Pathogenesis Of Ams [1114

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It is highly likely that the pulmonary, peripheral, and cerebral forms of high altitude sickness share similar pathogenic mechanisms of impaired acclimatization (Fig. 1). Patients susceptible to AMS tend to demonstrate less weight loss than normal, do not diurese adequately and may actually gain weight; they

Hypoxia + Delayed Ventilatory Acclimatization

Hypoxia + Delayed Ventilatory Acclimatization

FIGURE 1. Pathogenesis of AMS. PAP, pulmonary artery pressure; PVP, pulmonary venous pressure; ANF, atrial natriuretic factor; U Na+, urinary sodium concentration; U vol, urinary volume; SVR, systemic vascular resistance.

generally show higher plasma levels of renin, angiotensin II, aldosterone, and ADH at altitude than control subjects [3]. They may also show higher levels of atrial natriuretic factor (ANF) associated with a larger right atrial diameter as a result of a higher extracellular fluid volume. In animals exposed to chronic hypoxia, the administration of ANF is associated with a dose-dependent reduction in pulmonary artery pressure [17], but this beneficial effect may be partially offset by its direct effect in causing fluid shift to the extravascular compartment [3, 26]. Increases in plasma aldosterone, ADH, norepinephrine, and ACTH during exercise which occur in most subjects are greater in individuals who develop AMS than in those who do not. Individuals who fail to lower their extracellular fluid volume during acclimatization are at a higher risk for developing AMS. In addition, susceptible subjects are more hypoxemic in part due to a reduced ventilatory response to hypoxia; hence they tend to develop a higher pulmonary vascular resistance. A higher circulating fluid volume in conjunction with the increased pulmonary vascular resistance may render them particularly prone to pulmonary edema.

The abnormal fluid retention is not evenly distributed throughout the body, but produces edema in specific sites depending on local conditions. Both hydrostatic pressure and altered vascular permeability have been postulated as mechanisms of edema formation. According to the hydrostatic edema theory, nonuniform regional hypoxic vasoconstriction in the lung leads to nonuniform regional increases in pulmonary blood flow and pressure that may be sufficiently high (particularly after exercise) to cause stress failure of thin walled arterioles and the alveolar epithelium or to stretch the alveolar pores so that large molecules leak out of the vascular space [1, 25]. This theory is consistent with the observation that patients with a restricted pulmonary vascular bed from any etiology are more susceptible to developing HAPE and may develop the syndrome at a lower altitude than in normal subjects. Similarly, cerebral vasodilation combined with systemic hypertension would predispose to cerebral edema which is believed to underlie the generalized symptoms of AMS (Table 1). Cutaneous vasodilation would in turn predispose to peripheral edema. On the other hand, hypoxia may alter capillary membrane permeability either directly or through the local release of specific vasoactive and inflammatory mediators [22], This permeability theory is supported by the finding of a similar cerebral blood flow in subjects with or without AMS [12], a normal pulmonary capillary wedge pressure in patients with florid HAPE, an increased pulmonary lymph flow and microvascular fluid filtration rate observed in animals exposed to hypoxia, and the finding of numerous microvascular thrombi in the lung at postmortem. The edema fluid in HAPE is highly proteinaceous containing an elevated neutrophil count, fragments of complements, and other mediators of inflammation. It remains unclear whether the release of inflammatory mediators is the cause or result of the fluid leak.


Effective steps for the prevention and treatment of AMS are summarized in Tables 2 and 3. The definitive prevention is slow ascent with adequate time spent at intermediate altitudes to allow gradual acclimatization. The definitive treatment is immediate descent and administration of oxygen; even a modest descent by 300 m may result in rapid and dramatic clinical improvement. Despite generalized fluid retention, aggressive diuresis should be avoided in patients suffering from AMS. High altitude pulmonary or cerebral edema is not due to cardiac failure although severe myocardial hypoxia can depress cardiac contractility. Vigorous diuresis may be harmful by further impairing cardiac output and oxygen transport. Furosemide and other potent diuretics do not prevent the development of AMS, do not accelerate normal acclimatization, and can be associated with undesirable side-effects such as hypovolemia, potassium wasting, exaggerated polycythemia, and pulmonary thromboembolism. In animal studies, furosemide-treated animals became volume contracted and had a higher death rate from high altitude sickness than animals given placebo [15]. Furthermore, symptoms of AMS and HAPE typically improve with rest alone; therefore anecdotal reports of clinical improvement after administration of furosemide cannot be solely attributed to the diuretic.

TABLE 2 Treatment of Acute Mountain Sickness

Mild to moderate symptoms Rest

Acetaminophen Acetazolamide (250 mg q8h)

Severe symptoms Descent Oxygen

Dexamethasone (4 mg q6h) Acetazolamide (250-500 mgq8h) Nifedipine

(10 mg sublingual X 1 + 20 mg po q6h) Inhaled nitric oxide (40 ppm)

Positive pressure breathing Compression chamber


Mild symptoms of AMS can be alleviated with rest and analgesia. The only diuretic routinely administered for both prevention and treatment of AMS is the carbonic anhydrase (CA) inhibitor acetazolamide. The primary action of ace-tazolamide is to hasten the rate of ventilatory acclimatization by:

(i) accelerating the renal loss of bicarbonate. The resulting mild metabolic acidosis enhances ventilatory response to hypoxia.

(ii) increasing the Pcc>2 gradient between brain tissue and alveolar air by preventing the equilibration of C02 between cerebral tissue and capillary blood as well as between pulmonary capillary blood and the alveolar air. The resultant relative respiratory acidosis in the brain further stimulates ventilation.

Inhibition of renal CA is considered the main action of the drug that accelerates ventilatory acclimatization. However, acetazolamide can also directly induce generalized tissue C02 retention. In the pulmonary capillaries, CA inhibition of the red blood cells and the pulmonary endothelium produces an alveolar-arterial C02 gradient which accentuates stimulation of the chemore-ceptors to increase ventilation [ 13]. Although CA is present in the cerebral glial cells and the formation of HC03" in the CSF is likely CA-dependent, it has not been clearly shown whether CA inhibition can cause direct acidification of the CSF independent of systemic acidosis. Nonetheless such a direct action seems plausible. Cerebral blood flow may or may not increase significantly in response to administration of acetazolamide but the production of CSF is reduced. Acetazolamide augments the ventilatory response to hypoxia by elevating the relationship of ventilation to arterial 02 saturation without changing the slope of the relationship [ 23 ]. In patients with established AMS, acelazolamide has been shown to ameliorate symptoms as well as increase ventilation, improve oxygenation, and lower arterial PC02; the increase in resting alveolar ventilation occurs without any change in C02 chemosensitivity [6]. Acetazolamide reduces the wide fluctuations in arterial 02 saturation associated with periodic breathing during sleep at altitude. The action of acetazolamide is superior to that of other respiratory stimulants such as almitrine. In acclimatized normal subjects studied at high altitude, both acetazolamide and almitrine improve oxygenation during sleep; however, the duration of periodic breathing during sleep is reduced in subjects given acetazolamide but increased in subjects given almitrine [9], Subjects taking acetazolamide during acclimatization demonstrate significantly better preservation of body weight, muscle mass, and total body fat than subjects given placebo and similar dietary intake [5]. In addition to stimulation of ventilation, acetazolamide also causes a mild diuresis which may augment the hypoxia-induced increase in hematocrit and further improve oxygen transport.

Although earlier studies have utilized high doses of acetazolamide (e.g., 1500 to 2000 mg orally in a single dose) which inhibit renal, red blood cell, pulmonary, and cerebral CA, lower doses (e.g., two to three doses of 250 to 500 mg orally 8 hr apart) which predominantly inhibit renal CA also result in significant clinical improvement within 24 hr in patients suffering from AMS. Benzolamide, a more impermeant CA inhibitor that acts on luminal CA in the renal tubules with relatively little effect on red cell and tissue C02 transport, is effective in reducing periodic breathing and improving daytime 02 saturation in subjects exposed to high altitude [24].

Other medications effective in the treatment of high altitude sickness include dexamethasone, nifedipine, and inhaled nitric oxide. Dexamethasone suppresses the inflammatory mediators associated with altered capillary permeability; it is often given concurrently with acetazolamide to treat severe cases of AMS [8,16]. By blocking calcium influx in pulmonary artery smooth muscle cells, nifedipine effectively relieves pulmonary hypertension and improves arterial oxygenation in mountaineers who develop HAPE [18]. Nifedipine may also block the calcium-mediated steps of the inflammatory response, including the activation of phospholipase A2, leading to a lower permeability of the capillary membrane. Acute inhalation of the endothelium-derived smooth muscle relaxing factor nitric oxide at a concentration of 40 ppm produces a greater decrease in systolic pulmonary artery pressure at high altitude in subjects prone to HAPE than in subjects resistant to HAPE and improves arterial oxygenation in subjects with active HAPE [20]. These changes result from the redistribution of pulmonary blood flow away from edematous segments toward non-edematous segments, thereby improving ventilation-perfusion matching (see Table 3).

TABLE 3 Prevention of Acute Mountain Sickness

Identify individual susceptibility Previous history Cardiopulmonary disease

Slow ascent

<300 m per day above 3000 m

Avoid alcohol, sedatives, and excessive exertion


250-500 mg qhs up to 250 mg q8h X 3 to 5 days starting on day before ascent


20 mg qd X 2 days before ascent

20 mg q8h X 3 days starting on day of ascent

(Dexamethasone) 4 mg q!2h starting on day of ascent Continue for 3-5 days with taper

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