REVIEW ARTICLE Sports Med. 20 (3): 148·159. 1995 0112·1642/95/CXXl9-QI48/S06.00/0

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Medicine and Mechanisms in Altitude Sickness Recommendations

John H. Coote

Department of Physiology, The Medical School, The University of Birmingham, Birmingham, England

Contents

Summary 1. Altitude Sickness 2. Physiology . . . . 3. Symptoms and Acclimatisation

148 149 150 151 152 153 155 156 156 157 157 157

4. Prevention and Therapy . 4.1 Acetazolamide . 4.2 Dexamethasone . . 4.3 Spironolactone . . . 4.4 Progesterone and Other Drugs 4.5 Oxygen, Carbon Dioxide and Hyperbaria

5. Sleep and Acute Mountain Sickness. 6. Conclusions . . . . . . . . . . . . . . . . . . . . .

Summary Acute mountain sickness (AMS) has long been recognised as a potentially life-threatening condition afflicting otherwise healthy normal individuals who ascend rapidly to high altitude where the partial pressure of oxygen (p02) in the air is reduced. The symptoms of AMS (e.g. headache, poor appetite and nausea, fatigue and weakness, dizziness or light-headedness and poor sleep) are probably a consequence of disturbances in fluid balance brought about by severe tissue hypoxia. AMS can be prevented by an adequately slow ascent, which is the best method, but for those with limited time there are several drug therapies that provide a relatively good protection. Acetazolamide (250mg twice daily or 500mg slow release once daily), taken before and during, ascent is probably the treatment of choice; it improves gas exchange and exercise performance and reduces the symptoms of AMS in most individuals. Dexamethasone (4mg, 4 times daily) is more of value for short term treatment or prevention, and should never be used for more than 2 to 3 days. Prophy lactic use of progesterone looks prom­ising, but more studies are required.

Altitude Sickness

A search through the extensive literature on mountain travel reveals many accounts of illness associated with altitude. The early explorers of the European Alps, the Andes and Himalayas referred often to the problem and gave vivid accounts of its effects.f l-3] An ascent of Mt Blanc, at 4841.5m the highest peak in the European Alps, is now taken for granted, but nonetheless its altitude imposes a con­siderable hypoxic stress. Many of the accounts of the earliest attempts to scale this mountain refer again and again to the debilitating effects of moun­tain sickness.f4]

Highland areas form both physiological and physical barriers. The former is no less a danger than the latter and needs to be treated with respect. Felice Benuzzi described his attempt on Mt Kenya after an escape from a nearby prisoner of war camp during the Second World War.fS] At 3962.5m, he records, 'I found that I could not take more than ten steps without stopping for a long breathing spell . .. slow, short, steady steps . . . I tried but could not manage it. I rested for another spell . .. I was rather depressed and hurt in my pride as I began to suspect I was suffering from mountain sickness. I felt so weak and dizzy' .lS] These symptoms are a conse­quence of the body's inadequate response to the lower partial pressure of oxygen (p02) in the at­mosphere, and are but part of a whole list of less or more severe symptoms of the condition described as mountain sickness.

In various accounts of altitude sickness different criteria have been applied in determining symp­toms and their severity. A scoring system to recog­nise and quantify the condition has been derived and is known as the Lake Louise Consensus and it is hoped that it will become universally accepted.f6]

1. Altitude Sickness

The benign form of this condition is commonly known as acute mountain sickness (AMS). The usual symptoms include, headache, anorexia, nau­sea, vomiting, lethargy, unsteadiness of gait, breathlessness on moderate exertion and poor sleep. The occurrence of retinal haemorrhages is somewhat more variable.[7-IO] The haemorrhages

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may be widespread in the retina and if near the optic disc there may be some blurring of vision, but otherwise they are usually symptomless. There may be other indications of changes in the physio­logy of the vascular wall such as proteinuria which is common in the first few days at altitude and this may be due to increased microvascular perme­ability in the kidneys.lll]

The severity of AMS is unrelated to physical fitness, gender, or age, and there is a wide variation in individual susceptibility. Rapid ascent to alti­tudes of 2500m to 3000m will produce symptoms in some climbers whilst rapid (2 to 3 days) ascent to 5000m will cause most individuals to be af­fected. In general, the more rapid the ascent, the higher the altitude reached, and the greater the physical exertion involved, the more severe the AMS.

If an individual stops for 2 to 3 days at the alti­tude reached acclimatisation usually occurs; oxy­gen delivery to the tissues improves, and symptoms remit. Therefore a slow rate of ascent is recom­mended as the best way to avoid AMS.

The typical form of AMS described above can be troublesome, but is not dangerous. However, in a few individuals (>4%),[12] at altitudes above 4000m (but even as low as 3000m) sickness pro­gresses unpredictably to a malignant, and poten­tially fatal form, involving severe fluid distur­bances in either the lungs or brain or both.

Probably the most common malignant form of AMS is high altitude pulmonary oedema. Typical features are cough, frothy sputum, lung crackles and paroxysmal nocturnal breathlessness which is relieved on sitting up. The other form is high alti­tude cerebral oedema which causes mental distur­bances, ataxia, severe headache, drowsiness, stu­por and coma.

Despite the hazards, about I % of the world's population reside above 3300m where atmospheric pressure is two-thirds of the sea level value. These people have become adapted to the low oxygen levels.fl3,14]

A minority of individuals, usually men, who have lived for long periods at high altitude develop

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a syndrome known as chronic mountain sickness (CMS) or Monge's disease.[14.15) In these individ­uals there is a raised red cell count (polycythae­mia), above the level that corresponds to the alti­tude of residence. The marked polycythaemia results in high haematocrits, with packed cell vol­ume in excess of 80% and haemoglobin levels above 25 g/d!. The high haematocrit increases the viscosity of the blood, there is a raised systemic and pulmonary artery blood pressure, and the increased resistance to flow in the pulmonary vascular bed leads to right ventricular hypertrophy. CMS is prevalent in the Quechua and Aymara Indians of the Andes. It has also been described in Caucasians in the North American Rockies and recently in the Han people of Tibet.[13.14) Since the condition re­sults in right ventricular failure, treatment is essen­tial. The symptoms clear up on descent to sea level, but for those remaining at altitude venesection (bleeding) is beneficial because it lowers the haematocrit. An alternative is to use respiratory stimulants and some success has been claimed with medroxyprogesterone.[16)

Lowlanders are also able to ascend and survive briefly on high mountains such as Everest (8848m) where pressures are less than one third of the sea level value. These ascents are possible because of short term acclimatisation. Short term acclimatisa­tion allows oxygen availability to tissues to be in­creased while also protecting against the tissue ef­fects of low p02.

2. Physiology

The following account is a brief overview of the physiology of AMS. Unfortunately there are few data which identify conclusively a mechanism for each of the symptoms. Therefore the most likely cellular events triggered by hypoxia are presented and pathways by which drugs may have a benefi­cial effect are suggested.

Air pressure falls with increasing altitude but the component gases remain in the same proportion as at sea level. Thus, lower oxygen pressure in the inspired air gives a lower pressure in the lung alve­oli which in turn leads to a lower oxygen saturation

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Coote

Table I. Components of the response to hypoxia that are relevant to acute mountain sickness

System Response to hypoxia

Brain choroid plexus CSF pH ! Interstitial fluid pH !

Cardiovascular Red blood cell number i Microcirculation: prostaglandins i. permeability i Vasodilation: cerebral blood flow i Vasoconstriction: pulmonary pressure i

Respiratory Ventilation i: p02 i. pC02!

Renal Microcirculation: prostaglandins i. permeability i HCOo- diuresis i. Na+ loss

Endocrine ADH: ! ACTHi Plasma renin activity !. angiotensin-converting enzyme !. angiotensin II !. aldosterone !. atrial natriuretic peptide i

Abbreviations: ACTH = adrenocorticotrophic hormone; ADH = anti­diuretic hormone; CSF = cerebrospinal fluid.

in the arterial blood. Acclimatisation comprises the physiological changes that compensate for the lower oxygen availability at altitude (table I). Within a few days the blood thickens, raising the proportion of the oxygen-carrying red cells from 45% to greater than 50%. This is achieved initially by a reduction in plasma volume, but in the longer term by an increase in the production of red cells induced by erythropoietin. Thus, the drop in the blood-oxygen saturation is partly compensated by a greater oxygen carriage per lOami of blood.

However, there is still insufficient atmospheric oxygen pressure to saturate the haemoglobin of each red cell fully, so aerobic exercise capacity and maximum ability to take up oxygen is impaired compared to sea level. This problem is exacerbated in unacclimatised individuals by a lack of a sus­tained increase in ventilation at altitudes up to 5000m. This is because the increasing stimulation to ventilation of the peripheral arterial chemore­ceptors is offset by the increased ventilatory loss of arterial CO2 and hence removal of central chemo­receptor drive (fig. 1). Within days, the resting ven­tilation increases, due to improved drive from the central chemoreceptors. This change is possible

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Altitude Sickness

because the cerebrospinal fluid (CSF) and brain interstitial fluid become more acidic.!18-2I) Lower levels of C02 following a hyperventilation are now sufficient to generate enough free H+ to stimulate the central chemoreceptor.

Initial acidity is due to lactacidosis of brain tissue, a consequence of hypoxic stimulation of anaerobic metabolism of glucose. This partial switch of metabolism certainly occurs but there is argument about whether sufficient lactic acid is produced to titrate the CSF pH towards more acid levels. (18)

More recently, the idea that enough lactic acid is generated has gained more support. It is known that lactic acid dissociates to lactate and H+ in the cell and that these then pass through the cell mem­brane into the extracellular fluid to CSF and then to blood with different rates for each species at each stage. Therefore, the lactate level that Severinghaus et al. (18) measured in CSF is likely to be much smaller than the actual H+ production from lactic acidpl] Later, the active or possibly passive transport of HC03- out of the brain fluids into the blood either against a concentration gradi­ent[18.22) or down an electrochemical gradient[23] contributes to high H+ (fig. 2).

A further mechanism of still slower onset (2 to 3 days) is the 'classical' pathway as follows. As a result of the hypoxic stimulation of ventilation a respiratory alkalosis is compensated for by the kid­neys excreting more HC03- . Subsequently, a gra­dient develops for HC03- across the blood-brain barrier and CSF HC03- passes out slowly down a concentration gradient. (21)

This change in CSF pH is critical because it shifts the C02 operating point around which the central chemoreceptors are stimulated. If resting ventilation did not increase from sea level values, the p02 in the alveoli would be 50mm Hg below that of the inspired air (as it is at sea level) and the arterial p02 would be critically low at altitudes above 5000m (fig. 3). Despite this important in­crease in resting ventilation, arteriolar oxygenation inevitably falls as a function of altitude and tissue

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hypoxia appears to be the primary cause of AMS.!24)

3. Symptoms and Acclimatisation

The symptoms of AMS are probably manifesta­tions of the hypoxia-induced changes in fluid bal­ance. The shifts in fluid are partly secondary to haemodynamic changes. Hypoxia-induced vaso­dilatation increases the hydrostatic pressure in the capillaries, favouring a greater loss of fluid to the tissues. Although this concept is somewhat more controversial, it is also likely that the movement of fluid out of the capillaries is increased by protein loss to the interstitium.19.25.26] These factors are probably responsible for the tissue oedema (e.g. face and limbs) which accompanies AMS, and each is probably exacerbated by exercise.

Low PI02

Respiratory neuron

excitability .j.

Peripheral t---~ chemoreceptor

activity i

+

Respiratory neuron

excitability i

Vel

Central chemoreceptor activity .j.

Vesame

Fig. 1. The conflicting stimuli to ventilation in the person un­acclimatised to a low partial pressure of oxygen in inspired air (low PI02). Although low arterial oxygen (p02) stimulates periph­eral arterial chemoreceptor activity which will promote ventila­tion (Ve). it also directly decreases excitability of respiratory neurones. This effect will be reinforced by a decrease in central chemoreceptor activity caused by a fall in arterial CO2 (pC02). that is in turn driven by any increase in ventilation. As a conse­quence of these interactions in the first day or so at altitude. ventilation is little changed from euoxic levels (reproduced from CooteI1 ?1, with permission).

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152

Increases in permeability and hydrostatic pres­sure in the cerebral capillaries are also the most likely cause of the headache from AMS which probably reflects a limited cerebral oedema (in­crease in intracerebral pressure), and a tugging by pulsating dilated blood vessels. Even the breath­lessness (dyspnoea) could be a consequence of a limited accumulation of fluid in the lung alveoli following hypoxia-induced pulmonary hyper­tension.

Since acclimatisation involves a diuresis, changes in fluid balance might be expected to in­voke alterations in output of the volume-regulatory hormones. A decrease in circulating antidiuretic hormone might be expected[27,28] but the evidence

is conflicting. A contributory factor to the diuresis could be a decrease in the Na+ -retaining hormone, aldosterone. A more likely alternative (based on preliminary findings),[21] is an increase in the Na+­excreting hormone atrial natriuretic peptide (ANP), since right heart pressures are increased due to a pulmonary hypertension and an increase in circulating blood volume, which has been stim­ulated by erythropoietin.

Periphery

~penpheral

\ K~~~ ~7'~~o, 1 artery ( Cranium

Coote

Exercise produces a number of physiological changes, some of which could worsen the effects of tissue hypoxia and can augment the incidence and severity of AMS.[29] Thus, systemic hyperten­sion associated with intense bouts of activity will lead to higher pressure in the dilated cerebral vas­cular bed, and an accompanying pulmonary hyper­tension may lead to increased fluid loss into both the tissue of the brain and lungs, respectively. Ex­ercise also stimulates renin-release via activation of the adrenosympathetic system and this will lead, via the production of angiotensin II, to an elevation of aldosterone, quite the opposite to the direct ef­fect of hypoxia per se and inappropriate for good acclimatisation. The response to hypoxia therefore involves a number of physiological adjustments (table I) . Adequate acclimatisation takes time and slow ascent is usualIy the best way of avoiding AMS.[30]

4. Prevention and Therapy

With an increasing number of people going to moderate and high altitude, many for only a limited stay, there is a need for preventative measures. A

Fig. 2. Key sites in the ventilatory control system involved in the response to hypoxia. At sea level 80% of ventilatory drive to the respiratory neurons emanates from the central chemoreceptor (W receptor). This responds to free W generated by hydration of CO2 to form carbonic acid that then dissociates. The capillary wall is freely permeable to CO2, which passes into the cerebrospinal fluid (CSF) and brain interstitial fluid. The changes in brain Ware buffered by HC03-, produced mainly from cells of the choroid plexus. The Wand K+ and partial pressure of oxygen (p02) in arterial blood stimulate peripheral chemoreceptors, providing additional drive to the respiratory neurones (reproduced from Coote1171, with permission).

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Altitude Sickness

100 90 80 70

Oi J: 60 E .s 50 0' 40 a.

30 20 10 0

PI02 (mm Hg) 150

Altitude (m) 0

• Ventilation remains constant & Acclimatised subjects

Summit of Everest

+

I I I

125 100 84 69 585043 1.0 .... M

Fig. 3. Alveolar pressure or oxygen (p02) measured at various altitudes on different mountains up to the summit of Everest in acclimatised individuals. The corresponding inspired pressure of oxygen (PI02) is shown for each altitude. As the PI02 de­creases with increasing altitude, the difference between PI02 and p02 lessens considerably (indicated by the decreased slope) due to hyperventilation. Above an altitude of 7000m (PI02 54mm Hg) the change in p02 for a change in PI02 becomes very small indeed. This is achieved by a process of extreme hyperventilation. The hypothetical p02 that would result if ven­tilation remained unchanged from its sea level resting value is shown by the filled circles. Thus hyperventilation is one of the most important features of acclimatisation to high altitude.!'71

great deal more information is now available about such measures)30-321

AMS can nearly always be relieved by rapid descent, although in the mild case the symptoms will wear off anyway, as acclimatisation occurs. Sometimes the progress of the illness is so rapid that even descent does not prevent a fatal outcome.

Oxygen therapy causes a dramatic improve­ment, but a simpler method of improving oxygen­ation and correcting the disturbances in fluid bal­ance would obviously be preferred. A number of compounds such as acetazolamide, dexametha­sone, and spironolactone have proved of particular benefit. Others such as progesterone or medroxy­progesterone stimulate breathing, but until re­cently have only been used to reduce sleep apnoeas at aititudeP31 Almitrine, another respiratory stim­ulant, has been used but with only partial success.

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Table II summarises the sites of action of these drugs as relevant to altitude sickness.

Potassium supplements are of historical interest because agents such as potassium chloride were used by early explorers to combat the sickness of high altitude. Whymper (1892) provides a graphic account of the use of 'chlorate of potash' J21 It is difficult to see that such medication could have had more than a placebo effect.

4.1 Acetazolamide

The sulphonamide acetazolamide, given pro­phylactically (SOOmg daily begun in the 24 hours before ascent), reduces the severity of, or prevents, AMSJ241 Once high altitude has been reached, it can be discontinued without serious effect, which suggests it does not impair normal acclimatisa­tionJ341 It can also be used effectively in the acute treatment of established, mild mountain sick­nessP51 According to the latter authors, doses of 1 to I.Sg daily are needed. However, a more recent study has shown good improvement in gas ex­change and reduction of symptoms of AMS with an initial dose of 2S0mg acetazolamide orally fol­lowed by a further 250mg tablet after 8 hoursJ361

Acetazolamide inhibits carbonic anhydrase. In the kidney this results in a bicarbonate diuresis, a consequent extracellular acidosis and lowering of blood pH. Acetazolamide treatment also increases arterial p02 and lowers arterial pC02 indicating an

Table II. Therapeutic agents used to combat acute mountain sickness Agent Acetazolamide

Dexamethasone

Spironolactone

Progesterone Almitrine 02 C02 hyperbaria Symbol: * = in brain.

Probable site of action Choroid plexus· Kidney proximal tubule cell Capillary wall Choroid plexus· Kidney Kidney distal tubule cell Choroid plexus· Respiratory neuron· Peripheral arterial chemoreceptor Most organs

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154 Coote

Blood Choroid p lexus epithelial cell CSF

Na+

~---r~--~-------H + +

Acetazo lamide

Na+/K+ ATP

.. ---1'----"--"--- K+

~~

-

ase

..

Na+

HCOa .. HCOa-

Carbonic anhydrase

.. H2O

Na+ .. Na+

Fig. 4. The events occurring in the brain choroid plexus leading to production of bicarbonate (HC03-) in the cerebrospinal fluid (CSF) and the transport of Na+ and H20. Combination of CO2 from the blood with H20, catalysed by the enzyme carbonic anhydrase, produces carbonic acid. This dissociates to yield HC03-, which is secreted into the CSF, and H+, which moves back into the blood via a Na+IW, exchanger, Na+ may also be actively transported across the capillary wall in exchange for K+, Na+ diffuses from the epithelial cell into the CSF, taking H20 with it. As an inhibitor of carbonic anhydrase, acetazolamide may interfere with this sequence of events, resulting in a decrease in CSF HC03- and in ion and H20 transport (reproduced from Coote[17), with permission).

increase in ventilation.l24,37,38] The leakiness of the renal glomenular capillaries to protein is reduced, there are improvements in exercise performance and loss of muscle mass is reduced;[39,40] these ef­fects are probably all due to improvement of the oxygen supply to the tissues. Sleep hypoxaemia is strikingly lessened[33,41] and the quality of sleep is improved.l42]

The use of acetazolamide leads to a build up of C02 in the tissues. Because of this there has been concern that it might impair exercise performance at high altitude as it does at sea level - but this is not the case.

The beneficial effect on exercise performance at high altitude of taking acetazolamide was shown in a study by the Birmingham Medical Research Ex­peditionary Society.[39] Of the study participants, II received acetazolamide and 10 received placebo during 12 days of trekking to 5000m. At altitude, mean p02 was 45mm Hg in the acetazolamide

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group and 39mm Hg in the placebo group, whilst the pC02 was 19mm Hg and 22mm Hg respec­tively. Thus, the acetazolamide group had a relative hyperventilation. Work capacity was tested on an exercise bicycle at maximum heart rate and 85% maximum heart rate over periods of 15 minutes. The work at maximum heart rate fell to 75% of the sea level values in the acetazolamide group and to 67% in the placebo group. At 85% maximum heart rate the values were 63% and 55% respectively. The differences between drug and placebo groups were significant (p < 0.01).

It appears therefore that any detrimental effect of carbonic anhydrase inhibition is offset by the continuously higher arterial oxygen levels in the acetazolamide group. The acetazolamide-induced hyperventilation would be facilitated by a relative acidosis in this group causing a greater rightward shift in the haemoglobin dissociation curve thus favouring oxygen uptake by the muscles.

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Altitude Sickness

How the compound brings about these improve­ments is still something of a puzzle, but there are mechanisms worthy of consideration. It has been

suggested that the metabolic acidosis results in en­hanced stimulation of the peripheral arterial chem­oreceptors. However, a similar acidosis produced by injection of ammonium chloride does not pro­duce as marked an increase in ventilation or im­prove AMS symptoms. Equally, almitrine which acts mainly by stimulating the peripheral arterial chemoreceptors is not as effective in preventing AMS symptoms as is acetazolamide.[43) These fea­

tures also rule out the possibility that it is the pre­vention of the hyperventilatory alkalaemia per se

which permits a greater increase in ventilation dur­ing hypoxia.

It seems most likely that a major part of the value of acetazolamide is due to a direct action in blocking carbonic anhydrase within the central nervous system. Although the exact role of car­bonic anhydrase in brain function is unclear, the enzyme is present in abundance and its inhibition by acetazolamide would cause an increase in intra­cellular C02 tension. It would also reduce the bi­carbonate content of the CSF by blocking carbonic anhydrase in the cells of the choroid plexus (fig. 4). This would also reduce the rate of CSF forma­tion because the movement ofNa+ and hence water is linked to that of HC03-. As a result CSF and brain interstitial fluid would become more acidic. Hence, together with a hypoxia-induced brain lactacidosis that further reduces the CSF/intersti­tial pH, a lower pC02 is able to generate sufficient free H+ in the brain to stimulate the central chem­oreceptors. In addition, a reduction in CSF forma­tion would lessen the mechanical deformation pro­duced by brain oedema causing the headache to disappear.

The diuretic actions of acetazolamide could also reduce tissue oedema. Therefore, these beneficial actions of acetazolamide together with the non­toxic nature of the drug make it highly suitable as a prophylactic treatment of AMS.

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4.2 Dexamethasone

Dexamethasone is a potent synthetic gluco­corticoid with negligible mineralocorticoid activ­

ity. It is effective in the management of cerebral oedema and hence has been used successfully to treat AMS caused by rapid ascent to high alti­tude. [44,45) Although dexamethasone reduces vaso­

dilatation of cerebral and other blood vessels dur­ing hypoxia, this cannot be the main mechanism for its action in relieving the sickness since there is no direct correlation between the increase in ce­rebral blood-flow at high altitude and symptom score of AMS,l35)

The main effect of dexamethasone on fluid bal­

ance is probably via a reduction in capillary wall permeability. Hypoxia may increase permeability via the stimulation of prostaglandins such as PGI2.[46,47) PGh is formed from free arachidonic

acid that is released from the endothelial cell mem­brane via a Ca++ dependent enzyme phospholipase A2. Hypoxia increases cytosolic Ca++ levels and also reduces the re-esterification of arachidonic acid into the phospholipid-bound form, so free ara­chidonic acid increases (see fig. 5). Steroids such as dexamethasone block the production of free ara­chidonic acid by an indirect action, involving lipocortin, on phospholipase A2.[48) Dexametha­sone also reduces CSF formation[49] and causes a diuresis, possibly by decreasing the release of anti­diuretic hormone.

Dexamethasone is equally good or better than acetazolamide at relieving the symptoms of AMS[45] but is inferior to acetazolamide because it

has no known actions on respiratory control. In addition it also has negative effects on erythropoi­etin production, so limiting the enhancement of red cell manufacture. These features together with the large doses (4mg every 6 hours) necessary for ben­eficial effects, which can be associated with seri­ous adverse effects, such as complete suppression of adrenocorticotrophic function, make it unattrac­tive for prophylactic use.

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4.3 Spironolactone

There are advocates of spironolactone in pro­phylaxis[50,51] and it certainly reduces the incidence of AMS symptoms. The effects of spironolactone probably result from competitive inhibition at al­dosterone receptor sites, thus it reduces Na+ reabsorption in the distal tubules of the kidney leading to a natriuresis. K+ and H+ are retained causing a weak metabolic acidosis. Spironolactone might be expected to have a similar action on Na+ movement in the choroid plexus and so reduce CSF formation. A disadvantage of this steroid is that it is only effective in the presence of aldosterone, levels of which are usually reduced by hypoxia. There might therefore be quite a wide variation in its efficacy.

4.4 Progesterone and Other Drugs

Progestational agents are known to stimulate ventilation and pose some intriguing questions. The surge in progesterone levels during the luteal phase of the menstrual cycle leads to an increase in ventilation and a raised level of progesterone is re­sponsible for the maintained increase in ventilation during pregnancy.l52] Administration of a single dose of progesterone to healthy young men pro­duces a pronounced and prolonged increase in ven­tilation and accompanying alkalosis. For this rea­son progesterone, or the synthetic analogue medroxyprogesterone, have been used to treat a number of respiratory related conditions such as chronic obstructive pulmonary disease.

The evidence so far suggests that progesterone acts in the CNS (not at the peripheral chemorecep­tor) to increase the drive to breathe although the mechanism is unresolved[53] (see fig. 2). This intri­guing action of progesterone is of interest in that susceptibility to AMS might be expected to vary in women depending on the stage of their menstrual cycle when they arrive at altitude. There is little information on this point. To my knowledge, there has so far been only 1 trial of the prophylactic effect of progesterone in prevention of AMS and so far the report has only appeared as an abstract. This

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Coote

Phospholipase A2 + iCa++ +-- Hypoxia

+ Phospholipid t Arachidonate

;t:~~i~~n;~; + \ Re·esterifieation dexamethasone ) (ATP and 0;rdependent)

Free arachidonic acid 1 eye/o-oxygenase

Capillary Prostaglandins

--~~~-------~------------------i Permeability of i Erythropoietin

capillaries production in renal vasculature

Fig. 5. Possible mechanism for the reduction of tissue oedema be dexamethasone. Hypoxia increases free arachidonic acid and hence leads to an increase in permeability of capillary walls . The steroid would block this pathway via activation of lipo­cortin.l 17,47]

was conducted in a group of 24 male volunteers ascending to 5200m over 7 days. Progesterone (60mg daily) started 7 days before ascent, reduced AMS symptom-score in a similar fashion to aceta­zolamide (500mg daily) and improved arterial ox­ygen levels and the ability to perform exercise. Ad­verse effects of progesterone were reported to be minimaU541

Other prescriptions such as the diuretic furose­mide (frusemide) or the calcium channel-blocker nifedipine are undoubtedly useful in the acute man­agement of pulmonary oedema but are really last resorts.

Furosemide (40 to 80mg orally, intramuscularly or intravenously) is a powerful diuretic that is use­ful in drawing fluid from the lungs, but a careful watch is required for a hypovolaemia and the asso­ciated haemoconcentration that may induce throm­bosisJ551 I have used furosemide successfully in an individual with severe pulmonary oedema at 3353m in the European Alps. Nifedipine reverses hypoxia induced pulmonary hypertension in the rat[56] presumably by reducing the degree of smooth muscle tone in the pulmonary vessels. It

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Altitude Sickness

was argued that since pulmonary hypertension is a predisposing feature of pulmonary oedema, its re­duction would lessen further oedema formation, and indeed this appears to be the case.l57,581 How­ever, as a prophylactic to protect against the devel­opment of AMS, nifedipine does not appear to be beneficial. In a double-blind trial, Bartsch and col­leagues showed, in a group of 27 mountaineers who were not susceptible to high altitude pulmo­nary oedema, after rapid ascent to 4559m, that low­ering of pUlmonary artery pressure by nifedipine (20mg 3 times daily) did not improve gas exchange or reduce the symptoms of AMS.l591

4.5 Oxygen, Carbon Dioxide and Hyperbaria

Breathing pure oxygen at the prevailing ambi­ent pressure is beneficial although its prolonged use will not help acclimatisation. As an emergency treatment it has value in treating both pulmonary oedema and cerebral oedema of high altitude. There has been controversy as to whether similar beneficial effects can be produced by increasing the pressure of the air breathed. This has been com­prehensively reviewed by Roach and Hackett.l601 Essentially, it is concluded that hyperbaria of about 200mm Hg above ambient pressure (produced by pumping ambient air into a portable pressure bag, containing the patient) is as effective as oxygen breathing for the treatment of AMS, high altitude pulmonary oedema and cerebral oedema.

The idea that C02 is beneficial is an old one[3,61 1 and has recently been reviewed[621 although not without criticism.l631 Early suggestions were that it was the decrease in C02 that was the cause of alti­tude sickness; but this has been discredited by nu­merous authors.l211 It is interesting that the early work led it to being used in the cylinders of 'oxy­gen' placed in the carriage of trans-Andean rail way trains in Peru to aid passengers who become sick on the journey up to 4572m. Of course, it was never indicated on the cylinders otherwise victims of AMS may have been put off from using the gas. A recent study showed that inhalation of air contain­ing 3% CO2 at an altitude of 5486m increased ven-

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tilation and improved p02 with subsequent reduc­tion in AMS symptoms.[621 It therefore might be useful as an emergency treatment of AMS, but I would have reservations about using it if there are signs of cerebral oedema.

5. Sleep and Acute Mountain Sickness

At altitudes around 3048m, some individuals report poor sleep quality and above 4267m, most visitors have their sleep markedly disturbed.[42,641 This to some extent is probably due to a worsening of the arterial oxygen saturation during sleep exac­erbated by periodic breathing (Cheyne-Stokes). Drugs like acetazolamide and medroxyprogester­one decrease periodic breathing and improve oxy­gen saturation and sleep is greatly improved.[33,42] AMS is worsened as individuals become more ex­hausted and hence, good sleep is helpful. To achieve this with hypnotics needs caution. Most hypnotics depress ventilation and prevent arousal. There is evidence that arousal is protective in pre­venting too great a degree of oxygen depriva­tion.[65-67] However, a combination of acetazolam­ide (500mg daily) and temazepan (lOmg at night) gives a significant improvement in sleep quality and reduces AMS symptoms.l42,641

6. Conclusions

Ascent to high altitude causes hypoxia and re­spiratory alkalosis and may lead to AMS. Occa­sionally this can progress to a malignant form in­volving oedema of the lungs or the brain. Tissue hypoxia is the primary cause of these conditions, and the symptoms in the brain are manifestations of changes in fluid balance between the various body compartments.

Treatments and means of prevention are gener­ally effective: acetazolamide for prevention, furo­semide and nifedipine for pulmonary oedema, and dexamethasone for prevention and for cerebral oe­dema.

The mainstay of prevention however, should be a sensible rate of ascent, which is modified should symptoms occur. This allows time for acclimatisa­tion, an interesting and puzzling phenomenon.

sports Med. 20 (3) 1995

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During this time, brain CSF and renal mechanisms partly correct the respiratory alkalosis that initially limits the ventilatory response to hypoxia. How­ever, the fact that given sufficient time, tissues can become resistant to damage from the increasing levels of hypoxia as altitude is gained, indicates that other mechanisms must play an essential part. Such mechanisms must be effective in those born and living at high altitude and suggests that cellular and metabolic factors are probably the most impor­tant. Membrane and cell surface integrity, the pro­duction of cytokines, the activation and adherance of leucocytes, controllers of Ca++ stores are just some of the factors that would handsomely repay concerted studies on the response to short term and long term hypoxia. These factors are of course dif­ficult to study in the field, but human ingenuity will no doubt overcome any obstacles.

Acknowledgements

It is a pleasure to thank my colleagues in the Birmingham Medical Research Expeditionary Society for stimulating my involvement in medical problems caused by high altitude, to which they have made so many important contributions. Also my thanks to colleagues in the Physiology Laboratory at Oxford and to my many friends and students who have accompanied me on numerous expeditions to climb and to conduct scientific research in the mountains.

References I. Gerard A. Account of Koonawar. Lloyd, editor. In: Ward M.

Mountain mdicine. London: Crosby Lockwood Staples. 1975 2. Whymper E. Travels amongst the great Andes of the equator.

London: Thomas Nelson and Sons. 1892 3. Mosso A. Life of a man on the high alps. London: Fisher Unwin ,

1898 4. Engel CEo Mountaineering in the Alps. London : George Allen

and Unwin Limited, 1971 5. Benuzzi F. No picnic on Mt Kenya. London: W Kimber & Co.

Limited, 1952 6. Sutton JR, Coates G, Houston CS, editors. Hypoxia and moun­

tain medicine. Proceedings of the 7th International Hypoxia Symposium; Feb 1992: Lake Louise, Canada. Advances in the Biosciences. Vol. 84. Oxford: Pergamon Press, 1993

7. Frayser R, Houston CS, Bryan AC, et al. Retinal haemorrhage at high altitude. N Engl J Med 1970; 282: 1183-4

8. Rennie D, Morrisey J. Retinal changes in Himalayan climbers. Archives Ophtalmol1975; 93: 395-400

9. Clarke C, Duff J. Mountain sickness, retinal haemorrhage and acclimatisation on Mount Everest in 1975. BMJ 1976; 2: 495-7

10. Nakashima M. High altitude medical research in Japan. Jpn J Mountain Med 1983; 3: 23-7

© Adis International Limited, All rights reserved.

Coote

II. Winterborn MH, Bradwell AR, Chesner I, et al. Mechanisms of proteinuria at high altitude. Clin Sci 1986; 70: 58P

12. Hackett PH, Rennie D. Rales, peripheral edema, retinal haem­orrhage and acute mountain sickness. Am J Physiol 1979; 67: 214-8

13. Heath D, Williams DR. High altitude medicine and pathology. London: Butterworths, 1989

14. Winslow RM, Monge CC. Hypoxia, polycythemia and chronic mountain sickness. London: John Hopkins University Press, 1987

15. Monge Me. Life in the Andes and chronic mountain sickness. Science 1942; 95: 79-84

16. Kryger M, McCullough RE, Collins D, et al. Treatment of ex­cessive polycythemia of high altitude with respiratory stimu­lant drugs. Am Rev Respir Dis 1978; 117: 455-64

17. Coote JH. Pharmacological control of acute mountain sickness. Trends Pharmacol Sci 1991; 12: 450-5

18. Severinghaus JS, Mitchell RA, Richardson BW, et al. Respira­tory control at high altitude suggesting active transport regu­lation of CSFpH. Journal of Applied Physiology 1963; 18: 1155-66

19. Lahiri S, Milledge JS. Acid-base in Sherpa altitude residents and lowlanders at 4880m. Respir Physiol 1967; 2: 323-34

20. Milledge JS. Acid-base changes associated with respiratory acclimatisation to altitude. Postgrad Med J 1979; 55: 459-63

21. Ward MP, Milledge JS, West lB. High altitude medicine and physiology. London: Chapman and Hall Medical, 1989

22. Fencl V, MillerTB, Pappenheimer JR. Studies on the respiratory response to disturbances of acid-base balance with deductions concerning ionic composition of central interstitial fluid. Am J Physiol 1966; 210: 459-72

23. Bledsoe SW, Hornbein TF. Central chemosensors and the reg­ulation of their chemical environment. In: Hornbein TF, edi­tor. Regulation of breathing (Pt I). New York: Marcel Dekker Inc, 347-428: 1981

24. Birmingham Medical Research Expeditionary Society. Aceta­zolamide in control of acute mountain sickness. Lancet 1981; I: 180-3

25. Hunter DJ, Smart J R, Whitton L. Increased capillary fragility at high altitude. Br J Med 1986; 292: 98

26. Winterborn MH, Bradwell AR, Chesner 1M, Jones GT. The or­igin of proteinuria at high altitude. Postgrad Med J 1987; 63: 179-81

27. Bartsch P, Maggiorini M, Schobersberger W, et al. Enhanced exercise-induced rise of aldosterone and vasopressin preced­ing mountain sickness. J Appl Physiol 71: 136-143, 1991

28. Bartsch P, Shaw S, Weidmann P, et al. Aldosterone, antidiuretic hormone and atrial natriuretic peptide in acute mountain sick­ness. In : Sutton JR, Coates G, Houston CS, editors. Hypoxia and mountain medicine . Vol. 84. Adv Biosci 1992: 73-81

29. Fulco CS, Rock PB, Trad LA, et al. Increased physical-activity augments the incidence and severity of acute mountain sick­ness (AMS) during a simulated ascent to 4600m [abstract] . FASEB J 1994; 8: A298

30. Wright AD, Fletcher RF. Acute mountain sickness. Postgrad Med J 1987; 63: 163-4

31. Coote JH, Bradwell AR, Winterborn MH, el al. Birmingham Medical Research Expiditionary Society. The use of Aceta­zolamide at altitude. Bulletin Union Int. des Assoc de Guides de Montagne 1985; 8: 1-4

32. Hackett PH. Mountain Sickness. Prevention, recognition and treatment. American Alpine Club. 6th ed. New York: Ameri­can Alpine Club Inc, 1992

Sports Med, 20 (3) 1995

Altitude Sickness

33. Weil JV. Kryger MH. Scoggin H. Sleep and breathing at high altitude. In: Guilleminault C. Dement WC. editors. Sleep ap­noea syndromes. New York: Alan R. Liss Inc .• 1978: 19-136

34. Harrison GL. Evans J. Coote JH. Discontinuation of acetazol­amide after rapid ascent to 4300m. Sixth International Hyp­oxia Symposium; Feb 1989: Lake Louise. Canada. New York: Alan R. Liss Inc .• 1990

35. Jensen JB. Wright AD. Lassen NA. et al. Cerebral blood flow in acute mountain sickness. J Appl Physiol 1990; 69: 430-33

36. Grissom CK. Roach RC. Sarnquist FH. et al. Acetazolamide in the treatment of acute mountain sickness and clinical efficacy and effect on gas exchange. Ann Intern Med 1992; 116: 461-5

37. Cain SM. Dunn JE. Increase of arterial oxygen tension at alti­tude by carbonic anhydrase inhibition. J Appl Physiol 20; 1965: 882-4

38. Forwand SA. Landowne M. Follansbee IN. et al. Effect of ace­tazolamide on acute mountain sickness. N Engl J Med 1968; 279: 839-45

39. Bradwell AR. Dykes PW. Coote JH. et al. Effect of acetazolam­ide on exercise performance and muscle mass at high altitude. Lancet 1986: 1001-5

40. Bradwell AR. Dykes PW. Coote JH. Effect of acetazolamide on exercise at altitude. Sports Med 4; 1987: 157-63

41. Sutton JR. Houston CS. Mansell AL. et al. Effect of acetazol­amide on hypoxaemia during sleep at high altitude. N Engl J Med 1979; 301: 1329-31

42. Nicholson AN. Smith PA. Stone BM. et al. Altitude insomnia: studies during an expedition to the Himalayas. Sleep 1979; II: 354-61

43. Hackett PH. Roach RC. Harrison GL. et al. Respiratory stimu­lants and sleep periodic breathing. Almitrine versus Acetazol­amide. Am Rev Respir Dis 1987; 135: 896-8

44. Johnson TS. Rock PB. Fulco CS. et al. Prevention of acute mountain sickness by dexamethasone. N Engl J Med 1984; 310: 683-6

45. Ferrazzini G. Maggiorini M. Kriemler S. et al. Successful treat­ment of acute mountain sickness with dexamethasone. BMJ 1987; 294: 1380-2

46. Lands WEM. Sauter J. Stone Gw. Oxygen requirements for prostaglandin biosynthesis. Prostaglandins Med 1978; I: 117-\20

47. Lote CJ. Haylor J. Eicosanoids in renal function . Prostaglan­dins.leukotrienes and essential fatty acids: Reviews 1989; 36: 203-17

48. Flower RJ. Blackwell GJ. Anti-inflammatorysteroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature 1979; 278: 456-9

49. Gutin PH. Corticosteroid therapy in patients with cerebral tu­mours: benefits. problems. practicalities. Semin Onco11975; 2: 49-56

50. Currie IT. Carter PH. Champion WL. et al. Spironolactone and acute mountain sickness. Med J Aust 1976; (II): 168-70

51. Jain SC. Sing MV. Sharma VM. et al. Amelioration of acute mountain sickness: comparative study of acetazolamide and spironolactone. Int J Biometeor 1986; 30: 293-300

© Adis International Um~ed. All rights reserved.

159

52. Goodland RL. Pommerenke WT. Cyclic fluctuation of the al­veolar carbon dioxide tension during the normal menstrual cycle. Fertil Steril 1952; 3: 394-8

53. Dempsey JA. Olson EB. Skatrud JB. Hormones and neuro­chemicals in the regulation of breathing. In: Handbook of physiology: the respiratory system. Vol. II. Pt I . Bethesda: American Physiological Society. 1986: 181-221

54. Bradwell AR. Wright AD. Irnray C. et al. Progesterone in acute mountain sickness. Hypoxia and mountain medicine [ab­stract]. Proceedings of the Ninth International Hypoxia Sym­posium; Feb 1995: Lake Louise. Canada. 1996

55. Dickenson JG. Acetazolamide in acute mountain sickness. Postgrad Med J 1979; 55: 454-8

56. Stan brook HS. Morris KG. McMurtry IF. Prevention and rever­sal of hypoxic pulmonary hypertension by calcium antago­nists. Am Rev Respir Dis 1984; 130: 81-5

57. Oelz O. Ritter M. Jenni R. et al. Nifedipinefor high altitude pulmonary oedema. Lancet 1989; II: 1241-4

58. Bartsch p. Maggiorini M. Ritter M. et al. Prevention of high altitude pulmonary edema by Nifedipine. N Engl J Med 325: 1284-9. 1991

59. Hohenhaus E. Niroomand F. Goerre S. et al. Nifedipine does not prevent acute mountain sickness. Am J Respir Crit Care Med 1994; 150: 857-60

60. Roach R. Hackett PH. Hyperbaric and high altitude illness. In Sutton JR. Coates G. Houston CS. editors. Hypoxia and mountain medicine. Vol. 84. Adv Biosci 1992: 266-73

61. Childs SB. Hamlin H. Henderson Y. Possible value of inhalation of carbon dioxide in climbing great altitudes. Nature 135; 1935: 457-8

62. Harvey TC. Winterborn MH. Lassen NA. et al. The effect of carbon dioxide in acute mountain sickness: a rediscovery. Lancet 1988; 2: 639-41

63. Hackett P. Mechanisms of high altitude illness. In: Sutton JR. Coates G. Houston CS. editors. Hypoxia and mountain med­icine. Vol. 84. Advances in the Biosciences. Oxford: Per­gamon Press 1992: 292-5

64. Coote JH. Sleep at high altitude. In: Cooper R. Sleep. London: Chapman Hall 1994; 243-264

65. Selvamurthy W. Raju VRK. Ranganathan S. et al. Sleep pat­terns at an altitude of 3500 metres. Int J Biometeorol 1986; 30: 123-35

66. Coote JH. Tsang G. Baker A. et al. Polycythemia and central sleep apnoea in high altitude residents of the Andes. J Physiol (Lond) 1993;459: 749P

67. Coote JH. Tsang G. Baker A. et al. Respiratory changes and quality of sleep in young high altitude dwellers in the Andes of Peru. Eur J Appl Physiol 1993; 66: 249-53

Correspondence and reprints: Professor John H. Coote, Department of Physiology, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, England.

Sports Med. 20 (3) 1995