High-Altitude Cardiopulmonary Diseases

Etiology

High-altitude pulmonary edema is classically associated with rapid ascent without adequate time for acclimatization. Individual susceptibility, environmental conditions, and underlying medical comorbidities influence the likelihood of developing this condition.

High-altitude pulmonary edema occurs more frequently in men and individuals who consume substances that depress respiratory function, such as alcohol and sedatives. A prior history of high-altitude pulmonary edema significantly increases the risk of recurrence, with rates reaching up to 60% in some studies.[4][5]

A rapid rate of ascent is a major predisposing factor for high-altitude pulmonary edema, whether through sudden elevation gain by air travel or progressive ascent by trekking. Higher altitudes, colder temperatures, and destinations requiring greater physical exertion are associated with a higher incidence of high-altitude pulmonary edema.[6]

Underlying medical conditions also increase the risk of developing high-altitude pulmonary edema. High-risk conditions include pulmonary hypertension, restrictive or obstructive lung disease, and congenital cardiac abnormalities.[7] Individuals with a patent foramen ovale appear disproportionately affected by high-altitude pulmonary edema.[8] Other structural defects that result in left-to-right shunts, such as atrial septal defects, ventricular septal defects, and patent ductus arteriosus, also predispose to high-altitude pulmonary edema.[9] Congenital absence of the right pulmonary artery is associated with a particularly high risk of developing high-altitude pulmonary edema.

Although not fully understood, genetic factors influence susceptibility to high-altitude pulmonary edema. At-risk individuals exhibit lower nitric oxide levels and elevated endothelin levels during hypoxic exposure compared to less sensitive counterparts. These individuals also demonstrate impaired sodium and water transport across the alveolar epithelium, limiting fluid clearance and contributing to pulmonary edema.[10] Ongoing research continues to explore the genetic contributions of pathways involving nitric oxide, nitric oxide synthase, angiotensin-converting enzyme, and the renin-angiotensin-aldosterone system.[11][12]

Epidemiology

The cardiovascular and cerebral effects of altitude become more pronounced at higher elevations. High altitude is typically defined as 1500 to 3500 m (4921–11,483 ft), very high altitude as 3500 to 5500 m (11,483–18,045 ft), and extreme altitude as above 5500 m (18,045 ft).[13]

Altitude-related illnesses occur most frequently above 2500 m (8200 ft), with more severe forms rarely observed below 3000 m.[14] Overall incidence varies due to factors such as rate of ascent and time allowed for acclimatization.[15] At moderately high-altitude resorts in Colorado, the incidence may reach 1 in 10,000 travelers. At extreme altitudes, such as during summit attempts of Denali (6200 m), incidence rises to 2% to 3%. Among Indian Army soldiers rapidly deployed by helicopter to 5500 m, a 15% incidence was reported, attributed to abrupt ascent.

The incidence of high-altitude pulmonary edema correlates strongly with ascent rate. When ascending to 4500 m over 4 days, the incidence of high-altitude pulmonary edema is approximately 0.2%, increasing to 6% with an ascent over 1 to 2 days.

Pathophysiology

The hallmark of high-altitude pulmonary edema is noncardiogenic pulmonary edema that progresses to respiratory distress and failure. The condition is multifactorial. Hypoxia at altitude induces pulmonary vasoconstriction, leading to pulmonary hypertension, capillary overperfusion, vascular leak, and pulmonary edema.

In normally ventilated lungs, localized hypoxia, such as that observed in lobar pneumonia, triggers regional vasoconstriction to divert blood flow toward well-ventilated areas, optimizing oxygenation. This adaptive response, known as the hypoxic pulmonary vasoconstrictor response, enhances gas exchange and maintains systemic oxygenation.[16] At high altitudes, decreased ambient oxygen leads to global alveolar hypoxia. In response, the pulmonary vasculature undergoes widespread vasoconstriction, resulting in diffuse pulmonary artery hypertension.[17][18] Pulmonary hypertension is consistently observed in patients with high-altitude pulmonary edema, although not all individuals with pulmonary hypertension develop high-altitude pulmonary edema.

Increased pulmonary artery pressures occur in an unequal distribution throughout the lung, creating focal capillary beds with elevated pressures, overperfusion, and edema secondary to capillary leak. This uneven distribution of overperfusion and vascular leak likely accounts for the patchy edema patterns observed on imaging.

As capillary leak progresses, disruption of epithelial membranes worsens, leading to further accumulation of edema. Autopsy studies have reported lung weights 2 to 4 times the normal. Alveolar hemorrhage and pulmonary infarcts are common. Edema fluid collected from bronchoalveolar lavage and autopsy often contains proteinaceous debris, plasma, red blood cells, and microthrombi, but lacks neutrophils and bacteria.[19]

History and Physical

In the wilderness setting, high-altitude pulmonary edema is primarily a clinical diagnosis, making a detailed history and physical examination essential. Most cases of high-altitude pulmonary edema develop within the first 2 to 4 days of ascent, with symptoms commonly beginning on the second night at altitude. Early symptoms are often subtle and mistaken for the effects of exertion, including a nonproductive cough, mild exertional dyspnea, reduced exercise tolerance, and prolonged recovery after activity.[20]

Without recognition, high-altitude pulmonary edema progresses to increasing fatigue and weakness, mild cyanosis, tachypnea, and tachycardia. Dyspnea at rest, especially worsening at night, is the hallmark of high-altitude pulmonary edema. At this stage, most individuals recognize the severity of their symptoms and seek medical attention. Pink, frothy sputum typically appears only in the late stages of high-altitude pulmonary edema.

Approximately 50% of high-altitude pulmonary edema cases present with symptoms of acute mountain sickness, including headache, nausea, vomiting, insomnia, or dizziness. About 14% of patients with high-altitude pulmonary edema also develop high-altitude cerebral edema, which presents with mental status changes such as ataxia and confusion, progressing to coma in severe cases.

Profound hypoxia is the most consistent clinical finding in high-altitude pulmonary edema. On physical examination, respiratory distress with increased work of breathing is observed. Tachypnea, tachycardia, cyanosis, and rales are frequently noted on pulmonary auscultation. Low-grade fever up to 38.5 °C (101.3 °F) can occur but is uncommon. High-altitude pulmonary edema must remain high on the differential diagnosis in any patient at altitude who presents with hypoxia and altered mental status, regardless of subjective respiratory complaints.

Evaluation

A thorough history, physical examination, and vital sign assessment are sufficient to diagnose high-altitude pulmonary edema. Laboratory tests and imaging are not required but may provide supportive evidence and help assess severity.

Chest x-rays in high-altitude pulmonary edema typically show pulmonary infiltrates in an unequal, patchy distribution, which may be unilateral or bilateral. The right middle lobe is most commonly involved. The extent of infiltrates correlates with clinical severity.[21] Consistent with noncardiogenic edema, cardiomegaly is absent. Serial radiographs often show rapid resolution, aligning with clinical improvement following descent and treatment.

Pulmonary ultrasound in high-altitude pulmonary edema reveals comet-tail artifacts, also known as B-lines. Although initially designed for cardiogenic pulmonary edema, the comet-tail scoring system is also effective in assessing altitude-related pulmonary edema. These artifacts arise from fluid-induced acoustic interference that reflects the ultrasound beam.[22] Echocardiography may show elevated pulmonary artery pressures and, in severe cases, signs of right heart strain.

No laboratory test confirms the diagnosis of high-altitude pulmonary edema. Arterial blood gas typically shows hypoxemia and respiratory alkalosis. Mild leukocytosis is common but nonspecific. Brain natriuretic peptide may be mildly to moderately elevated.[23] Troponin levels can also be mildly elevated, particularly when right heart strain is present.

Treatment / Management

Treatment of high-altitude pulmonary edema depends on illness severity, available resources, and evacuation logistics in wilderness settings. The primary interventions are descent and supplemental oxygen. Patients with mild-to-moderate high-altitude pulmonary edema typically show rapid clinical improvement with a descent of just 500 to 1000 m. However, environmental challenges and the patient's reduced exercise tolerance or inability to ambulate may limit descent feasibility.

Oxygen therapy should begin immediately upon clinical suspicion of high-altitude pulmonary edema to correct hypoxia, blunt the hypoxic pulmonary vasoconstrictor response, and improve symptoms. The goal is to maintain oxygen saturations at or above 90%. If descent is delayed or not possible, hyperbaric oxygen therapy is an effective alternative. Portable hyperbaric chambers are sometimes available for field use by rescue teams. Cold exposure and continued exertion exacerbate pulmonary artery pressures and may worsen high-altitude pulmonary edema, so patients should be kept warm and at rest unless descending.

In hospital settings, supplemental oxygen remains the cornerstone of therapy. The treatment improves oxygenation, reduces pulmonary vasoconstriction and shunting, and leads to rapid symptomatic improvement, including decreased work of breathing, resolution of tachypnea, and normalization of heart rate. In severe cases, positive airway pressure support, such as continuous positive airway pressure or expiratory positive airway pressure, may be beneficial.

Medications play a limited role in the management of high-altitude pulmonary edema, as descent and oxygen therapy remain the most effective interventions. Pharmacologic agents are primarily reserved for situations in which descent or oxygen is not feasible, or as adjunctive therapy in severe cases to reduce pulmonary artery pressures.

Nifedipine, a calcium channel blocker, reduces pulmonary vascular resistance and pulmonary artery pressure. The typical dosing for high-altitude pulmonary edema is 30 mg extended-release every 12 hours. Phosphodiesterase-5 inhibitors, such as sildenafil and tadalafil, have shown utility as prophylaxis and may provide benefit by enhancing nitric oxide–mediated pulmonary vasodilation.[24] Prophylactic dosing includes sildenafil 50 mg every 8 hours or tadalafil 10 mg every 12 hours. However, insufficient data exist to recommend treatment dosing for established high-altitude pulmonary edema.(B3)

Dexamethasone may be indicated for concurrent high-altitude cerebral edema but has no proven benefit when used alone for high-altitude pulmonary edema. Other medications such as diuretics, nitrates, and morphine have been studied in the past but are no longer recommended due to limited efficacy and potential for harm. The therapeutic effects of these agents are markedly inferior to descent and oxygen.

Patients with mild symptoms that resolve completely after descent can resume ascent after resting at a lower altitude for 2 to 3 days. In cases occurring at moderately high-altitude resorts, some patients may be managed without descent using low-flow supplemental oxygen for 2 to 3 days, provided symptoms are mild and healthcare providers are experienced in managing altitude illness.

Differential Diagnosis

Although altitude-related illnesses commonly cause clinical decompensation, exacerbations of underlying chronic conditions must remain on the differential. Pulmonary artery hypertension, congestive heart failure, peripheral edema, symptomatic valvular disease, dysrhythmias, pulmonary embolism, and acute pneumonia or bronchitis can all present at altitude and may contribute to hypoxia or dyspnea.

High-altitude pulmonary edema can occur in isolation or concurrently with other altitude-related conditions. A thorough history and assessment are crucial to evaluate for additional syndromes, such as high-altitude cerebral edema, acute mountain sickness, high-altitude headache, high-altitude syncope, and high-altitude bronchitis or cough. Thrombotic events, including cerebral vascular accidents and pulmonary emboli, are more frequent at high altitude. Immunosuppression has also been observed, increasing the risk of infection and delaying wound healing in otherwise immunocompetent individuals.

Prognosis

Although high-altitude pulmonary edema is the leading cause of altitude-related mortality, the overall prognosis is excellent with early recognition and prompt treatment. Identifying symptoms in the early stages and initiating therapy quickly are critical to preventing disease progression. Continued ascent or exertion after symptom onset increases the risk of worsening respiratory compromise. Even in moderate-to-severe cases, symptoms often resolve rapidly with supplemental oxygen and descent. Most patients who present to a hospital require only supportive care, primarily oxygen therapy.

Mildly affected individuals may be treated conservatively with cessation of ascent, rest, and observation until complete resolution of symptoms and acclimatization occurs. Once stable, these individuals may resume a gradual, cautious ascent with close monitoring for recurrence. Patients with a prior history of high-altitude pulmonary edema remain at increased risk for recurrence but can often tolerate reascent if they ascend slowly and allow adequate time for acclimatization. Long-term complications are rare.

Complications

Most individuals with high-altitude pulmonary edema who receive prompt treatment have a favorable prognosis with no complications. However, altitude exposure is associated with an increased risk of thrombosis and immunosuppression. Therefore, clinicians must consider concurrent pulmonary embolism or pneumonia in patients presenting with high-altitude pulmonary edema.[25] Many patients with high-altitude pulmonary edema also have coexisting acute mountain sickness or high-altitude cerebral edema, which may require additional therapies. No evidence supports a link between high-altitude pulmonary edema and long-term cardiopulmonary complications such as persistent pulmonary hypertension, congestive heart failure, recurrent pneumonia, obstructive lung disease, or similar conditions.