High-altitude regions are defined as areas situated at elevations exceeding 3,000 meters above sea level. These environments are characterized by thin air, low atmospheric and oxygen partial pressures, cold and dry climates, and intense ultraviolet radiation. When individuals from low-altitude (plains) regions relocate to or temporarily stay at high-altitude areas, their insufficient adaptability to these conditions may lead to a group of disorders prominently characterized by hypoxia. These disorders are collectively referred to as high altitude sickness or unacclimatization to high altitude, also known as mountain sickness. High-altitude sickness can also occur in areas below 3,000 meters. Acute high-altitude sickness is generally self-limiting and has a favorable prognosis, but complications such as high-altitude pulmonary edema or high-altitude cerebral edema can be life-threatening. With the growth of tourism, the incidence of this condition has significantly increased, making it a common cause of illness and death among high-altitude travelers.
Etiology
In high-altitude regions, the reduced atmospheric and oxygen partial pressures lead to hypoxia upon entry. As elevation increases, the partial pressure of inhaled oxygen drops dramatically, creating serious limitations in oxygen delivery. Hypobaric hypoxemia is a key factor in the development of acute high-altitude sickness.
- At altitudes of 2,400–2,700 meters, arterial oxygen saturation decreases slightly.
- At 3,500–4,000 meters, arterial oxygen saturation falls below 90%.
- At 5,000 meters, it drops further to 75%.
- Above 5,500 meters, severe hypoxemia and hypocapnia occur, and acclimatization may take weeks or months—or may not occur at all.
- At 7,000 meters, arterial oxygen saturation decreases to 60%.
- At 8,000 meters, where atmospheric pressure is approximately 268 mmHg (35.62 kPa)—about one-third of sea level pressure (760 mmHg)—the partial pressure of inhaled oxygen drops to only 56 mmHg (7.46 kPa).
The speed of onset, severity, and incidence of high-altitude sickness are influenced by the altitude reached, the rate of ascent, the duration of stay, and individual susceptibility.
Pathogenesis
Upon transitioning from low altitude to high altitude, the body must undergo adaptive changes to cope with hypoxic conditions and maintain the pressure gradient necessary for gas exchange in capillaries. However, each individual has a limited capacity to adapt to hypoxia, and excessive hypoxia can result in maladaptation.
Nervous System
The brain has high metabolic activity and oxygen demand, making the cerebral cortex particularly intolerant to hypoxia. During acute hypoxia, cerebral vasodilation, increased cerebral blood flow, and elevated intracranial pressure occur initially. This leads to heightened cortical excitability and symptoms such as headaches, talkativeness, insomnia, and ataxia.
As hypoxia worsens, anaerobic metabolism in brain cells increases, reducing ATP production. Dysfunction in the sodium-potassium pump of cell membranes leads to intracellular sodium and water retention, resulting in high-altitude cerebral edema.
Respiratory System
When arterial oxygen partial pressure decreases at high altitude, chemoreceptors in the carotid and aortic bodies are stimulated, triggering reflexive increases in respiration depth and rate. This enhances alveolar ventilation and improves arterial oxygen partial pressure. However, excessive ventilation causes the loss of CO2, leading to respiratory alkalosis.
In individuals with strong adaptive capacities, renal compensation increases the excretion of bicarbonate (HCO3-) to counteract respiratory alkalosis. Acute hypoxia also causes pulmonary arteriolar spasms, and sustained spasm leads to thickening of the smooth muscle layer, increased pulmonary vascular resistance, and elevated pulmonary capillary wedge pressures. Increased vascular permeability and plasma extravasation result in high-altitude pulmonary edema.
Additionally, damage to alveolar walls and pulmonary capillaries, reduced surfactant levels, and release of vasoactive substances (such as arachidonic acid, prostaglandins, and thromboxane A2) exacerbate endothelial injury and leakage, worsening pulmonary edema and causing bloody sputum. Climbers often exhibit endothelin levels in their blood that are twice as high as normal. Endothelin binds to vascular endothelial cell receptors, activating calcium channels and inducing vasoconstriction. As oxygen delivery improves, endothelin levels and pulmonary artery pressure decrease.
In chronic high-altitude sickness, the central respiratory center’s sensitivity to CO2 and the peripheral chemoreceptors’ sensitivity to hypoxia diminish, leading to insufficient alveolar ventilation. Prolonged exposure to a hypoxic environment can cause hypertrophy of pulmonary arteriolar smooth muscle and intimal fibrosis, ultimately resulting in pulmonary hypertension and chronic high-altitude sickness.
Cardiovascular System
Hypoxia at high altitudes stimulates chemoreceptors in the carotid and aortic bodies, leading to an accelerated heart rate as an early compensatory response. This accelerated heart rate and increased cardiac output aim to maintain oxygen delivery. During acute hypoxia, blood redistributes within the body; vasoconstriction in the skin and abdominal organs, particularly the kidneys, reduces blood supply to these areas, while vasodilation in the heart and brain increases blood flow to these vital organs. This redistribution mechanism is crucial for maintaining blood supply to key tissues. Compensatory coronary artery dilation has a limit, and prolonged or severe hypoxia may result in myocardial damage.
For those living long-term at high altitudes, persistent pulmonary artery resistance leads to pulmonary hypertension. Pulmonary hypertension serves as a compensatory mechanism to improve pulmonary blood flow under hypoxic conditions; however, sustained elevation in pulmonary arterial pressure places significant strain on the right heart, resulting in right ventricular hypertrophy, a condition referred to as high-altitude heart disease. High-altitude heart disease falls under the umbrella of pulmonary heart disease. Secondary polycythemia induced by hypoxia elevates blood viscosity, thereby increasing cardiac workload. Hypoxia also stimulates the secretion of catecholamines, antidiuretic hormones, and adrenal corticosteroids while increasing renin-angiotensin-aldosterone system activity, leading to elevated blood pressure and exacerbating high-altitude heart disease. Chronic hypoxia can damage the myocardium and impair adrenal cortical function, which may result in reduced systolic blood pressure and narrowed pulse pressure.
Hematopoietic System
Adaptation to hypoxia at high altitudes includes compensatory increases in red blood cell counts and hemoglobin levels. Acute hypoxia primarily triggers peripheral chemoreceptors, which reflexively stimulate sympathetic nervous system activity to enhance the release of stored red blood cells. Anaerobic glycolysis intensifies, increasing lactate levels and causing a drop in blood pH. The oxygen dissociation curve shifts to the right, and reduced hemoglobin levels alongside increased 2,3-diphosphoglycerate (2,3-DPG) synthesis lower hemoglobin’s affinity for oxygen, promoting oxygen release to tissues.
Hypoxemia also stimulates erythropoietin production, encouraging the proliferation of red blood cell systems in the bone marrow. Consequently, the number of red blood cells and hemoglobin concentration within them increase, thereby enhancing the oxygen-carrying capacity of the blood.
Pathology
The fundamental pathological feature of high-altitude sickness is cellular swelling. The brain, lungs, and peripheral blood vessels often exhibit platelet fibrin thrombi or venous thrombosis.
Acute High-Altitude Reaction
There are no characteristic pathological changes associated with acute reactions.
High-Altitude Pulmonary Edema
The lungs exhibit significant weight gain due to congestion and edema. Fibrin exudates and hyaline membrane formation can be seen within small airways and alveoli. Alveolar walls and pulmonary capillary cell membranes show degeneration, with apparent vascular dilation, congestion, and increased permeability. Scattered thrombosis is observed in pulmonary arteries, arterioles, and capillaries.
High-Altitude Cerebral Edema
Gross pathological findings reveal congestion of the cerebral cortex and pia mater, and brain hernias may develop. Microscopic examination reveals brain cell swelling, edematous brain tissue, punctate hemorrhages, localized capillary damage, erythrocyte stasis, and platelet aggregation. Some brain cells exhibit degeneration or necrosis.
Chronic High-Altitude Sickness
Right ventricular enlargement, ventricular wall thickening, and chamber dilation are observed. At the microscopic level, myocardial cells exhibit cloudy swelling, necrotic foci, disrupted myocardial fibers, interstitial edema, and fibrosis. Enlargement of the right pulmonary artery trunk is seen, with loss of elastic fibers from the pulmonary artery trunk. Pulmonary arteriole medial hypertrophy, connective tissue proliferation, and arteriole sclerosis are evident.
Clinical Manifestations
The onset and severity of high-altitude sickness depend on the speed and extent of adaptation to high-altitude conditions.
Acute High-Altitude Sickness
Acute high-altitude sickness manifests in three types, which may overlap or coexist.
Acute High-Altitude Reaction
This is a common occurrence, typically appearing within 6–24 hours after arrival at high-altitude regions among unacclimated individuals. Manifestations include bilateral frontal headache, palpitations, chest tightness, shortness of breath, loss of appetite, nausea, and vomiting. Neurological symptoms resemble those observed during alcohol intoxication. Cyanosis of the lips and nail beds may be visible in some cases. Symptoms generally improve within 24–48 hours of staying at high altitude and disappear within several days. However, in rare cases, symptoms may progress to pulmonary edema and/or cerebral edema.
High-Altitude Pulmonary Edema
This life-threatening and common type of high-altitude sickness typically develops within 2–4 days after rapid ascent to high-altitude regions. It begins with symptoms of acute high-altitude reaction, followed by tachycardia, dyspnea, worsening dry cough, orthopnea, and productive cough with foamy white or pink sputum. Auscultation may reveal dry or wet rales in the lungs. Risk factors include excessive salt intake, rapid ascent, overexertion, cold exposure, respiratory infections, use of sleeping pills, or a prior history of pulmonary edema.
High-Altitude Cerebral Edema
Also known as nervous puna, this rare but severe form of acute high-altitude sickness typically develops within 1–3 days after reaching high-altitude regions. Symptoms include severe headache accompanied by vomiting, mental confusion, ataxia, hallucinations, auditory or visual disturbances, language impairment, and disorientation. Disease progression may result in an unsteady gait, drowsiness, stupor, or coma, and some patients may experience seizures.
Chronic High-Altitude Sickness
Chronic high-altitude sickness (also known as Monge's disease) is relatively rare and primarily occurs in individuals who have resided long-term or for generations at altitudes above 4,000 meters. The clinical manifestations can be categorized into the following types:
Chronic High-Altitude Reaction
This condition is characterized by persistent symptoms of acute high-altitude reaction that fail to resolve after three months. Common manifestations include headaches, dizziness, insomnia, memory decline, difficulty concentrating, palpitations, shortness of breath, loss of appetite, indigestion, numbness in the extremities, and facial edema. Some patients may experience arrhythmia or transient syncope.
High-Altitude Polycythemia
This is a compensatory physiological adaptation to hypoxia at high altitudes. However, excessive blood viscosity may result in the formation of microthrombi in cerebral blood vessels. Symptoms often include dizziness, headaches, memory impairment, insomnia, or transient ischemic attacks, along with facial cyanosis and clubbing of the fingers.
High-Altitude Blood Pressure Changes
Individuals living long-term or for generations at high altitudes typically exhibit lower blood pressure levels (≤90/60 mmHg), accompanied by symptoms such as headaches, dizziness, fatigue, and insomnia, which are indicative of nervous system fatigue. When blood pressure rises, high-altitude hypertension may be diagnosed. This condition resembles primary hypertension but rarely leads to damage to the heart or kidneys. In some cases, high-altitude hypertension may transition into low blood pressure.
High-Altitude Heart Disease
This condition commonly occurs in infants born at high altitudes and in adults after inhabiting high-altitude locations for 6–12 months. Common symptoms include palpitations, shortness of breath, chest tightness, coughing, cyanosis, jugular vein distention, arrhythmia, hepatomegaly, ascites, and peripheral edema. Intermittent sleep apnea or snoring may also develop and should be differentiated from obesity hypoventilation syndrome (Pickwickian syndrome).
Laboratory Examinations
Hematologic Tests
Patients with acute high-altitude sickness may exhibit mild leukocytosis. Chronic cases often show red blood cell counts exceeding 7.0×1012/L, hemoglobin concentrations above 180 g/L, and hematocrit levels above 0.60.
Electrocardiographic Tests
Chronic high-altitude heart disease may show findings such as right axis deviation, pulmonary P waves, right ventricular hypertrophy and strain, T-wave inversion, and/or right bundle branch block.
Chest X-Ray
Patients with high-altitude pulmonary edema may display diffuse patchy or hazy opacities in both lung fields. High-altitude heart disease is associated with prominent pulmonary arteries, a transverse diameter of the right lower pulmonary artery trunk ≥15 mm, and right ventricular enlargement.
Pulmonary Function Tests
Arterial blood gas analysis in patients with high-altitude pulmonary edema may show hypoxemia, hypocapnia, and respiratory alkalosis. Patients with high-altitude heart disease may present with hypoxemia and elevated PaCO2. Pulmonary function tests in chronic high-altitude sickness often reveal reduced vital capacity, decreased peak expiratory flow, and lower minute ventilation. Right heart catheterization identifies elevated pulmonary arterial pressure, right atrial pressure, and right ventricular pressure, with normal pulmonary capillary wedge pressure (PCWP).
Diagnosis and Differential Diagnosis
The diagnosis of high-altitude sickness is based on the following criteria:
- The condition develops after ascent to a high-altitude area.
- Symptoms are clearly related to altitude, ascent rate, and level of acclimatization.
- Other diseases with similar manifestations are excluded.
- Symptom improvement is observed with oxygen therapy or relocation to a lower-altitude environment.
Additionally, differentiation should be made between different clinical types of high-altitude sickness and related conditions:
Acute High-Altitude Reaction
This should be differentiated from motion sickness and acute gastroenteritis.
High-Altitude Pulmonary Edema
This should be differentiated from pneumonia, high-altitude bronchitis, pulmonary embolism, pulmonary infarction, or pneumothorax. Cases presenting with pulmonary edema or acute respiratory distress syndrome (ARDS) should also be differentiated from cardiogenic or other non-cardiogenic pulmonary edema, such as that caused by drugs or neurological conditions.
High-Altitude Cerebral Edema
This should be differentiated from metabolic or toxic encephalopathy, cerebrovascular events, and traumatic brain injury.
High-Altitude Polycythemia
This should primarily be differentiated from polycythemia vera, which is more common in middle-aged and elderly individuals and is associated with pronounced splenomegaly. In addition to red blood cell proliferation, polycythemia vera also involves increases in white blood cells and platelets. Unlike high-altitude polycythemia, it does not respond to oxygen therapy or relocation.
Treatment
Acute High-Altitude Reaction
Rest
Acute high-altitude reaction requires cessation of climbing and bed rest until symptoms improve, along with sufficient fluid intake.
Oxygen Therapy
Symptoms can be alleviated in nearly all cases through nasal cannula or mask oxygen inhalation at 1–2 L/min.
Medication
Headaches may be managed with oral aspirin (650 mg), acetaminophen (650–1,000 mg), ibuprofen (600–800 mg), or prochlorperazine. In cases of nausea and vomiting, intramuscular prochlorperazine (or promethazine) is recommended. Severe cases may benefit from oral dexamethasone (4 mg every 6 hours) alone or in combination with acetazolamide (500 mg, taken once daily in the afternoon).
Relocation Therapy
Patients whose symptoms do not improve or worsen should be relocated to lower altitudes as soon as possible. A reduction of just 300 meters in altitude can lead to significant symptom improvement.
High-Altitude Pulmonary Edema
Rest
Absolute bed rest in a half-sitting or elevated pillow position is necessary to maintain warmth and reduce strain.
Oxygen Therapy
Inhalation of 40–50% oxygen at 6–12 L/min via a mask can effectively relieve breathlessness and tachycardia. Portable hyperbaric (Gamow) bags, if available, can also be employed.
Relocation Therapy
When oxygen therapy is ineffective, patients should be relocated to lower altitudes immediately. Most cases recover within two days of descending below 3,000 meters.
Medication
For patients unable to be transferred, sublingual or oral nifedipine (10 mg every 4 hours) can reduce pulmonary arterial pressure and improve oxygenation to relieve symptoms. Aminophylline, with its bronchodilator, diuretic, and pulmonary arterial pressure-lowering properties, is given as a slow intravenous injection of 0.25 g diluted in 20–40 ml of 5–50% glucose solution, repeated every 4–6 hours as needed. Intravenous furosemide (40–80 mg) helps reduce blood volume and cardiac strain. Severe cases may require corticosteroid therapy, such as intravenous hydrocortisone (200–300 mg) or dexamethasone (10–20 mg). Rapid atrial fibrillation necessitates the use of digitalis and antiplatelet drugs (e.g., aspirin, dipyridamole, ticlopidine, or cilostazol). Recovery generally occurs within 24–48 hours following these treatments.
High-Altitude Cerebral Edema
Treatment principles are similar to those for acute high-altitude reaction and high-altitude pulmonary edema, with early recognition being critical for successful management.
Relocation Therapy
If ataxia is detected, patients must be relocated to a lower altitude, with a descent of at least 600 meters.
Oxygen Therapy
Oxygen inhalation at 40–50% (2–4 L/min) via a mask is recommended. In cases where relocation is not possible, portable hyperbaric bag therapy should be used.
Medication
Intravenous dexamethasone (8 mg initially, followed by 4 mg every 6 hours) is administered. Intravenous mannitol and furosemide (40–80 mg) are also given to reduce intracranial pressure. Urine output should exceed 900 ml within the first 24 hours.
Airway Management
For comatose patients, maintaining airway patency is essential, and intubation may be required. Over-ventilation should be avoided due to the common presence of respiratory alkalosis in these patients.
Chronic High-Altitude Sickness
Relocation Therapy
Relocation to sea-level areas is suggested when feasible.
Oxygen Therapy
Low-flow oxygen at night (1–2 L/min) can alleviate symptoms.
Medication
Acetazolamide (125 mg, twice daily) or medroxyprogesterone acetate (20 mg, three times daily) improves oxygen saturation.
Phlebotomy
Phlebotomy may serve as a temporary treatment measure.
Prevention
Education on high-altitude environmental characteristics, daily living tips, and high-altitude sickness prevention and treatment should be conducted before entering high-altitude areas.
Individuals with organic diseases, severe nervous fatigue, or respiratory infections are not suitable for travel to high-altitude regions.
Acclimatization exercises are recommended before climbing. Stair-step ascension is preferred, and if not possible, prophylactic administration of acetazolamide (250 mg every 8 hours) and/or dexamethasone (4 mg every 6 hours) starting 24 hours before ascent may help.
Upon reaching high-altitude areas, physical exertion should initially be minimized, with labor intensity increased gradually after acclimatization. Proper precautions against frostbite and cold exposure should be taken. Smoking, alcohol, and sedative-hypnotic drugs should be avoided. Adequate hydration must be maintained.
Prognosis
With timely diagnosis and active treatment, the prognosis of acute high-altitude sickness is generally favorable. However, delays in diagnosing and treating high-altitude pulmonary edema and cerebral edema can lead to fatal outcomes. Survivors of high-altitude pulmonary edema are prone to recurrence upon re-exposure to the same altitude. Most individuals with chronic high-altitude sickness recover within 1–2 months after descending to lower-altitude regions. However, those with high-altitude heart disease, characterized by pulmonary hypertension and right ventricular hypertrophy, are generally less likely to recover.