Hypobaric hypoxia is the term used to describe thehypoxia of altitude which is due to the exponential decrease in barometric pressure with subsequent decrease in the partial pressure of oxygen. (Figure 2) The oxygen concentration of the atmosphere remains nearly constant at 21% up to an elevation of 8800 m. It is the decreased partial pressure with subsequent decrease in the partial pressure of oxygen rather than a decreased concentration which causes the hypoxia of altitude. Acclimatization is the process by which the body physiologically adapts to the hypobaric hypoxia of altitude. This is a complex process which begins at elevations above 1500 m,(hence why thedefinition of altitude begins at 1500 m of elevation).



The first response of an individual to altitude is increased ventilation in an effort to reduce the hypoxia. This response is mediated by the carotid body chemo-receptors and results in a blowing off of alveolar CO2 which then allows the retention of alveolar oxygen.⁴⁴ Hyperventilation results in a respiratory alkalosis which stimulates the respiratory center in the medulla to inhibit the ventilatory rate. There is then a somewhat compensatory metabolic acidosis which results from the increased renal excretion of bicarbonate, allowing for continued hyperventilation. There physiologic processes, such as increasing red cell mass, changes in delivery of oxygen to tissues, and uptake of oxygen in the lungs, are also involved in acclimatization. The process of acclimatization requires time for these physiologic processes to occur. Given a gradual increase in elevation, the body can adapt effectively; failure to provide adequate time for acclimatization increases the risk for illness.

In order to promote acclimatization, it is generally recommended that after 3000 m, the sleeping elevation be advanced only by 300 m a day with a rest day every third day.⁴⁵ A study by the US Army Institute of Environmental Medicine (USARIEM) showed that returning to sea level results in a gradual loss of the acclimatization.⁴⁶ However, the researchers also reported that, following two to threeweeks of acclimatization at 4300 m, a return to sea level for eight days did not result in a loss of acclimatizedexercise ability. Intermittent altitude exposure has also been shown to result in acclimatization. In one experimental study using six subjects subjected to low intensity exercise, intermittent altitude exposure in a chamber for three to five hours a day for 17 days reduced AMS on subsequent altitude exposure. ⁴⁷ In another USARIEM study it was shown that exercise was not required for this effect as intermittent exposure to altitude for four hours a day five days a week for three weeks at 4300 m effectively reduced AMS severity.⁴⁸ Acclimatization to altitude does require exposure to hypobaric hypoxia; i.e., breathing normobaric hypoxic gas at sea level does not decrease the incidence of AMS.⁴⁹

Acute Mountain Sickness (AMS)

While failure to acclimatize results in AMS, the pathophysiology is complex, involving generalized fluid retention, hypoventilation, and CNS changes. Fluid retention is associated with AMS, generally developing within three hours and resulting in a rise of ADH. Individuals who do not develop AMS do not retain fluid on altitude exposure and have been found to have a rapid drop in ADH.⁵⁰ The actual hydration status of an individual does not appear to affect the development of AMS.⁵¹
 
Failure to hyperventilate on altitude exposure is another factor associated with AMS. Individuals who develop AMS appear to have a relativehypoventilation as compared to those who do not develop AMS, and are relatively hypoxic compared to those who are not sick.^52,53
 
Hypoxemia-related CNS swelling resulting in increased cerebral blood volumes has also been implicated in AMS.⁵⁴ In cases of moderate to severe AMS, an MRI study of seven individuals found four of the subjects to have an increase T2 signal in the brain white matter (these subjects did not have clinically definable HACE as they had no ataxia or alteration in mental status).⁵⁵ The presence of brain swelling alone, however, does not correlate with AMS; a 1999 study by Muza et al showed that, in seven  ubjects who ascended to 5000 m in a chamberfor eight hours, all had increased brain volume on MRI regardless of whether they had AMS or not.⁵⁶ It is unclear why all individuals develop brain swelling at altitude but only some individuals develop AMS. One hypothesis is that AMS is related to craniospacial capacitance to accommodate swelling; i.e., those with limited capacitance who cannot accommodate the cerebral swelling of altitude develop AMS, while those who can accommodate it do not.⁵⁷ This hypothesis also might explain why the elderly, with their decreased brain volumes, have a lower incidence of AMS.⁵⁸

High Altitude Pulmonary Edema

HAPE susceptible individuals show an exaggerated pulmonary artery pressure elevation on exposure to hypoxia and to exercise in both normoxic and hypoxic environments.⁵⁹ This exaggerated pulmonary response, which initially results in non-homogeneous vasoconstriction and regional overperfusion, is a hallmark of those susceptible to HAPE, but this factor alone is not sufficient to cause HAPE.⁶⁰ Cardiaccatheterization of HAPE victims shows a normal wedge pressure but a markedly elevated pulmonary artery pressure of 60 mm on average.⁶¹ Broncheoalveolar lavage of patients with HAPE shows high protein concentrations, aracadonic acid metabolites, and complement activation products. The edema to serum protein ratio is 0.7:1, demonstrating that HAPE represents a break down in the alveolar/endothelial barrier.⁶² These findings show that HAPE is a result of a change in pulmonary vascular endothelial permeability and increased pulmonary arterial pressures, and not a problem of fluid overload. Treatments of cardiac etiology traditionally used for pulmonary edema are therefore relatively ineffective for treating HAPE.

Other changes in vascular permeability are also required for HAPE to develop. Recent research points to changes in sodium-dependent absorption of liquid from the airways which may be defective in patients who are susceptible to high-altitude pulmonary edema,63 as well as nitric oxide production deficiencies in those susceptible to HAPE.^64,65

Increased intra-cranial pressure may also play a role in the development of HAPE. Pulmonary edema has been shown to be a pathophysiological consequence of increased inter cranial pressure.^66-68 It has also been shown that those who are HAPE susceptible have an exaggerated sympathetic response (a two to three fold increase in sympathetic discharge compared to controls) to the hypoxia of altitude. ⁶⁹ Those susceptible to HAPE also have an increase of pulmonary artery pressure when exposed to the cold as compared to those who are not HAPE susceptible.⁷⁰

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