Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment
Section snippets
Symptoms and signs
High-altitude headache (HAH) is the primary symptom of AMS.4 High-altitude headache in AMS usually occurs with some combination of other symptoms including insomnia, fatigue (beyond that expected from the day's activities), dizziness, anorexia, and nausea. The headache often worsens during the night and with exertion.4, 5 Insomnia is the next most frequent complaint. Poor sleep can occur secondary to periodic breathing, severe headache, dizziness, and shortness of breath, among other causes.
The setting
As altitude increases, barometric pressure falls (see Fig 1). This fall in barometric pressure causes a corresponding drop in the partial pressure of oxygen (21% of barometric pressure) resulting in hypobaric hypoxia. Hypoxia is the major challenge humans face at high altitude, and the primary cause of AMS and HACE. It follows that oxygen partial pressure is more important than geographic altitude, as exemplified near the poles where the atmosphere is thinner and, thus, barometric pressure is
Acclimatization
It is important for any discussion of AMS and HACE to have as a starting point an understanding of acclimatization. The process of acclimatization involves a series of adjustments by the body to meet the challenge of hypoxemia. While we have a general understanding of systemic changes associated with acclimatization, the underlying molecular and cellular processes are not yet fully described. Recent findings suggest that the process may be initiated by widespread molecular up-regulation of
Ventilation, circulation, and the blood in acclimatization to high altitude
The initial and immediate strategy to protect the body from hypoxia is to increase ventilation. This compensatory mechanism is triggered by stimulation of the carotid bodies, which sense hypoxemia (low arterial Po2), and increase central respiratory drive. This is a fast response, occurring within minutes of exposure to hypoxia persisting throughout high altitude exposure. This is why one cautions against the use of respiratory depressants such as alcohol and some sleeping medications, which
Epidemiology and risk factors
AMS occurs in susceptible individuals when ascent to high altitude outpaces the ability to acclimatize. For example, most people ascending very rapidly to high altitude will get AMS. The symptoms, although often initially incapacitating, usually resolve in 24 to 48 hrs. The incidence and severity of AMS depend on the rate of ascent and the altitude attained, the length of time at altitude, the degree of physical exertion, and the individual's physiological susceptibility.27 The chief
Differential diagnosis
Symptoms suggestive of AMS in a setting of recent ascent to a new altitude are probably due to altitude sickness and should be treated as such until proven otherwise.31 It is common to misdiagnose AMS as a viral flulike illness, but alcohol hangover, exhaustion, and dehydration are also commonly suspected. All misdiagnoses must be eliminated by physical exam, history, or treatment. As noted previously, fever is usually absent in AMS, and alcohol or other drug use can be excluded by the history.
Pathophysiology of AMS and HACE
Despite dozens of investigations, the basic pathogenic mechanisms of AMS (and HACE) remain elusive. The extremely low incidence of HACE limits research into its pathophysiology largely to conclusions drawn from the similarity of the clinical presentation of severe AMS and early HACE. To be clear, it is not certain that AMS and HACE have the same underlying pathophysiology, but the idea of a continuum of severity between AMS and HACE serves as a useful construct for researchers exploring the
Ventilation
A low ventilatory response to hypoxia coupled with increased symptoms of AMS led to intensive investigation of a link between the chemical control of ventilation and the pathogenesis of AMS.13, 14 As stated previously, the results of these investigations suggest that for most people, the ventilatory response to hypoxia has little predictive value for AMS risk.13, 14 Only if the extremes of ventilatory responsiveness are contrasted can accurate predictions be made, where those with extremely low
Fluid homeostasis
As persons become ill with AMS, the renal processing of water switches from net loss or no change to net gain of water. Singh et al35 noted less of a diuresis (urinary output minus fluid intake: -1100 to +437 mL) in 118 soldiers with known susceptibility to AMS, compared with that seen in 46 “absolutely immune” (+930 to +4700 mL) soldiers. They also noted that clinical improvement was preceded by diuresis. Subsequent investigations have failed to elucidate the exact mechanism of the fluid
Brain volume
All studies to date generally support the idea that hypoxia causes elevated brain volume, but a direct relationship of greater brain volume to AMS is not apparent, or is at least beyond current measurement capabilities. However, Ross argued that only when buffering capacity is exhausted will elevated brain volume result in AMS. No study has yet linked brain volume to intracranial compliance measurements (a quantifiable measurement of intracranial volume buffering); thus, this core tenet of the
Brain edema
Hackett's pioneering MRI study in HACE, with marked white matter edema suggestive of a vasogenic origin, has led to a decade of studies looking for a similar finding in AMS. In moderate to severe AMS, all imaging studies have shown some degree of cerebral edema. But in mild to moderate AMS, admittedly an arbitrary and subjective distinction, brain edema is present in some MRI studies of AMS subjects, but not in all. It seems reasonable to conclude from the available data that the increase in
Intracranial pressure
From Singh's initial report in 1969, all subsequent studies in HACE and severe AMS have revealed elevated ICP. The recent publication of the fascinating case history of Brian Cummings tantalized all high altitude researchers with the possibilities of field studies. This article was long lost and only recently discovered and published.58 In it is recounted the story of a neurosurgeon who has an ICP monitoring bolt implanted in his own skull prior to going on an expedition in the Himalayas. From
Cerebral blood flow
As mentioned previously, cerebral blood flow is initially elevated with hypoxia, and with acclimatization it returns to pre-ascent values. We also briefly mentioned above that while all brain imaging studies have shown elevation in CBF with acute hypoxia, some noninvasive transcranial Doppler (TCD) studies have not show such elevation. We propose that whole brain imaging studies more reliably represent the underlying physiology of the hypoxic brain during acute hypoxia. Whether CBF plays a role
Alternative explanations for the onset of AMS
If studies reveal that intracranial volume buffering, pressure, and hemodynamics do not play a role in AMS, then where can we turn for an explanation of the headache of high altitude which marks the onset of AMS, and is its cardinal symptom—HAH? High-altitude headache is the most prominent symptom in AMS29, 35, 62 The pathophysiology of HAH, such as that of migraine or tension headache, is not fully understood. Recent clinical surveys of HAH have advanced its clinical characterization,4, 5, 63
Animal model of AMS and HACE
A final consideration for readers curious about how to advance the field of AMS and HACE pathophysiology is the absence of a validated animal model. Great advances could be made in studying the hypoxic brain if an animal model were available. The elegant early work of Krasney51, 73, 70, 71, 72 on sheep was promising, but never widely adapted. To those who argue that it is difficult to know when a guinea pig has a headache, a page can be taken from the remarkable recent progress in migraine
Prevention and treatment of acute mountain sickness
The levels of evidence have been assessed according to the methods described by the Oxford Centre for Evidence-based Medicine,76 which are summarized in Table 2. The evidence based recommendations for the prevention of AMS and HACE are found in Table 3, and the recommendations for the treatment of AMS and HACE are found in Table 4. A summary of the field treatment of AMS and HACE is found in Table 5.
A slow ascent with sufficient time for acclimatization is the best way of preventing AMS and
Predisposing factors
Individual susceptibility, rate of ascent, and previous recent exposure are major, independent determinants for AMS. There is generally no relationship between AMS and either age, gender, training, alcohol intake, or cigarette smoking.30, 109 Acute mountain sickness is associated with obesity,110 and with sleep desaturation at high altitude in one study.111
Physical exertion at altitude increases the incidence and severity of AMS, likely because of further reductions in arterial oxygen
Ascent profiles
In an interesting field study in climbers ascending to very high altitudes, differences of a few days in acclimatization had a significant impact on symptom severity, the prevalence of AMS and subsequent mountaineering success.27, 113 Different ascent profiles have been assessed, and acclimatization benefits after 5 days at 4200 m are lost within a few days.114 More recently, it has been reported that repetitive 7-month high altitude exposures increasingly protect lowlanders against AMS, even
Oxygen
Low arterial oxygen saturations are related to subsequent development of AMS120 and supplementary oxygen has been used to prevent AMS, and is one of the mainstays for the treatment of AMS and HACE,6, 35, 85 but short-term oxygen supplementation does not reverse all signs of AMS.121 However, any strategy to improve SaO2 will help prevent or treat AMS and HACE. Strategies shown to boost SaO2 in humans suffering from environmentally induced hypoxemia include CO2 breathing which stimulates
Diet
A high-carbohydrate diet was reported to reduce symptoms of AMS and increase endurance for heavy work.88 Although a high carbohydrate diet for 4 days did not reduce the symptoms of AMS after 8 hours of 10% normobaric oxygen,126 there are 2 reports that ingestion of carbohydrates can improve arterial oxygenation during acute hypoxic exposure.128, 127
Drugs
The main approaches to therapy of AMS and HACE are to improve oxygenation by the use of such drugs as carbonic anhydrase (CA) inhibitors or medroxyprogesterone, or by attenuating the cytokine and inflammatory responses with for example glucocorticoids or antioxidants.
Carbonic anhydrase inhibitors
Carbonic anhydrase enzymes catalyze the hydration of carbon dioxide to bicarbonate and protons and consequently play a vital role in acid-base balance. In mammals, 16 isoenzymes with different distributions have been described.132 Inhibitors of CA act by binding to the zinc ion of the enzyme.133 Sulfonamides are organic inhibitors of CA and 2 derivatives, acetazolamide and methazolamide, have been used in the management of altitude-related illnesses.
Glucocorticoids: prophylaxis
The exact mechanism of action of glucocorticoids, such as dexamethasone, is largely speculative, but is likely to be mediated through changes in capillary permeability and cytokine release. Dexamethasone 8 mg/d in divided doses has been used in the prevention of AMS95, 96, 149 with lower doses being relatively ineffective.150 Most consider that the potential side effects of glucocorticoids outweigh the benefits thus they are not normally justified for prophylaxis. Exceptions are if
Phosphodiesterase inhibitors
The effects of PDE inhibitors on AMS and HACE have been less studied than in HAPE, but it seems promising that sildenafil increases cerebral oxygentation155 and therefore, such treatment might be helpful for AMS and HACE. However, in the study of tadalafil and dexamethsone, tadalafil was no better than placebo in preventing AMS and 2 of the 10 subjects on tadalafil withdrew from the study because of severe AMS.156
Theophyllines
Theoretically theophylline should be of value in AMS and HACE as it reduces periodic breathing, cerebral and pulmonary microvascular permeability and also pulmonary artery pressure. A trial of slow-release theophylline 375 mg BID PO at 3454 m showed increased oxygenation and lower AMS scores on arrival and after 18 hours.157 A direct comparison of acetazolamide and theophylline showed that both helped to normalize sleep-disordered breathing, but only acetazolamide improved oxygen saturations.98
Magnesium
Magnesium is a physiological N-methyl-d-aspartate antagonist (NMDA) and may protect the hypoxic brain. The NMDA receptor is involved in the pathophysiology of hypoxic convulsions.158 and blockage of NMDA receptors has been shown to be beneficial.159 There is, however, no human data to link the NMDA receptor to the pathogenesis of AMS and oral magnesium in a randomized, controlled trial at 4559 m did not prevent AMS.160 In the treatment of AMS, intravenous magnesium reduced symptoms compared
Antioxidants
Ginko biloba is a traditional Chinese medicine containing flavonol glycosides and terpene lactones, which, among many effects, scavenge excess free radicals.162 There is conflicting evidence of its effectiveness in the prevention of AMS with some studies showing a benefit.104, 100, 101, 102, 103 More recent randomized trials showed that Ginko biloba was not effective in comparison with acetazolamide and placebo.101, 105, 106 The lack of a standardized chemical preparation for Gingko biloba may
Diuretics
Diuresis is a general physiological response to hypoxia. Subjects with AMS report less diuresis and have been shown to lose less weight than subjects who are free of AMS. In the only large trial in acute altitude-related illnesses, furosemide was reported to be successful in the prevention and management of AMS and in the prevention of HAPE.35 In smaller, chamber studies at 4270 m166 and in field studies at 5340 m,167 no benefit from diuretics lacking ventilatory stimulating action, such as
Sedatives and other drugs
Sleep disorders are commonly experienced at altitude and acetazolamide reduces the time spent in periodic breathing.170 Similar findings have been reported with theophylline. Improved sleep quality has also been shown using temazepam173, 171, 172 without any significant adverse effects.174
Gabapentin has been used to treat high altitude headache175 and the same group have shown that sumatriptan can prevent AMS.107 A leukotriene receptor blocker did not prevent AMS induced by normobaric hypoxia.
Summary and future directions
The management of AMS and HACE is based on our current understanding of the physiological and pathophysiological responses to hypoxia. Hypoxia itself, however, does not immediately lead to AMS as there is a delay of several hours after arrival at high altitude before symptoms develop. Increased knowledge of hypoxic inducible factor and cytokines that alter capillary permeability may lead to the discovery of new drugs for the prevention and alleviation of AMS and HACE.
Much work has focused on
Statement of Conflict of Interest
All authors declare that there are no conflicts of interest.
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Statement of Conflict of Interest: see page 479.