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The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1β, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1β, VEGF, TNF-α, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1β was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.

Acute mountain sickness (AMS) and high-altitude cerebral edema share common clinical characteristics, suggesting cerebral swelling may be an important factor in the pathophysiology of AMS. Hypoxia and hypocapnia associated with high altitude are known to exert strong effects on the control of the cerebral circulation, yet how these effects interact during acute hypoxia, and whether AMS-susceptible subjects may have a unique response, is still unclear. To test if self-identified AMS-susceptible individuals show altered brain swelling in response to acute hypoxia, we used quantitative arterial spin-labeling and volumetric MRI to measure cerebral blood flow and cerebrospinal fluid (CSF) volume changes during 40 min of acute hypoxia. We estimated changes in cerebral blood volume (CBV) (from changes in cerebral blood flow) and brain parenchyma swelling (from changes in CBV and CSF). Subjects with extensive high-altitude experience in two groups participated: self-identified AMS-susceptible (n = 6), who invariably experienced AMS at altitude, and self-identified AMS-resistant (n = 6), who almost never experienced symptoms. During 40-min hypoxia, intracranial CSF volume decreased significantly [-10.5 ml (SD 6.9), P < 0.001]. There were significant increases in CBV [+2.3 ml (SD 2.5), P < 0.005] and brain parenchyma volume [+8.2 ml (SD 6.4), P < 0.001]. However, there was no significant difference between self-identified AMS-susceptible and AMS-resistant groups for these acute-phase changes. In acute hypoxia, brain swelling occurs earlier than previously described, with significant shifts in intracranial CSF occurring as early as 40 min after exposure. These acute-phase changes are present in all individuals, irrespective of susceptibility to AMS.

Increased intracranial pressure is suspected in the pathogenesis of acute mountain sickness (AMS), but no studies have correlated it with the presence or severity of AMS. We sought to determine whether increased optic nerve sheath diameter, a surrogate measure of intracranial pressure, is associated with the presence and severity of AMS. We performed a cross-sectional study of travelers ascending through Pheriche, Nepal (4,240 m), from March 3 to May 14, 2006. AMS was assessed using the Lake Louise score. Optic nerve sheath diameter was measured by ultrasound. Ultrasound exams were performed and read by separate blinded observers. Two-hundred eighty seven subjects were enrolled. Ten of these underwent repeat examination. Mean optic nerve sheath diameter was 5.34 mm [95% confidence interval (CI) 5.18-5.51 mm] in the 69 subjects with AMS vs. 4.46 mm (95% CI 4.39-4.54 mm) in the 218 other subjects (P < 0.0001). There was also a positive association between optic nerve sheath diameter and total Lake Louise score (P for trend < 0.0001). In a multivariate logistic regression model of factors associated with AMS, optic nerve sheath diameter was strongly associated with AMS (odds ratio 6.3; 95% CI, 3.7-10.8; P < 0.001). In 10 subjects with repeat examinations, change in Lake Louise score had a strong positive correlation with change in optic nerve sheath diameter (R(2) = 0.84, P < 0.001). Optic nerve sheath diameter, a proxy for intracranial pressure, is associated with the presence and severity of AMS.

To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.

Free radical-mediated changes in vascular permeability and subsequent inflammatory response may be a contributory pathogenetic cofactor responsible for the development of neurological sequelae associated with acute mountain sickness (AMS). To investigate this, 49 subjects were examined at sea level and serially after rapid ascent to 4,559 m. Although the venous concentration of total creatine phosphokinase activity was measured in all subjects, a complementary examination of lipid peroxidation (F(2)-isoprostanes), inflammatory (TNF-alpha, IL-1beta, IL-2, IL-6, IL-8, C-reactive protein), and cerebrovascular tissue damage (neuron-specific enolase) biomarkers was confined to a subcohort of 24 subjects. A selective increase (P < 0.05) in total creatine phosphokinase was observed in subjects diagnosed with AMS at high altitude (n = 25) compared with apparently healthy controls (n = 24). However, despite a marked increase in IL-6 and C-reactive protein attributable primarily to subjects developing high-altitude pulmonary edema, subcohort analyses demonstrated no selective differences in F(2)-isoprostanes, neuron-specific enolase, or remaining proinflammatory cytokines due to AMS (n = 14). The present findings are the first to demonstrate that free radical-mediated neuronal damage of sufficient degree to be detected in the peripheral circulation does not occur and is, therefore, unlikely to be an important, initiating event that is critical for the development of AMS. The pathophysiological significance of increased sarcolemmal membrane permeability and inflammatory response, either as a cause or epiphenomenon of AMS and/or high-altitude pulmonary edema, remains to be elucidated.

Hilltop (H) strain Sprague-Dawley rats are more susceptible to chronic mountain sickness than are the Madison (M) strain rats. It is unclear what role pulmonary vascular remodeling, polycythemia, and hypoxia-induced vasoconstriction play in mediating the more severe pulmonary hypertension that develops in the H rats during chronic hypoxia. It is also unclear whether the increased sensitivity of the H rats to chronic mountain sickness is specific for a hypoxia effect or, instead, reflects a general propensity toward the development of pulmonary hypertension. Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonary hypertension. We hypothesized that the difference in the pulmonary vascular response to chronic hypoxia between H and M rats reflects an increased sensitivity of the H rats to any pulmonary hypertensive stimuli. Consequently, we expected the two strains to also differ in their susceptibility to MCT-induced pulmonary hypertension. Pulmonary arterial pressures in conscious H and M rats were measured 3 wk after a single dose of MCT, exposure to a simulated high altitude of 18,000 ft (barometric pressure = 380 mmHg), and administration of a single dose of saline as a placebo. The H rats had significantly higher pulmonary arterial pressures and right ventricular weights after MCT and chronic hypoxia than did the M rats. The H rats also had more pulmonary vascular remodeling, i.e., greater wall thickness as a percentage of vessel diameter, after MCT and chronic hypoxia than did the M rats. The H rats had significantly lower arterial PO2 than did the M rats after MCT, but the degree of hypoxemia was mild [arterial PO2 of 72.5 +/- 0.8 (SE) Torr for H rats vs. 77.4 +/- 0.8 Torr for M rats after MCT]. The H rats had lower arterial PCO2 and larger minute ventilation values than did the M rats after MCT. These ventilatory differences suggest that MCT caused more severe pulmonary vascular damage in the H rats than in the M rats. These data support the hypothesis that the H rats have a general propensity to develop pulmonary hypertension and suggest that differences in pulmonary vascular remodeling account for the increased susceptibility of H rats, compared with M rats, to both MCT and chronic hypoxia-induced pulmonary hypertension.

Progressive body weight loss occurs during high mountain expeditions, but whether it is due to hypoxia, inadequate diet, malabsorption, or the multiple stresses of the harsh environment is unknown. To determine whether hypoxia due to decompression causes weight loss, six men, provided with a palatable ad libitum diet, were studied during progressive decompression to 240 Torr over 40 days in a hypobaric chamber where hypoxia was the major environmental variable. Caloric intake decreased 43.0% from 3,136 to 1,789 kcal/day (P less than 0.001). The percent carbohydrate in the diet decreased from 62.1 to 53.2% (P less than 0.001). Over the 40 days of the study the subjects lost 7.4 +/- 2.2 (SD) kg and 1.6% (2.5 kg) of the total body weight as fat. Computerized tomographic scans indicated that most of the weight loss was derived from fat-free weight. The data indicated that prolonged exposure to the increasing hypoxia was associated with a reduction in carbohydrate preference and body weight despite access to ample varieties and quantities of food. This study suggested that hypoxia can be sufficient cause for the weight loss and decreased food consumption reported by mountain expeditions at high altitude.