Etiology
The cause is hypoxia; an ascent to altitude is accompanied by a fall in barometric pressure that results in a reduction in the partial pressure of inspired oxygen (PIO2).[1]
On the summit of Kilimanjaro (5895 m [19,340 feet]) the PIO2 is approximately one half of that found at sea level, and on the summit of Mount Everest (8850 m [29,035 feet]) it is just one third. Although the human body tries to acclimatize to this change in PIO2, in cases of acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE), this process is incomplete.
Pathophysiology
Despite acute mountain sickness (AMS) being by far the most common of illnesses to occur in new arrivals to altitude, less is known about the pathophysiology of this condition than its fatal complications high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE). The leading explanation suggests that AMS may be due to an increase in cerebral volume that is due to either an increase in cerebral blood flow or the presence of cerebral edema.[7][15] While vasodilation itself may be enough to stimulate the trigeminovascular system and cause headache and other AMS symptoms, the presence of edema has been suggested by a number of high-altitude clinicians to explain the pathophysiology of the condition.[16] Many argue that AMS is a mild form of HACE and is therefore caused by edema, either directly or by the effect of edema on intracranial pressure (ICP). Unfortunately, little evidence is available to support this conclusion, with studies being unable to show a consistent pattern of edema or ICP elevation in AMS.[17][18][19]
On ascending to altitude, falling levels of PIO2 trigger hypoxic pulmonary vasoconstriction (HPVR) in the pulmonary vasculature. HPVR directs blood flow away from hypoxic areas of the lung, and toward areas that are well oxygenated.[7] This results in a rise in mean pulmonary artery pressure and a heterogeneous blood flow to different parts of the lung. In areas that receive high blood flow the capillary transmural pressure rises and the walls of the capillary and alveolus are exposed to stress failure. In the majority of those who ascend to altitude, this remains no more than a threat. However, in cases of HAPE, these changes are more pronounced and the alveolar capillary membrane becomes extensively damaged. This allows edema, rich in high molecular weight proteins and red blood cells, to pass freely into the alveoli and impair oxygenation.[20][21][22]
In HACE, hypoxia triggers a rise in cerebral blood flow that increases shear forces directed towards the blood-brain barrier (BBB). Breakdown of the BBB results in the formation of "vasogenic edema" that tends to accumulate in the white matter of the corpus callosum.[14] This area is particularly prone to edema as it has a rich supply of blood vessels and, more importantly, an orderly network of extracellular channels that encourage the accumulation of fluid. T2-weighted MRI scans of those with HACE often demonstrate this clearly.[23] Eventually, large quantities of vasogenic edema interfere with the metabolism of the cells and affect oxygen-dependent ion pumps in the cell membrane. Ion pump failure results in an increase in sodium ions inside the cell and the absorption of water in order to maintain normal cell osmolarity. The accumulation of this fluid or "cytotoxic edema" has been postulated as a contributing factor to the later stages of HACE.
Damage to the alveolar capillary membrane and BBB not only encourages the formation of edema, but it also exposes the basement membranes of injured cells to the circulation. This results in (1) the activation of platelets resulting in the formation of thrombi and (2) the release of neutrophils triggering an inflammatory response. It is reasonable to assume that these processes contribute to the rapid deterioration that is often seen in cases of untreated HAPE and HACE.
All those who ascend to altitude are exposed to hypoxia and therefore experience an increase in cerebral blood flow and the effects of hypoxic pulmonary vasoconstriction. Although these changes may be more pronounced in HACE and HAPE, it may be that differences in the tissues of the brain and lung are largely responsible for the formation and clearance of edema. In those susceptible to HAPE, concentrations of epithelial sodium channel proteins are reduced, preventing the clearance of edema from alveoli.[24][25] In HACE a number of different molecules have been implicated in weakening the BBB during hypoxia. These include bradykinin, histamine, arachidonic acid, oxygen and hydroxyl free-radicals, nitric oxide, noradrenaline, and vascular endothelial growth factor.[14]
Classification
Clinical entities
Acute mountain sickness (AMS)
A syndrome of nonspecific symptoms that occurs following arrival at altitudes above 2500 m (about 8200 feet). It is defined by the Lake Louise Consensus Group as the presence of headache, together with 1 or more of the following: gastrointestinal symptoms (anorexia, nausea, or vomiting), fatigue, dizziness, and lightheadedness.[2]
High-altitude pulmonary edema (HAPE)
A noncardiogenic form of pulmonary edema characterized by the presence of fatigue, breathlessness, cough, productive sputum, and chest pain.[3][4]
High-altitude cerebral edema (HACE)
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