with an increased risk of infection and delayed healing in otherwise immunocompetent individuals.

Prognosis

Although HAPE is the leading cause of altitude-related death, the prognosis for most individuals suffering from high-altitude pulmonary edema is excellent. Recognition of early symptoms with prompt initiation of therapy is key to a mild course of illness. Attempts to continue ascent and exertion after symptom onset will lead to the progression of the disease. Even moderate to severe HAPE will improve dramatically with oxygen therapy and descent.[2] Upon arrival to a hospital, most patients will require only supplemental oxygen. It is reasonable to manage mildly affected individuals with pausing ascent, rest, and supportive care until acclimatization to altitude has occurred and symptoms have resolved fully. At this time, patients may elect to proceed with a slower, cautious ascent while monitoring for symptom recurrence.[4] Although individuals who have previously developed HAPE are prone to subsequent episodes, many can tolerate reascent at a slower pace with increased time to acclimatize. Rare long-term sequelae have been described.

Complications

Most individuals with high-altitude pulmonary edema who receive prompt treatment have a favorable prognosis and no complications. Increased incidence of thrombosis and immunosuppression have been noted at altitude. Therefore concurrent pulmonary emboli or pneumonia must be considered in HAPE patients.[25] Likewise, many patients with HAPE also have coexisting acute mountain sickness or high-altitude cerebral edema, which may require additional therapies. There is no evidence to support long-term cardiopulmonary complications such as persistent pulmonary hypertension, congestive heart failure, recurrent pneumonia, obstructive lung disease, or similar.

Deterrence and Patient Education

Healthcare providers should educate patients regarding a proper rate of ascent and the importance of time to acclimatize. Emphasize recognition of early symptoms of HAPE and stop ascent to allow additional time to acclimatize; descend/seek treatment if symptoms are more pronounced. Education should be available regarding means by which patients should seek medical attention if symptomatic, and individuals should familiarize themselves with available local resources prior to a trip to altitude.

Patients diagnosed with or suspected to have HAPE should receive education on the possibility of recurrence with subsequent trips to altitude. Pharmacologic prophylaxis and a slow rate of ascent (with altitude gains of 300 meters/day or less above 2500 meters) with additional time to acclimatize are critically important if patients with a history of HAPE wish to perform high-altitude activities in the future.[4] Prophylaxis is not generally recommended for all ascents, only for individuals who are HAPE sensitive.[2]

Nifedipine is the most studied agent for HAPE prophylaxis, typically dosed at 30 mg every 12 hours. This regimen should be initiated a day before ascent and continued for five days at peak altitude.[15]

Although less studied, sildenafil and tadalafil may prevent HAPE. Prophylaxis dosing varies, with a common regimen being sildenafil 50 mg every 8 hours or tadalafil 10 mg every 12 hours.

Dexamethasone clearly can prevent AMS/HACE, and one small study showed promise for HAPE prophylaxis with a dose of 8 mg every 12 hours.[2]

Pearls and Other Issues

High-altitude pulmonary edema is largely preventable for most individuals with a slow rate of ascent and adequate time to acclimatize to the altitude. Maintain a high index of suspicion, with early attention to those developing even mild symptoms such as cough or decreased exercise tolerance at altitude. If diagnosed early, patients may be able to pause ascent until symptoms resolve fully and then continue activities at a slowed rate. Shortness of breath at rest, especially at night, is highly suspicious for developing HAPE in an otherwise healthy individual.

Supplemental oxygen, if available, should be the first-line therapy in conjunction with descent for anyone suffering from more than mild symptoms. Logistics of treating HAPE in the wilderness may dictate what therapy is most appropriate. Oxygen is difficult to carry on a trek, and an oxygen concentrator may not be available. Portable hyperbaric oxygen chambers are easier to transport than oxygen and may be the best option for treatment in austere environments.

Nifedipine, sildenafil, tadalafil, and dexamethasone are useful for HAPE prophylaxis in known HAPE susceptible individuals. However, their role in the treatment of HAPE is limited. Dexamethasone shows no utility in the treatment of HAPE. These should not be used as monotherapy unless oxygen, hyperbaric therapy, and descent are all impossible.

Enhancing Healthcare Team Outcomes

Caring for patients in an austere environment presents a unique set of challenges regarding logistics, availability of therapies, and ability to perform diagnostic tests. The primary challenges in HAPE center around the ability to deliver supplemental or hyperbaric oxygen therapy to a patient at altitude and challenges with descent. The ability of those involved in a patient’s care to work as a team to meet these demands is critical. Unlike in a traditional hospital setting, the healthcare team member may have less experience than other team members, such as non-medical guides, who have knowledge of local resources and can coordinate descent. In wilderness settings, ideal therapies may not be feasible, and the only treatment option may be temporizing until definitive care.