High-Altitude Illnesses

Introduction

• High-altitude illnesses arise from decreased arterial oxygen saturation and partial pressure of oxygen above 2500 meters, leading to hypobaric hypoxia and reduced oxygen delivery to tissues.
• Acute high-altitude illnesses include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE).
• AMS and HACE are believed to exist along a clinical spectrum, with AMS commonly preceding the more severe form of HACE.^1,2
• CMS represents a long-term maladaptation to high-altitude hypoxia, and its prevalence varies significantly depending on genetic and geographic factors.

Epidemiology and Risk Factors

• AMS affects approximately 25% of individuals ascending to 2500–3000 meters and up to 50% of those who ascend above 4000 meters.^1,2
• Risk factors include rapid ascent, poor acclimatization, physical exertion at altitude, and individual susceptibility. Of note, pre-ascent physical conditioning does not decrease risk.^1,2
• HACE, a severe progression of AMS, occurs in approximately 1% to 2% of individuals ascending to 4000 meters and is rare below 2500 meters.³
  • Less than 1% of cases of AMS progress to HACE.³
  • HACE shares the same risk factors as AMS.^1,2
• HAPE has an incidence of 0.01–0.1% at 2500 meters, increasing to 2–6% when ascending to 4000 meters.³
  • Risk increases with rapid ascent, male sex, cold exposure, cardiopulmonary disease, and reentry to high altitude after time at lower elevations.¹
• CMS affects long-term residents above 3000 meters, with prevalence ranging from 1.2% in Tibetans to 33.7% in Andean populations, suggesting a genetic influence on disease development.¹

Pathophysiology

• AMS is thought to result from central nervous system dysfunction secondary to hypoxia.^1,2
  • Central hypoxia leads to cerebral vasodilation and mild brain edema. Additionally, blood-brain barrier permeability is increased in AMS, which lowers oncotic pressure through protein leakage, contributing to cerebral edema.^1,2
  • Individuals with lower cerebrospinal fluid-to-brain ratios may be more susceptible to developing AMS.²
• HACE represents a severe extension of AMS, characterized by severe, vasogenic cerebral edema from continued blood-brain barrier breakdown.^1,2
  • Microhemorrhages, particularly in the corpus callosum, are a distinguishing feature of HACE from AMS and may indicate venous obstruction as a key pathological process of disease progression.¹
• HAPE is believed to result from exaggerated hypoxic pulmonary vasoconstriction leading to elevated pulmonary artery pressure and noncardiogenic pulmonary edema.^1,2
  • Uneven pulmonary vasoconstriction and reduced nitric oxide availability contribute to elevated pulmonary vascular pressures and the subsequent development of edema.²
  • Pulmonary artery pressures can exceed 60 mm Hg in susceptible individuals.¹
• CMS develops from chronic hypoxia at altitude, which triggers excess erythropoietin production that results in polycythemia and increased blood viscosity.¹
  • Genetic predispositions such as SENP1 gene variants and poor ventilatory acclimatization may contribute to disease development.¹

Clinical Features and Diagnosis

• AMS typically presents 4–12 hours after ascent to high altitude and presents with headache, fatigue, nausea, dizziness, insomnia, and anorexia.^1,2
  • Symptoms peak after the first night and resolve with rest in 1–3 days.³
  • Headache is the hallmark symptom of AMS. The Lake Louise Score (LLS) is commonly used in research and may aid clinical assessment, with a score ≥3 with headache being diagnostic for AMS (Table 1).^1-3

• HACE presents 3-5 days after ascent and presents as worsening AMS with ataxia, confusion, irritability, drowsiness, and potentially coma.^1,3
• Neurologic exam findings such as truncal ataxia, papilledema, cranial nerve palsies, or retinal hemorrhages may be present.^2,3
• Magnetic resonance imaging may show T2/FLAIR hyperintensities of the corpus callosum.²
• HAPE presents 2–4 days after ascent, often without preceding AMS. Symptoms include dry cough and exertional dyspnea, which may progress to rest dyspnea, pink frothy sputum, and cyanosis.^1,2
• Exam findings include tachypnea, tachycardia, fever, and inspiratory crackles.^1-3
• Radiographic findings are not specific for HAPE; however, chest radiographs may reveal bilateral patchy infiltrates, and echocardiography may show evidence of right-ventricular strain.²
• CMS presents with fatigue, dyspnea, cyanosis, headache, and reduced exercise tolerance. Longstanding disease can progress to right heart failure and pulmonary hypertension.¹
• Hemoglobin levels often exceed 21 g/dL in men and 19 g/dL in women.¹
• A summary of clinical and diagnostic features is presented in Table 2.

Prevention and Treatment

• Primary prevention of all acute high-altitude illnesses is centered around gradual ascent (300–600 meters per day above 3000 meters) with rest days every 2–3 days.^1,2
  • Sleeping at lower altitudes, adequate hydration, oxygen supplementation, and pre-acclimatization are effective nonpharmacological prevention strategies.¹
• Adjunct pharmacologic prophylaxis may be considered for high-risk individuals.
  • Acetazolamide is first-line pharmacologic prophylaxis for AMS and HACE. Dexamethasone is considered an alternative or adjunct for prevention.^1,2
  • Nifedipine is first-line pharmacologic prophylaxis for HAPE. Salmeterol and tadalafil are potential adjuncts.^1,2
• Treatment of acute high-altitude illness begins with rest, immediate descent, and symptomatic therapy such as nonsteroidal anti-inflammatory drugs or antiemetics.^1-3
  • Supplemental oxygen or hyperbaric oxygen, if available, should be started if descent is not immediately possible.^1,2
  • A diagram for the management algorithm of acute high-altitude illnesses is shown in Figure 1.
• Pharmacologic treatment is appropriate for severe AMS, HACE, and HAPE, with specific therapies summarized in Table 3.⁴