High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral...

Review

10.1517/14656566.9.1.119 © 2008 Informa UK Ltd ISSN 1465-6566 119

High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema AD Wright † , SP Brearey & CHE Imray †University Hospital (Selly Oak), The Diabetes Centre, Raddlebarn Road, Selly Oak, Birmingham, B29 6JD, UK

The pharmacotherapy of prevention and treatment of acute altitude-related problems – acute mountain sickness, high-altitude cerebral oedema and high-altitude pulmonary oedema – is reviewed. Drug therapy is only part of the answer to the medical problems of high altitude; prevention should include slow ascent and treatment of the more severe illnesses should include appropriate descent. Carbonic anhydrase inhibitors, in parti-cular acetazolamide, remain the most effective drugs in preventing, to a large extent, the symptoms of acute mountain sickness, and can be used in the immediate management of the more severe forms of altitude-related illnesses. Glucocorticoids in relatively large doses are also effective preven-tative drugs, but at present are largely reserved for the treatment of the more severe acute mountain sickness and acute cerebral oedema. Calcium channel blockers and PDE-5 inhibitors are effective in the management of acute pulmonary oedema. Further work is required to establish the role of antioxidants and anticytokines in these syndromes.

Keywords: acetazolamide , acute cerebral oedema , acute mountain sickness , acute pulmonary oedema , dexamethasone , high altitude

Expert Opin. Pharmacother. (2008) 9(1):119-127

1. Introduction

1.1 The clinical syndromes The increasing popularity of high-altitude sports and trekking, and the relative ease of travelling at altitudes > 2000 m, has resulted in a much greater awareness of the clinical problems that may result. Yet tragedies still occur. Acute exposure to hypobaric hypoxia causes a number of clinical problems depending on the partial-pressure of inspired oxygen and the duration of exposure. Acute exposure to modest altitude (1500 – 4000 m) results in exertional dyspnoea, tachycardia and impaired night vision. Above 4000 m there may be additional dizziness, a feeling of unreality and some paraesthesiae and at altitudes between 5000 and 7000 m unconsciousness occurs. In some subjects, acute exposure to modest altitudes causes altitude-related illnesses ranging from the common, mild, self-limiting forms of acute mountain sickness (AMS), to the rare, life-threatening forms of acute cerebral oedema (HACE) and acute pulmonary oedema (HAPE). The purpose of this review is to highlight the pharmacotherapy of the prevention and the treatment of these acute altitude-related problems. A number of review articles have been published recently [1-5] . The processes of acclimatisation and the syndromes of chronic mountain sickness have not been covered in this article.

1. Introduction

2. Non-pharmacological

management of acute

high-altitude syndromes

3. Pharmacotherapy

4. Conclusion

5. Expert opinion

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High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema

120 Expert Opin. Pharmacother. (2008) 9(1)

1.1.1 Acute mountain sickness AMS consists of headache, malaise, lethargy, loss of appetite, nausea, vomiting, dizziness and disturbances of sleep often with periodic respiration. None of these symptoms on their own, and no specific features on examination, are diagnostic. Also no laboratory measurement is diagnostic. The severity of AMS can be scored using the Lake Louise Questionnaire [6] or the more detailed Environmental Symptoms Questionnaire [7] or by the use of a simple analogue scale [8] . As the clinical features of AMS are non-specific, diagnostic confusion with other medical problems for example simple respiratory infections, sinusitis, gastritis, dehydration and physical exhaustion may occur. The exact pathophysiology of AMS is uncertain, but is probably based on changes in the blood–brain barrier and the formation of vasogenic oedema as a result of increases in capillary flow and hypoxia-induced cytokines and free radicals [9] . Early changes on acute exposure to hypoxia show a mild increase in brain volume and an increase in cerebral blood flow, but no change in cerebrospinal fluid pressure. However, these changes are found in all subjects and do not correlate with the presence or absence of AMS [10-12] .

AMS occurs in susceptible, unacclimatised individuals 6 – 24 h after ascending to > 2500 m and usually resolves after a 2- to 3-day stay at the same altitude. Reported prevalence rates vary according to the altitude and the rate of ascent. It is rare below 3000 m, but occurs in most indivi duals ascending acutely to > 4500 m. For example, in the Mount Everest region of Nepal ∼ 50% of trekkers who walk to altitudes > 4000 m over ≥ 5 days develop AMS and 84% of people who fly directly to 3860 m are affected. Prevalence rates will also be affected by the history of recent exposure to altitude [13] . Younger individuals are probably more susceptible and physical activity, obesity, respiratory infection and dehydration are possible contri-butory factors. Both men and women are at risk of AMS and most studies show an equal prevalence. At present, susceptible individuals can only be identified by complex hypoxia testing [14] , although previous experience of AMS is highly predictive [13] .

1.1.2 High-altitude cerebral oedema HACE is characterised by increasing ataxia, mental confusion, hallucinations and altered consciousness. On examination, ataxia, papilloedema, retinal haemorrhages and focal neurological signs may be found. Coma and death may follow. HACE has been shown to be associated with raised intracranial pressure and with reversible oedema of the white matter, particularly of the corpus callosum [15] . HACE is thought to be an extension of the benign form of AMS into the more serious and potentially fatal form [4] . Therefore, HACE generally follows 24 – 36 h after the onset of AMS and may occur in association with HAPE. Prevalence studies are limited, but it has been reported in 0.5 – 1% in visitors > 4200 m [16] .

1.1.3 High-altitude pulmonary oedema HAPE is a non-cardiogenic form of pulmonary oedema occurring between 1 and 4 days after arrival at altitudes > 2500 m. It occurs in 0.1 – 4% of subjects depending on the ascent rate [16] . Risk factors include individual susceptibility, as shown by previous episodes of HAPE, pulmonary hypertension and abnormalities such as uni lateral absence of a pulmonary artery, and exercise and exposure to cold. Respiratory infection may predispose, especially in children [17] . HAPE is recognised clinically by a greater reduction in exercise tolerance than might be expected for the altitude, followed by a dry cough, which then becomes productive with blood-stained sputum. Crackles may be present on auscultation of the chest. HAPE is not necessarily preceded by AMS.

Hypoxic pulmonary vasoconstriction increases pulmonary vascular resistance and pulmonary artery pressure. The mechanism by which this is thought to occur is at least in part via hypoxic-sensitive channels expressed in pulmonary-endothelial and smooth-muscle cells. Hypoxia reduces the activity of voltage-gated potassium channels and downregu-lates their expression leading to membrane depolarisation, calcium ion influx into pulmonary artery smooth-muscle cells and vasoconstriction. [18,19] . The rise in pulmonary artery pressure in response to hypoxia appears to be an important factor in the development of HAPE [20,21] . Susceptible individuals have an exaggerated rise in pulmo-nary artery pressure in response to hypoxia and exercise, and, more importantly, regional pulmonary blood flow becomes more heterogeneous [22,23] . A rise in capillary pressure > 19 mmHg was found in susceptible subjects who developed HAPE and this was thought to be critical in leading to capillary stress failure, fluid leakage and alveolar haemorrhage [24] . Drugs lowering pulmonary artery pressure have been shown to be effective in the prevention and treatment of HAPE.

2. Non-pharmacological management of acute high-altitude syndromes

A slow ascent and sufficient time for acclimatisation are the best ways of preventing acute altitude-related illnesses. Above 3000 m the recommended ascent rate is ≤ 300 m daily with a rest day for every 1000 m climbed. This is not always practical. Avoiding strenuous activity on arriving at a new altitude is also recommended and maintaining adequate hydration at all times is probably important [25] . Oxygen therapy is effective in alleviating symptoms of AMS [26] and portable hyperbaric chambers and positive end-expiratory pressure devices may also be of temporary benefit [27,28] . The management of headache usually requires simple analgesia. Further ascent should be avoided if symptoms of AMS have not settled and descent should be arranged if moderate symptoms of AMS persist or if symptoms worsen [29] .

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Wright, Brearey & Imray

Expert Opin. Pharmacother. (2008) 9(1) 121

3. Pharmacotherapy

The two main approaches to therapy of high altitude illnesses are to improve oxygenation by increasing ventila-tion (for example carbonic anhydrase [CA] inhibitors and medroxyprogesterone) or reducing cytokine and inflammatory responses (for example glucocorticoids and antioxidants). In addition, drugs that lower pulmonary artery pressure may be beneficial in the management of HAPE.

3.1 Carbonic anhydrase inhibitors CA enzymes are efficient catalysts of the hydration of carbon dioxide to bicarbonate and protons and, thus, play an important role in acid–base homeostasis. In mammals, 16 different isoenzymes have been described with different subcellular and tissue distributions [30] . Inhibitors of CA act by binding to the zinc ion of the enzyme [31] . Sulfonamides are organic inhibitors of CA and two derivatives, acetazolamide and methazolamide, have been used in the management of altitude-related illnesses.

3.1.1 Acetazolamide Acetazolamide blocks CA in red blood cells, renal tubules, chemoreceptors, the brain, and pulmonary and systemic blood vessels. The conventional view of the mechanism of action of acetazolamide in the treatment of AMS is that inhibition of renal CA leads to a bicarbonate diuresis with a metabolic acidosis. Acetazolamide increases the poikilocapnic hypoxic ventilatory response and results in a higher arterial partial pressure of oxygen [32-35] . Cerebrospinal fluid production is also reduced, which may contribute to its beneficial effect. However, CA inhibition in other tissues, particularly the vasculature and the chemoreceptors, may also be important.

Prophylactic acetazolamide has been shown to reduce symptoms of AMS [36] although this meta-analysis included several different doses, ranging between 250 mg and 1 g daily. It is usually recommended that acetazolamide is started at least one day before ascent and continued until descent has begun. It has been difficult to draw a firm conclusion on the dose of acetazolamide from the large number of studies because many have involved small numbers of subjects with a variety of altitudes and ascent rates. Another meta-analysis concluded that 750 mg daily prevented AMS, but lower doses did not [37] . However, this has not been generally accepted because different ascent rates were analysed together. On the other hand, an effective trial of 250 mg compared with 750 mg daily may have had a selection bias towards non-susceptible individuals [38] . Another report also found that 500 mg daily was effective, but 250 mg was not [39] .

Side effects of acetazolamide are usually well tolerated and include parasthesiae, a short-lived diuresis and an unpleasant taste of carbonated drinks. Rarely allergic reactions occur. Another concern that trekkers and climbers have about the use of acetazolamide is the possible effect on exercise capacity.

Hackett and colleagues [40] showed at a high altitude (6300 m) that three doses of acetazolamide 250 mg every 8 h reduced maximum work load in two out of four subjects. In another study of acetazolamide under hypoxic conditions at sea level, exercise capacity was reduced [41] . However, there are several findings of exercise being unchanged or even improved by acetazolamide [42,43] and the authors showed that muscle mass and exercise performance fell at < 4846 m in those on acetazolamide [44] . Some of these apparent discrepancies may arise because acute hypoxia and/or acute acetazolamide have been studied and results may be different under more usual field conditions of slower ascents and longer duration of therapy. Improvement in general well being and oxygen saturation may be more important than any adverse effect of metabolic acidosis on gas exchange in the muscle.

Although traditionally acetazolamide is mainly used for prophylaxis it should also be considered for acute therapy of AMS with moderate or severe persistent symptoms providing the subject has not been taking the drug prophylactically. A limited number of studies have shown improvement in overall AMS scores [45,46] , although relief of symptoms may take 24 h and headache may worsen.

There is evidence that acetazolamide reduces hypoxic pulmonary vasoconstriction [35] probably by selectively inhibiting hypoxia-induced calcium ion influx into pulmo-nary artery smooth-muscle cells [47] . It is of interest that the action of acteazolamide appears to be independent of CA inhibition as other CA inhibitors such as benzolamide and ethoxyzolamide do not have the same effect. There is no clinical data on the use of acetazolamide in the management of HAPE, but the effective lowering of pulmonary artery pressure suggests it may have a beneficial effect in this situation [48] .

3.1.2 Methazolamide Methazolamide is a CA inhibitor that is less bound to plasma proteins, diffuses more rapidly into tissues [49] and its side effects are thought to be less common [50] . In a comparative study, methazolamide 150 mg daily was equally effective in preventing AMS with slightly less parasthesiae [51] . The speed of action might be of benefit in the acute treatment of AMS, but no differences were found in comparison with acetazolamide [51] .

3.2 Steroids 3.2.1 Glucocorticoids The mechanism of action of glucocorticoids is largely speculative, but is likely to be largely through changes in capillary permeability and cytokine release. Dexamethasone 8 mg daily in divided doses has been used in the prevention of AMS [52,53] , but lower doses are relatively ineffective [54] . It is usually considered that the potential side effects of glucocorticoids in such doses mean they are not justified for prophylaxis unless acetazolamide is contraindicated or when a very rapid effect is required, as for example for

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rescue workers are called to ascend very fast. In a comparison of prednisolone 10 – 40 mg daily with dexamethasone 0.5 mg daily, reduction in symptoms of AMS occurred in all groups and interestingly the best results were obtained with prednisolone 20 mg daily [55] . When dexamethasone is given alone it should not be discontinued if the risk of AMS or HACE remains, as symptoms may recur. Although acetazolamide is probably more effective than dexamethasone in the prophylaxis of AMS [56] , more direct comparisons are needed. The combination of acetazolamide 500 mg with dexamethasone 4 mg b.i.d. in a small number of subjects was more effective than acetazolamide alone [57] . Prophylactic dexamethasone 8 mg daily in subjects prone to HAPE was protective against HAPE and partially protective against AMS [58] .

The main use of dexamethasone is in the acute management of severe AMS and of HACE when the serious nature of the illnesses justifies high-dose steroids. Dexamethasone 8 mg initially and 4 mg every 6 h orally or parenterally will improve the clinical situation sufficiently to make evacuation easier [59] , but how long the treatment should be continued for after the subject has descended is not known.

3.2.2 Medroxyprogesterone The known effect of progesterone in stimulating respiration has been used in one clinical trial using medroxyprogesterone 60 mg daily prophylactically. Although oxygenation improved, AMS symptoms were not significantly reduced in the relatively small number of subjects studied [60] .

3.3 Calcium channel blockers Calcium channel blockade inhibits the vasoconstriction induced by hypoxia in pulmonary arteries and has been shown to reduce pulmonary artery pressure. Slow-release nifedipine 20 mg every 8 h prevents HAPE in susceptible individuals ascending rapidly to 4559 m [61] . Acute treatment of HAPE using nifedipine 10 mg sublingually followed by 20 mg slow-release orally every 6 h may be added to other efforts to provide oxygen and arrange descent [62] .

3.4 Phosphodiesterase inhibitors 3.4.1 Phosphodiesterase type 5 inhibitors The main interest in this group of drugs lies in their effects on hypoxia-induced pulmonary hypertension. Sildenafil reduces hypoxia-induced pulmonary hypertension occurring both at rest and on exercise at altitude [63,64] . Prophylactic tadalafil 10 mg has been shown to lessen the rise in systolic pulmonary artery pressure at high altitude in HAPE-prone subjects and to a large extent protected subjects from HAPE, but not AMS [58] . The incidence of HAPE in these subjects was dramatically reduced from 7 out of 9 (78%) in the placebo group to 1 out of 8 (13%) in those on tadafil. The surprising finding was that HAPE did not occur in those on dexamethasone. Nifedipine in this situation would have been

expected to have reduced the risk to 10%. The effects of PDE inhibitors on AMS and HACE have been less studied, but the authors have shown that sildenafil increases cerebral oxygentation [65] and, therefore, such treatment might be helpful in these situations. However, in the study of tadalafil and dexamethsone [58] , tadalafil was no better than placebo in preventing AMS and 2 out of the 10 subjects on tadalafil withdrew from the study because of severe AMS.

3.4.2 Theophyllines Theoretically theophylline should be of value in altitude-related illness as it reduces periodic breathing, cerebral and pulmonary microvascular permeability and also pulmonary artery pressure. A trial of slow-release theophylline 375 mg b.i.d. p.o. at 3454 m showed increased oxygenation and lower AMS scores on arrival and after 18 h [66] . A direct comparison of acetazolamide and theophylline showed that both helped to normalise sleep-disordered breathing, but only acetazolamide improved oxygen saturations [67] .

3.5 Magnesium Magnesium is a physiological N -methyl-D-aspartate antagonist and may protect the hypoxic brain. The NMDA receptor is involved in the pathophysiology of hypoxic convulsions [68] and blockage of NMDA receptors has been shown to be beneficial [69] . There is, however, no human data to link the NMDA receptor to the pathogenesis of AMS and oral magnesium in a randomised, controlled trial at 4559 m did not prevent AMS [70] . In the treatment of AMS, intravenous magnesium reduced symptoms compared with placebo, but was not clinically important [71] .

3.6 Antioxidants Ginko biloba is a traditional Chinese medicine containing flavonol glycosides and terpene lactones, which, among many effects, scavenge excess free radicals [72] . There is conflicting evidence of its effectiveness in the prevention of AMS with some studies showing a benefit [73] . More recent, randomised trials showed that Ginko biloba was not effective in comparison with acetazolamide and placebo [74,75] .

Antioxidant supplementation with ascorbic acid, tocopherol acetate and α -lipoic acid in a 10-day ascent to 5180 m resulted in a lower AMS score and higher oxygen saturations [76] . On the other hand, there is concern that antioxidants may interfere with the action of acetazolamide on the normocapnic hypoxic ventilatory response [77] .

3.7 Diuretics The physiological response to hypoxia is generally a diuresis. 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 [78] .

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However, these studies were conducted before AMS assessment was standardised. In smaller, chamber studies at 4270 m [79] and in field studies at 5340 m [80] no benefit was demonstrated. Furosemide is potentially dangerous at high altitude as serious reductions in blood volume may occur. Although plasma aldosterone concentrations are reduced at altitude, spironolactone is of interest, not because of any diuretic effect, but the mild acidosis and reduction in cerebrospinal fluid production it causes may be beneficial. There have been conflicting reports on the use of spironolactone at altitude with one showing benefit [81] and another showing little value in preventing AMS [82] .

3.8 Sedatives and other drugs Sleep disorders are commonly experienced at altitude and acetazolamide reduces the time spent in periodic breathing [83] . Similar findings have been reported with theophylline (see Section 3.4.2). Improved sleep quality has also been shown using temazepam [84-86] without any significant adverse effects [87] .

The metabolism of drugs may be altered by hypoxia with the rate of clearance of drugs by cytochrome P450 potentially affected [88] . Although there is little data on drug metabolism at altitude, it is reassuring that only a small decrease in the activity of CYP2D6 and CYP3A4 at 4559 m and only small changes in the metabolism of cortisol, mephenytoin and antipyrine have been shown [89] . Similarly at 4500 m the metabolism of theophylline and verapamil was not impaired [90] .

4. Conclusion

Acute altitude-related problems consist of the common syndrome of AMS, which is relatively benign and usually self-limiting, and the rarer, more serious syndromes of high-altitude cerebral oedema and high-altitude pulmonary oedema. Rapid ascent to altitudes > 3000 m without sufficient time to acclimatise is a common feature. Individual susceptibility 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 management of serious illness requires oxygen, if available, and descent as soon as possible. Pharmacotherapy has two important roles – prophylaxis and treatment. Acetazolamide remains the most useful drug for the prophylaxis of AMS, although protection is not complete. Glucocorticoids can prevent AMS and are largely reserved for the treatment of the more severe forms of AMS and for HACE. Calcium channel blockers are established for the management of HAPE, but the reduction in pulmonary artery pressure with PDE inhibitors has provided an alternative for both the prevention and management of this serious problem. Other approaches to the pharmacotherapy of altitude-related syndromes include antioxidants.

5. Expert opinion

One of the unsolved problems is our limited ability to identify individuals who are susceptible to high-altitude-related illnesses. Such information is needed in order to give proper advice on prophylaxis to those travelling to high altitude and also to plan clinical trials. Genetic studies may offer some prospects for clarifying individual variation. Although the ventilatory response to hypoxia varies between individuals, only complex tests involving measurements of such responses have identified subjects susceptible to the different clinical syndromes. Arising from this variable response to hypoxia, is the serious problem in interpreting many of the trials performed in hypobaric chambers or at high altitude because so often studies have been under-powered. It is also difficult to compare trial results using differing ascent profiles. The severity of AMS is the end point of many therapeutic trials at altitude, but assessment of AMS itself remains difficult, being relatively subjective and highly dependent on self-reporting. All investigators and those responsible for people visiting high altitudes would welcome a diagnostic test for AMS that is both sensitive and specific.

The extent to which physical exercise is an aggravating factor for altitude-related illness has not been fully explored. On the other hand, drugs that improve oxygenation appear to improve exercise performance. The traditional prophylactic drug for AMS, acetazolamide, is not merely a respiratory stimulant, as drugs with such a limited action are not effective against AMS. Moreover, stimulation of respiration by this drug is complex, involving pulmonary and brain vascular endothelium, the kidneys and the peripheral chemoreceptors. Further investigations into its mechanism of action are warranted [34] . The dose of actazolamide used for prevention is not agreed, but in the authors’ opinion should be 500 mg daily, starting at least 24 h before ascent to high altitude. Further trials comparing different doses of acetazolamide at different altitudes in people with similar ascent rates are needed. The use of glucocorticoids in prophylaxis is supported by therapeutic trials, but there is a reluctance to advocate their general use and more head-to-head trials comparing acetazolamide and dexamethasone are needed. More data on the side effects of short-term treatment with high doses of dexamethasone at altitude are also needed. Glucocortiscoids are clearly effective in the management of AMS and HACE, but further studies of their use in the management of HAPE would be of interest. The role of PDE-5 inhibitors in limiting altitude-induced pulmonary hypertension [91] is an exciting area of research and the role of such treatment for clinical syndromes needs further assessment. The relative rarity of the more severe illnesses of high altitude makes clinical trials with adequate numbers and controls difficult.

The management of acute high-altitude-related illness is now based on a much better understanding of the

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physiological 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 hypoxia-inducible factors and cytokines that alter capillary permeability may allow for the use of newer drugs for the prevention and alleviation of AMS, HACE and HAPE. Studies designed to identify key mediators of capillary permeability at altitude have given differing results. IL-1 β , -6 and -8, and TNF- α did not change with hypoxia and were not related to the develop-ment of AMS [92] . Although increases in plasma C-reactive protein and IL-6 may be associated with development of HAPE, again no such associations were observed for IL-1, -2, -6 and -8, and TNF- α with the development of AMS [93] . Much work has focused on the role of VEGF, a potent permeability factor upregulated by hypoxia [94] . Some studies have found no evidence of an association of changes in

plasma concentrations of VEGF and AMS [95,96] whereas others support the hypothesis that VEGF contributes to the pathogensis of AMS [97] . Localised free-radical-mediated vascular damage has been investigated in relation to muscle damage and AMS [98] , and antioxidant therapies need further evaluation. Similarly, key mediators of pulmonary and intracerebral inflammation that may contribute to increased capillary permeability are still to be identified. Clearly a better understanding of the mechanisms of increased capillary permeability of both cerebral and pulmonary capillaries will greatly enhance the management of altitude-related illnesses.

Declaration of interest

The authors state no conflict of interest and have received no payment for preparation of this manuscript.

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Affi liation AD Wright †1,2 , SP Brearey3 & CHE Imray 4

†Author for correspondence 1University Hospital (Selly Oak), The Diabetes Centre, Raddlebarn Road, Selly Oak, B29 6JD, Birmingham, UK Tel: +44 121 627 1627 ; Fax: +44 121 627 8214; E-mail: [email protected] 2Honorary Senior Clinical Lecturer, University of Birmingham3Consultant Paediatrician, Countess of Chester NHS Foundation Trust, Chester4Consultant Surgeon and Honorary Readerin Surgery, Warwick Medical School, Coventry

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High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral...

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