Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment

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Abstract

Barometric pressure falls with increasing altitude and consequently there is a reduction in the partial pressure of oxygen resulting in a hypoxic challenge to any individual ascending to altitude. A spectrum of high altitude illnesses can occur when the hypoxic stress outstrips the subject's ability to acclimatize. Acute altitude-related problems consist of the common syndrome of acute mountain sickness, which is relatively benign and usually self-limiting, and the rarer, more serious syndromes of high-altitude cerebral edema and high-altitude pulmonary edema. A common feature of acute altitude illness is rapid ascent by otherwise fit individuals to altitudes above 3000 m without sufficient time to acclimatize. The susceptibility of an individual to high-altitude syndromes is variable but generally reproducible. Prevention of altitude-related illness by slow ascent is the best approach, but this is not always practical. The immediate management of serious illness requires oxygen (if available) and descent of more than 300 m as soon as possible. In this article, we describe the setting and clinical features of acute mountain sickness and high-altitude cerebral edema, including an overview of the known pathophysiology, and explain contemporary practices for both prevention and treatment exploring the comprehensive evidence base for the various interventions.

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.

References (185)

  • GoadsbyP.J.

    Pathophysiology of migraine

    Neurol Clin

    (2009)
  • NerinM.A. et al.

    Acute mountain sickness: influence of fluid intake

    Wilderness Environ Med

    (2006)
  • RichardsonA. et al.

    Hydration and the physiological responses to acute normobaric hypoxia

    Wilderness Environ Med

    (2009)
  • WrightA.D. et al.

    Medroxyprogesterone at high altitude. The effects on blood gases, cerebral regional oxygenation, and acute mountain sickness

    Wilderness Environ Med

    (2004)
  • HackettP.H. et al.

    High altitude cerebral edema

    High Alt Med Biol

    (2004)
  • WhymperE. et al.

    Travels amongst the great andes of the equator

    (1972)
  • RavenhillT.H.

    Some experiences of mountain sickness in the Andes

    J Trop Med Hygiene

    (1913)
  • SilberE. et al.

    Clinical features of headache at altitude: a prospective study

    Neurology

    (2003)
  • Serrano-DuenasM.

    High altitude headache. A prospective study of its clinical characteristics

    Cephalalgia

    (2005)
  • RoachR.C. et al.

    The Lake Louise acute mountain sickness scoring system

  • SampsonJ.B. et al.

    Procedures for the measurement of acute mountain sickness

    Aviat Space Environ Med

    (1983)
  • WagnerD.R. et al.

    Reliability and utility of a visual analog scale for the assessment of acute mountain sickness

    High Alt Med Biol

    (2007)
  • WestJ.B.

    Barometric pressures on Mt. Everest: new data and physiological significance

    J Appl Physiol

    (1999)
  • HackettP.H. et al.

    High altitude medicine

  • WebbJ.D. et al.

    Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing

    Cell Mol Life Sci

    (2009)
  • MatsuzawaY. et al.

    Low hypoxic ventilatory response and relative hypoventilation in acute mountain sickness

    Jpn J Mountain Med

    (1990)
  • MooreL.G. et al.

    Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness

    J Appl Physiol

    (1986)
  • LeafD.E. et al.

    Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness

    J Appl Physiol

    (2007)
  • HansenJ. et al.

    Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia

    J Physiol

    (2003)
  • KamimoriG.H. et al.

    Catecholamine levels in hypoxia-induced acute mountain sickness

    Aviat Space Environ Med

    (2009)
  • SeveringhausJ.W. et al.

    Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypoxia

    Circ Res

    (1966)
  • BuckA. et al.

    Changes of cerebral blood flow during short-term exposure to normobaric hypoxia

    J Cereb Blood Flow Metab

    (1998)
  • SubudhiA.W. et al.

    Acute hypoxia impairs dynamic cerebral autoregulation: results from two independent techniques

    J Appl Physiol

    (2009)
  • SubudhiA. et al.

    Effects of hypobaric hypoxia on cerebral autoregulation

    Stroke

    (2010)
  • JansenG.F. et al.

    Cerebral autoregulation in subjects adapted and not adapted to high altitude

    Stroke

    (2000)
  • HannonJ.P. et al.

    Effects of acute high altitude exposure on body fluids

    Fed Proc

    (1969)
  • HannonJ.P. et al.

    Effects of altitude acclimatization on blood composition of women

    J Appl Physiol

    (1969)
  • SmithT.G. et al.

    The increase in pulmonary arterial pressure caused by hypoxia depends on iron status

    J Physiol

    (2008)
  • SmithT.G. et al.

    Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials

    JAMA

    (2009)
  • SchneiderM. et al.

    Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate

    Med Sci Sports Exerc

    (2002)
  • HonigmanB. et al.

    Acute mountain sickness in a general tourist population at moderate altitudes

    Ann Intern Med

    (1993)
  • SchneiderM. et al.

    Susceptibility, rate of ascent and pre-acclimatization are major determinants for prevalence of acute mountain sickness (AMS)

    High Altitude Med Biol

    (2001)
  • HackettP. et al.

    High-altitude illness

    N Engl J Med

    (2001)
  • RoachR.C. et al.

    How well do older persons tolerate moderate altitude?

    West J Med

    (1995)
  • LyonsT.P. et al.

    Prior acclimatization to 4300 m reduces acute mountain sickness symptomatology with reinduction

  • WuT.Y. et al.

    Reduced incidence and severity of acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated 7-month exposures despite 5-month low altitude periods

    High Alt Med Biol

    (2009)
  • SinghI. et al.

    Acute mountain sickness

    N Engl J Med

    (1969)
  • BertP.

    Barometric Pressure

    (1978)
  • BarcroftJ.

    Mountain sickness

    Nature

    (1924)
  • LoeppkyJ.A. et al.

    Role of hypobaria in fluid balance response to hypoxia

    High Alt Med Biol

    (2005)
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