Etiology and pathogenesis
| • Acute mountain sickness is caused by an ascent to high altitude without acclimatization. |
| • Hypoxia is a contributing factor in the pathogenesis. |
| • High-altitude cerebral edema is likely due to vasogenic as well as cytotoxic mechanisms, and venous hypertension is a possible contributory factor. |
| • Cerebral edema increases peripheral sympathetic activity that acts neurogenically in the lungs to cause high-altitude pulmonary edema. |
The process of acute acclimatization to high altitude is mediated by the endocrine system and involves hemoconcentration through diuresis to increase the oxygen carrying capacity of the blood as compensation for reduced partial pressure of oxygen (40). Disturbance of this mechanism may lead to the development of mountain sickness.
Acute mountain sickness is caused by ascent to high altitude without acclimatization, and chronic mountain sickness may result after prolonged residence at high altitude even in acclimatized persons. There is no agreement as to the height at which symptoms of acute mountain sickness appear consistently, as it depends on the state of acclimatization of a person. Gender, age, or level of physical fitness plays no significant role in the susceptibility to acute mountain sickness.
Cerebral blood flow increases in acute hypoxia, but there is no difference between white matter and grey matter, irrespective of susceptibility to acute mountain sickness. Therefore, acute phase differences in regional cerebral blood flow during acute hypoxia are not a primary feature of susceptibility to mountain sickness. Vasogenic and cytotoxic mechanisms are proposed for high-altitude cerebral edema, and venous hypertension is a possible contributory factor (39).
Symptoms of acute mountain sickness are often attributed to raised intracranial pressure resulting from cerebral edema. However, diffusion-weighted MRI studies have shown only slight astrocytic swelling caused by redistribution of fluid from the extracellular space to the intracellular space without any evidence for further barrier disruption or increase in cerebral edema or pressure. Cerebral edema is not a valid explanation of symptoms because some vasogenic edema occurs with as well as without symptoms of acute mountain sickness. Findings of a study in human volunteers indicate that hypoxia stimulates cerebral oxidative-nitrative stress, which may be a risk factor for acute mountain sickness by a mechanism that appears to be independent of impaired blood-brain barrier function and cerebral oxidative metabolism (04).
Levels of arterial norepinephrine are significantly higher at baseline and during the first hour of hypoxia in subjects who later develop acute mountain sickness, and this may be a possible biomarker for individuals who may be relatively susceptible to the illness (23). Results of a study of cortical excitability using transcranial magnetic stimulation suggest that high altitude deeply changes cortical excitability by affecting both inhibitory and excitatory circuits and that this is reflected in acute mountain sickness symptoms (31).
In a study of acute mountain sickness, headache fulfilling the criteria of migraine increased in frequency, and this association may be due to common nonspecific symptoms, although a common underlying pathophysiology cannot be excluded (34). However, a history of migraine or other headache at low altitude is not a major risk factor for acute mountain sickness.
Stormy weather is another aggravating factor because a low-pressure front on the weather map is equivalent to several hundred feet of additional altitude. Hypoxia is an important factor in the etiology of acute mountain sickness, and a decrease in barometric pressure is the main cause of hypoxia at high altitude. Partial pressure of oxygen falls 30%, from 159 mm Hg at sea level to 112 mm Hg at a height of 2900 m, and a 50% decrease occurs at an altitude of 5500 m, which is the highest level of continuous human habitation (20). Residence above this level leads to some manifestations of chronic mountain sickness.
Various studies suggest that genotype contributes to capacity to rapidly and efficiently acclimatize to altitude, but the mechanism by which this occurs has not been elucidated (28). There is a wide variation among individuals regarding performance at high altitude and susceptibility to high-altitude illness, which may occur as a result of genetic variation. Only limited information is available about the genetic basis of high-altitude illness. No clear associations between gene polymorphisms and susceptibility to mountain sickness have been discovered.
A higher than anticipated occurrence of acute mountain sickness (42.85%) has been noted among athletes with neurologic impairments due to spinal cord injury, multiple sclerosis, and traumatic brain injury. Neurologic disability groups, history of acute mountain sickness, and prior occurrence of headache at high altitude could be used as predictors for the development of symptoms of acute mountain sickness (22).
Altitude sickness has been reported to occur in air force pilots flying above 5000 m in unpressurized aircrafts. Symptoms are subtle and often involve cognitive impairment or lightheadedness. The most common cause of hypoxia in these aircraft is the failure of the mask or regulator, or a mask leak. Rapid accidental decompression did not feature as a cause of hypoxia in these cases.
The pathomechanism of acute mountain sickness is not clear. Hypoxia at high altitude appears to be a triggering factor. Increased free plasma vascular endothelial growth factor, a hypoxia-induced protein that produces vascular permeability on ascent to altitude, is associated with acute mountain sickness and may play a role in its pathophysiology. Physiological and pathophysiological responses to extreme environmental challenges such as hypoxia of high altitude are like responses seen in critical illness. Study of human responses to hypobaric hypoxia may offer important insights into the pathophysiology of critical illness.
Both hypoxia as well as hyperoxia may alter reactive oxygen species (ROS) production by changing mitochondrial Po2 (PmO2), and high ROS levels may cause oxidative stress and cell damage. Altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. Because PmO2 depends on the balance between O2 transport and utilization, a mathematical model of O2 transport and utilization in skeletal muscle can be used to predict conditions that cause abnormally high ROS generation (08). According to this model, ROS generation in exercising normal muscle switches to high levels at approximately 5000 meters, which is the altitude above which permanent human residence is impossible.
Another study has shown that increases in severity of acute mountain sickness is independently related to normobaric hypoxia, hypobaric hypoxia, and duration of exercise, suggesting that hypobaric hypoxia may affect development of acute mountain sickness above the level induced by normobaric hypoxia alone and that the 2 conditions are not interchangeable for studying acute mountain sickness (11). However, the duration of exercise has an impact on physiological responses.
Hypoxia also leads to capillary leak and vasogenic cerebral edema, which is a major operating factor in high-altitude cerebral edema. This has been demonstrated by MRI studies that show reversible white matter edema. The flux of the fluid is influenced by the hydrostatic pressure in presence of an opening of the blood-brain barrier. With progression of extracellular vasogenic edema, the intercapillary distance is increased, rendering the cells ischemic. They may swell further, increasing the intracranial pressure. This cytotoxic mechanism, which has been used in the past to explain high-altitude cerebral edema, may become operational at a later stage and may be preventable by the earlier treatment of vasogenic edema. This concept is supported by the effectiveness of dexamethasone in treating high-altitude cerebral edema. Cerebral edema has been investigated by MRI in volunteers exposed to normobaric hypoxia and shown to be aggravated by exercise (29). Edema was associated with accumulation of water in the extracellular space but independent of development of acute mountain sickness, casting doubt on the concept that acute mountain sickness and high-altitude cerebral edema share a common mechanism.
Animal experimental studies have shown that hypoxia-induced cerebral edema and neuronal apoptosis are associated with increased expression of the neuropeptide corticotrophin releasing factor (CRF), which acts on type 1 receptor (CRFR1) to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of water channel aquaporin-4 (AQP4) and cerebral edema (09). These effects can be blocked by a CRFR1 antagonist.
High-altitude anterior ischemic optic neuropathy is likely due to inadequate autoregulatory response of the retinal vascular system.
Fever in acute mountain sickness is attributed to systemic inflammatory reaction. Rise of temperature may be correlated with reduction in arterial oxygen saturation at high altitude.
The pathophysiology of high-altitude pulmonary edema is unclear, but hypoxia-induced pulmonary artery hypertension is well documented. Pulmonary capillary pressure remains normal, indicating that high-altitude pulmonary edema is not cardiac in origin. The edema fluid has a high content of protein, red cells, and leukocytes, resembling the fluid characteristics in neurogenic pulmonary edema. The accumulation of this protein-rich fluid in the alveolar space implies an increase in the permeability of the pulmonary vascular epithelium that overwhelms the lung's capacity for removing fluid from the alveoli. Hypoxia, in addition to pulmonary hypertension, plays a part in the increased permeability. The role of pulmonary hypertension is supported by the effectiveness of nifedipine and nitric oxide in relieving pulmonary edema by reducing pulmonary hypertension. Sodium-driven clearance of alveolar fluid may also have a pathogenic role in pulmonary edema. This forms the basis of beta-adrenergic agonists therapy, which upregulates the clearance of alveolar fluid and attenuates pulmonary edema.
Primary intracranial events in high-altitude cerebral edema (cerebral edema, hypoxic cerebral vasodilatation, and elevated cerebral capillary hydrostatic pressure) elevate peripheral sympathetic activity that acts neurogenically in the lungs to cause high-altitude pulmonary edema. These events also act on the kidneys to promote salt and water retention.
Predisposing factors. Various factors that may predispose to acute mountain sickness include the following.
Genetic. In a case-control study, sequencing showed a significant association between the rs1008348 polymorphism and susceptibility to acute mountain sickness in a Han Chinese population, suggesting that this particular single nucleotide polymorphism might be a risk factor (25). This study provides a basis for further elucidation of the genetic mechanisms underlying acute mountain sickness.
Physical exercise at high altitude. This increases the incidence and severity of acute mountain sickness, probably by exercise-induced exaggeration of arterial hypoxemia. Increased ventilatory response to a hypoxic environment is a normal acclimatization response, and alterations in the response, such as inappropriate hypoventilation, have been implicated in the pathogenesis of acute mountain sickness. Support for this hypothesis comes from the prophylactic effectiveness of acetazolamide, a drug that increases ventilation.
Preexisting medical conditions. Persons with preexisting medical conditions, such as chronic obstructive pulmonary disease and sickle cell anemia, may face increased risks at high altitude.
Predisposing factors for acute mountain sickness are obesity, alcohol or sedative consumption, and physical exhaustion. The use of oral contraceptives at high altitudes is associated with an increased risk for the development of acute mountain sickness (15). The reason for this is lowering of circulating progesterone, which has antiinflammatory and antidiuretic effects, in addition to respiratory smooth muscle relaxation.
Individuals with low baseline insulin sensitivity levels are more susceptible to the development of acute mountain sickness (36). Potential diabetogenic side effects should be considered when using dexamethasone for treatment in these persons.
