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Key points k With increasing altitude, barometric pressure falls leading to a progressive fall in the inspired and arterial partial pressures of oxygen. k Hypoxaemia triggers a series of adaptive physiological responses, termed acclimatisation, which allow humans to tolerate exposure to even very high altitudes. k The respiratory response to altitude exposure consists of hyperventilation with a periodic pattern typically observed predominantly at rest and during sleep. k Rapid ascent, inappropriate time for acclimatisation, strenuous physical exertion and individual susceptibility predispose to high-altitude-related illnesses k Acute mountain sickness (AMS) is characterised by , , poor and fatigue. It may progress to high-altitude cerebral oedema with altered mental status, loss of consciousness and if not treated by descent, supplemental oxygen and dexamethasone. k High-altitude pulmonary oedema (HAPE) is due to exaggerated pulmonary during hypoxic exposure. It manifests itself within hours to days after rapid ascent to >3,000 m with , , and pulmonary rales. Treatment includes supplemental oxygen, descent and nifedipine to reduce pulmonary artery pressure. Breathe review altitude.qxd 22/11/2007 15:35 Page 3

Y. Nussbaumer-Ochsner Lessons from high-altitude K.E. Bloch physiology Pulmonary Division, University of Zurich, and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Educational aims

k To review the physiological response to high-altitude exposure. k To discuss the three major high-altitude : acute mountain sickness, high-altitude cerebral oedema and high-altitude pulmonary oedema. Correspondence k To provide information on prevention and treatment of high-altitude diseases. K.E. Bloch Pulmonary Division, University Hospital of Zurich Summary Ramistrasse 100, CH-8091 Zurich Switzerland High-altitude exposure causes a series of normal physiological responses, termed accli- Email: [email protected] matisation, which mitigate the effects of hypobaric . Hypoxic ventilatory stimu- lation results in improved oxygen uptake but is associated with respiratory that may trigger periodic breathing, particularly during sleep, thereby impairing sleep quality. Supported by grants from the As travelling to high altitude is popular, high-altitude related illnesses that affect sub- Swiss National Science jective wellbeing, reduce physical performance and alter mental status are also fre- Foundation and the Lung League quently observed. They encompass acute mountain sickness (AMS), high-altitude cere- of Zurich. bral oedema (HACE) and high-altitude pulmonary oedema (HAPE). Depending on ascent rate and individual susceptibility, symptoms usually occur at altitudes above 2,500 m. Therapeutic options include descent accompanied by administration of oxygen and as required. Prevention is based on appropriate acclimatisation, moderate ascent rate, low sleeping altitude and drugs, including acetazolamide, dexamethasone and nifedipine.

A mother, their 14-year-old son and his 14- continued until the next morning when the j year-old friend undertook a breathtaking family decided to return to the lowlands. Upon journey. From Interlaken, Switzerland (568 m), arrival in Interlaken, the son felt well again. they travelled for 2 h by train to the highest rail- This vignette illustrates common health way station in Europe: the Jungfrau Joch, at problems occurring with oxygen deprivation at 3,450 m. They enjoyed the beautiful view but high altitude in unacclimatised travellers and had to hurry to reach the Mönchsjoch hut at mountaineers. With the construction of roads, 3,650 m that same evening (figure 1). After trains and cable cars, high mountain areas hiking through the snow for 40 mins with heavy have become easily accessible and popular for backpacks they arrived at the hut, exhausted recreational activities (skiing, mountaineering) but happy. However, 2 h later when the dinner even for those who are unaware of the poten- was ready, the son had lost his appetite. He felt tial of a high-altitude sojourn. Many peo- dizzy and fatigued and complained of a throb- ple also pursue professional work in mountain bing . He went to bed without areas, and in the Americas, Asia and eastern but could not fall asleep. Every few minutes he Africa there are permanent settlements at alti- woke up with shortness of breath. This tudes >2,500 m.

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ascent, the altitude reached, sleeping altitude and individual susceptibility. Allowing appropri- ate time for acclimatisation to hypoxia reduces the of high-altitude . In addition to oxygen deprivation, other factors, such as dehy- dration and harsh weather conditions, may influ- ence the condition of travellers and moun- taineers at high altitude. The impact of these can be reduced with appropriate protection. Apart from the acute forms of altitude-related illnesses, subacute and chronic forms of mountain sickness with may occur in long- term high-altitude residents. The symptoms include polycythemia, hypoxaemia and impaired mental function. The atmosphere Figure 1 Although humans are able to adapt to quite Just before sunset a group of varying environmental conditions, hypobaric With increasing altitude, barometric pressure tourists is on the way from the hypoxia associated with rapid ascent to high alti- falls. The partial pressures of inspired (PI,O ) and Jungfrau Joch (peak seen in the 2 tude in unacclimatised subjects, and in particular arterial oxygen (Pa,O ) also decrease, as the par- background at 3,450 m), the 2 in with pre-existing cardiopulmonary tial pressure of a gas is a function of the total highest railway station in Europe, disease, may cause discomfort and even altitude- to the Monchsjoch hut (at pressure. Dry air has an O2 concentration of 3,650 m) where they plan to stay related illness [1, 2]. The major high-altitude dis- 20.9%. When air is inhaled it is warmed and sat- overnight. Easy access by train and eases mainly affect the cerebral and cardiopul- urated with water vapour. The partial pressure of other means of transportation monary systems: the cerebral form is AMS, which water vapour at body temperature (37°C) is entails the risk that people can progress to HACE, the cardiopulmonary form 47 mmHg. Thus, the PI,O2 at sea level is 149 unaware of potential hazards is HAPE. In its mild form, AMS is quite common. mmHg, i.e. 0.21 times barometric pressure minus travel to very high mountain At the Capanna Regina Margherita (Mount Rosa, water vapour pressure [0.21×(760-47)=149 areas. 4,559 m; figure 2), 22% of climbers have symp- mmHg]. At an altitude of 3,450 m, correspon- toms of AMS requiring a reduction of their physi- ding to that of the Jungfrau Joch, the barometric cal activity [3]. The development of these condi- pressure is 497 mmHg and the PI,O2 is [0.21× tions is influenced by the rate of the previous (497-47)]=94 mmHg, i.e. only about two-thirds of Figure 2 that at sea level. Figure 3 shows the relationship View of the Mount Rosa massif between barometric pressure, PI,O2 and altitude. from the south. The Cappanna Regina Margherita is situated on top of a rock at 4,559 m on the The normal Signalkuppe (also called Punta Gnifetti, arrow). The hut has a physiological response long-standing tradition as a high altitude medical research facility to high altitude since 1893. Nowadays, research groups from all over the world per- With increasing altitude, the human body experi- form high-altitude studies during ences a progressive oxygen deprivation and the summer months. hypoxia ensues. Oxygen, essential for normal cel- lular function can become a limiting factor. Over the course of a prolonged stay at high altitude, a series of adaptive changes to the environment take place. These changes are known as acclima- tisation and improve tolerance to high altitude. Hyperventilation and periodic breathing One of the first and most important physiological responses to hypoxic exposure is a compensatory

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increase in ventilation (figure 4). Hyperventilation Altitude (in 1000 ft) Figure 3 0510 15 20 25 30 Relationship between altitude, augments alveolar ventilation and a further 800 decrease in oxygen tension can be avoided or Sea level barometric pressure and PI,O2. mitigated. Respiratory stimulation is mediated by 700 Zurich 140 hypoxic stimulation of the peripheral chemo- 120 receptors, especially in the carotid body, and by 600 Jungfrau Joch mmHg 100 2 other changes in the chemical control of ventila- O 500 Capanna P tion. With increasing hyperventilation, alveolar Regina 80 and arterial oxygen tension are augmented but 400 Margherita Mont Blanc arterial carbon dioxide tension (PCO ) is reduced. 60 Inspired 2 300

Climbers may recognise hyperventilation by Barometric pressure mmHg Mount Everest 40 in their fingers. The reduction of 200 0123456789 alveolar and arterial PCO2 due to hyperventilation Altitude (in 1000 m) produces a in arterial . The pH gradually returns to normal by renal premature closure of peripheral airways during of bicarbonate. This metabolic compen- exhalation have been shown and related to sub- sation is slower and less complete at very high clinical interstitial pulmonary oedema or altitudes. bronchial obstruction associated with hypocap- Periodic breathing is characterised by wax- nia, exercise and cold air [8]. Oxygen uptake ing and waning of ventilation with periods of through the lungs at high altitude is affected by apnoea/hypopnoea alternating with hyperp- various factors including a reduced alveolar– noea. CHEYNE [4] and STOKES [5] described the capillary oxygen tension (PO2) driving gradient crescendo-decrescendo breathing pattern in and a reduced transit time of blood through pul- patients suffering from severe heart failure. monary capillaries, due to increased cardiac out- Subsequently, MOSSO [6] and others observed a put. This causes a diffusion limitation of oxygen similar breathing pattern in healthy individuals uptake, which is particularly relevant during exer- at high altitude. Periodic breathing is produced cise; thus, at high altitude, pronounced hypoxia by alternating periods of hypoxia that stimulate may occur during strenuous physical activities. ventilation thereby inducing . Once Acclimatisation to high altitude tends to optimise the arterial PCO2 falls below a certain level, oxygen transport from the atmosphere to the tis- called the apnoeic threshold, ventilation ceases sues of various levels of the oxygen cascade as in until arterial PCO2 rises again due to metabolic illustrated in figure 7. activity (figures 5 and 6). High-altitude periodic breathing mostly occurs at rest and during sleep, Pulmonary circulation when cortical drives to breathe diminish, but Hypoxia induces reflex vasoconstriction of the may also prevail during wakefulness and even small resistance pulmonary arteries and leads to during physical exercise at higher altitudes. It increased pulmonary artery pressure at high alti- has been observed that sleep disturbances and tude. Since heart rate and cardiac output are also periodic breathing are most pronounced during increased, thereby improving oxygen delivery as a the first few nights after ascent to altitude. There compensation for the reduced arterial oxygen is a tendency towards more regular breathing on saturation, pulmonary artery pressure rises even Figure 4 the subsequent days, even though persistence of 60 The hypoxic ventilatory response periodic breathing throughout sleep after 10 can be tested by letting a subject days to 5 weeks at altitudes >4,500 m have 50 rebreathe into a spirometer while been described. maintaining a constant PCO2 in the 40 inhaled air by means of a CO2

Spirometry and -1 absorber. Oxygen saturation (Sp,O ) is measured by a pulse Vital capacity is slightly reduced at moderate-to- 30 2 high altitudes (4,559 m) due to a reduced respi- oximeter. Once Sp,O2 falls below

VT L·min ~87%, (VE) ratory muscle strength and possibly pulmonary 20 measured breath by breath congestion and other factors [7]. Airflow is less increases progressively. The slope 10 affected as the reduced air density lowers the air- of the line fitted to the VE versus flow resistance. Using specialised techniques, Sp,O2 values represents the isocap- such as the single-breath nitrogen-washout test or 0 nic hypoxic ventilatory response. It 70 75 80 85 90 95 100 other measurements, an uneven distribution of is about 2L per min per % Sp,O in Sp,O % 2 mechanical properties throughout the lungs and 2 this case.

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Sum volume days and weeks, affects nearly all systems, including the cardiovascular, renal, digestive and musculoskeletal system and the blood. It is well known that high-altitude residents have increased erythrocyte concentrations and there- Rib cage fore have a higher oxygen carrying capacity of the blood compared to lowlanders. Polycythemia at high altitude, however, develops slowly over the course of several days and weeks. The Abdomen increased erythrocyte concentration of newcom- ers to high altitude is due to a reduced plasma volume and not a stimulated erythropoiesis. Dehydration is the most important factor.

100% Sp,O2 High-altitude related 60% illness 140 bpm Heart rate AMS and HACE AMS, the most common form of altitude-related

40 bpm illness, affects 10–40% of lowlanders ascending to moderate altitudes (3,000 m) and 40–60% at Figure 5 further. This is additionally promoted by heavy altitudes between 4,000 m and 5,000 m [2, 3]. At high altitude, a periodic breath- physical exercise. If pulmonary artery pressure is The incidence of AMS depends on ascent rate, ing pattern is typically observed excessively elevated, HAPE may occur. sleeping altitude, prior acclimatisation and indi- during sleep. The figure shows rib vidual susceptibility. There is no physiological cage and abdominal volume Sleep at high altitudes measurement that predicts individual susceptibil- curves and their sum, reflecting Rapid ascent to altitudes >2,500 m is commonly ity for AMS and it occurs in both sexes and at all lung volume changes recorded by associated with poor sleep quality. Mountaineers ages. AMS generally starts within 6–12 h after sensors of a respiratory inductive may perceive sleep disruption due to repetitive arrival at altitude, manifesting itself with nonspe- plethysmograph in a sleeping mountaineer at the Capanna awakenings with a sense of suffocation relieved cific symptoms such as headache, loss of Regina Margherita (4,559 m). The by a few deep breaths. These sleep disturbances appetite, or , weakness, fatigue are, at least partly, related to the periodic breath- Sp,O2 oscillates between 72% and and insomnia. The diagnosis of AMS relies on a 82% and there are pronounced ing induced by hypoxia [9], but they may also be constellation of typical symptoms in the setting variations in heart rate. promoted by headaches that commonly occur as of acute exposure to hypoxia. There are no spe- a symptom of AMS. cific objective signs. Depending on the severity of symptoms the disease can be graded as mild, Additional acclimatisation moderate or severe. Standardised assessment Figure 6 mechanisms may be performed with the help of the Lake Mechanisms responsible for peri- Acclimatisation, the physiological adaptation to Louise score (table 1) or other questionnaires. In odic breathing at high altitude. altitude exposure that takes place over several severe forms of AMS, headaches are resistant to With increasing altitude, ventila- tion is stimulated due to hypoxia. Ascent to high altitude . If additional neurological signs, such Hyperventilation induces hypocap- hypoxia as (detected for example by the heel-to-toe nic alkalosis, which promotes walking test), cognitive deficits and apnoea or hypopnoea in particular develop, a potentially life-threatening HACE must during sleep when chemical drives Hyperventilation hypocapnic alcalosis Sleep be suspected. While mild-to-moderate AMS is to breathe become more important and cortical drives diminish. mostly self-limiting and disappears with ongoing During apnoea, pronounced acclimatisation after 1–2 days, inappropriate or Pa,CO hypoxia with progressive oxygen 2 Apnoea delayed acclimatisation due to further ascent Pa,O desaturation and the increasing 2 may result in HACE, which is associated with pro- PCO2 stimulates an arousal and gressive loss of consciousness, and finally resumption of ventilation. With restoring ventilation, oxygenation death within 1–3 days due to brain herniation [1]. is restored and hypocapnic alkalo- Despite a high prevalence, the pathophysiol- Arousal Pa,CO sis returns, thereby perpetuating 2 hyperventilation Pa,O ogy of AMS and HACE is incompletely under- the oscillatory breathing pattern. 2 stood. The primary cause is hypobaric hypoxia

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180 Table 1 Lake Louise acute mountain sickness scoring system Sea level 160 Ambient air Moist air 5,500m Point Symptom Score Severity 140 Self-reported 120 1 Headache 0 No headache Alveolar air 1 Mild headache 100 Arterial 2 Moderate headache 80 Ambient air Moist air 3 Severe headache, incapacitating 80 2 Gastrointestinal symptoms 0 No gastrointestinal symptoms Alveolar air 1 Poor appetite or nausea Arterial 40 / 2 Moderate nausea or vomiting mixed venous 20 3 Severe nausea and vomiting, incapacitating Partial mmHg pressure of oxygen 3 Fatigue and/or weakness 0 Not tired or weak 0 1 Mild fatigue or weakness 2 Moderate fatigue or weakness Figure 7 3 Severe fatigue/weakness During transport of oxygen from ambient air to the tis- 4 or lightheadness 0 Not dizzy sues its partial pressure decreases progressively. 1 Mild dizziness Altitude exposure and acclimatisation modify several 2 Moderate dizziness steps of this cascade as illustrated in the diagram. The 3 Severe dizziness, incapacitating first step is related to saturation of inhaled air with 5 Difficulty sleeping 0 Slept as well as usual water vapur. A further drop to the alveolar PO2 (arrow) 1 Did not sleep as well as usual is related to the CO output and oxygen uptake in the 2 2 Woke many times, poor night's sleep alveoli. Hyperventilation at high altitude reduces the 3 Could not sleep at all alveolar PCO2 by the increase in alveolar ventilation. Clinical assessment Alveolar PO2 is thereby increased so that the alveolar- 6 Change in mental status 0 No change in mental status capillary driving gradient is partially preserved. 1 Lethargy or lassitude and different hypotheses on the mechanisms 2 Disoriented or confused 3 Stupor or semiconsciousness leading to brain swelling have been proposed. 4 Coma One possible mechanism could be fluid maldis- 7 Ataxia (heel-to-toe walking) 0 No ataxia tribution associated with an oversecretion of 1 Manoeuvres to maintain balance aldosterone and antidiuretic hormone, as 2 Steps off line observed in patients with AMS at high altitude 3 Falls down compared with suppression in acclimatised per- 4 Can't stand sons. Autopsy studies and MRI scans in patients 8 Peripheral oedema 0 No peripheral oedema with severe AMS showed vasogenic oedema with 1 Peripheral oedema at one location perivascular haemorrhages. Thus, hypoxia- 2 Peripheral oedema at two or more locations triggered increases in cerebral blood flow and Functional score Overall if you had any symptoms, 0 No reduction in activity impaired autoregulation, and an increased per- how did they affect your activity? 1 Mild reduction in activity meability of the blood-brain barrier may con- 2 Moderate reduction in activity tribute to HACE [10]. The clinical course and the 3 Severe reduction in activity (e.g. bed-rest) rapid recovery of HACE in response to oxygen The Lake Louise AMS scoring system tries to quantify the severity of disease by scoring administration and steroids are consistent with typical symptoms of AMS. The sum of the responses to the questions is calculated and a the vasogenic oedema theory. Symptoms and score of ≥3 points on the AMS self-reported questionnaire alone, or >3 in combination with signs of high-altitude related illnesses are the clinical assessment score, while at altitude >2,500 m constitutes AMS. summarised in table 2. first signs of HACE. Mild AMS can often be effec- Treatment of AMS and HACE tively improved by ceasing further ascent, Descent to lower altitudes alleviates AMS symp- minimising exertion and waiting 1–3 days for toms independent of AMS severity. Descending acclimatisation. can even be life-saving and is strongly advisable Headaches in mild forms of AMS respond in severe forms of AMS or if there is any sign of well to analgesics (acetaminophen, nonsteroidal HACE. Depending on the severity of AMS, a step- anti-inflammatory drugs). If AMS progresses from by-step procedure is recommended: symptomatic mild-to-moderate or even severe forms, further treatment of mild symptoms and no further pharmacological intervention is necessary. The ascent until the symptoms have improved; aim of is to stabilise the and enable descent to a lower altitude in patients with no descent by ≥1,000 m. Unless a patient has a response to medical treatment and in those with known to sulphonamide drugs, standard

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Table 2 Acute high-altitude diseases HAPE HAPE is a noncardiogenic and noninflammatory Symptoms Findings type of high-permeability pulmonary oedema Acute mountain Mild Headache, loss of appetite, No specific clinical findings caused by elevated pulmonary capillary pressure sickness nausea, insomnia leading to a red blood cell and -rich Moderate Headache (sensitive to oedema fluid. HAPE is rare at altitudes <3,500 m analgesics), loss of appetite, nausea, insomnia, mild but occurs in about 2–4% of mountaineers at dizziness and fatigue 4,559 m within 2–5 days of ascent with initial Severe Headache (resistant to onset often at night [11]. The prevalence varies analgesics), severe nausea, depending on the rate of ascent, physical exer- vomiting and severe fatigue tion and individual susceptibility. Mountaineers High-altitude cerebral oedema Headache (resistant to Ataxia, altered who develop HAPE at altitudes of 3,000–4,500 analgesics), vomiting, consciousness (confusion, m have a 60% recurrence rate when ascending dizziness, drowsiness impaired mentation, rapidly to these altitudes. HAPE can develop drowsiness, stupor, coma), low-grade independent of AMS or HACE. Initial symptoms High-altitude pulmonary Decreased performance, dry Resting (> 100 include decreased exercise performance due to oedema cough, dyspnoea at rest, beats per min), tachypnoea shortness of breath and a dry cough. With wors- orthopnoea, only late in (> 25 beats per min), ening disease, patients develop dyspnoea with illness pink or bloody low-grade fever, rales minimal activity and a cough productive of pink, , respiratory distress on pulmonary , frothy sputum. Physical examination often cyanosis reveals resting tachycardia, cyanosis, on auscultation and low-grade fever. Chest radio- is 250 mg acetazolamid (Diamox), twice daily. The carbonic anhydrase inhibitor acetazo- graph typically shows perihilar, interstitial or alve- lamide inhibits reabsorption of bicarbonate and olar opacities, increased pulmonary artery diame- sodium in the renal tubules and, thus, causes a ter but a normal-sized heart (figure 8). The most bicarbonate diuresis and metabolic . important differential diagnoses include pneu- Compensatory hyperventilation to correct the pH monia, and cardiogenic occurs, preventing the arterial oxygen saturation pulmonary oedema due to from falling further. Acetazolamide effectively or other heart disease. reduces the severity of AMS symptoms within 24 The elevated pulmonary capillary pressure in h. A more potent is dexamethasone, which HAPE is probably generated by excessive and het- has a well-documented effect in all degrees of erogeneous hypoxic pulmonary vasoconstriction AMS and in HACE. Although the mechanism of and consequent over-perfusion of lung areas not dexamethasone is not clear, it probably acts by protected by hypoxic vasoconstriction. Increased improving brain capillary integrity and reducing pulmonary capillary pressure results in capillary vasogenic oedema. In severe forms of AMS and stress failure and fluid leakage into the alveoli or HACE, dexamethasone is given initially at 8 mg into the interstitium. Individual susceptibility to i.v., followed by 4 mg four times daily p.o. If avail- HAPE is associated with excessive hypoxic pul- able, low-flow oxygen (2 L per min) relieves symp- monary vasoconstriction and a constitutively toms quickly and can be offered until drugs decreased transepithelial Na+ transport in alveolar become effective. Because bottled oxygen is cells resulting in impaired alveolar water . heavy and bulky it is rarely carried by trekking or mountaineering parties. The same is also true of Treatment of HAPE inflatable hyperbaric chambers that are some- Descent, supplemental oxygen or both are nearly times employed by large expeditions or those always successful in the treatment of HAPE. If with good transport links. A person enclosed in oxygen is not available or descent is not possible, such an airtight bag can be exposed to a pressure then becomes necessary (table 3). 140–220 mbar above the ambient pressure by Nifedipine lowers pulmonary artery pressure but operating foot- or hand-driven pumps, thus simu- barely increases the Pa,O2. Hence, for treatment, lating a descent of 1,500–2,500 m depending on nifedipine is adjunctive. Mild-to-moderate HAPE the altitude and the type of bag used. Hyperbaric can be treated with rest and oxygen. If the indi- bags can be life saving, especially in a remote set- vidual feels better on the next day and oxygen ting without oxygen or the possibility of descent. saturation is >90% without supplemental oxy- The treatment and prevention of AMS and HACE gen they can be discharged. Patients with mod- is summarised in table 3. erate or severe HAPE, as indicated by the failure

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complaints. Like acetazolamide, dexamethasone Figure 8 is effective for both treatment and prevention of Chest radiograph from a moun- AMS. A combination of dexamethasone and taineer with HAPE with bilateral, acetazolamide has been found to be most predominantly perihilar, patchy effective. infiltrates and a normal heart size. Most important for an effective prophylaxis (Courtesy of M. Maggiorini, Zurich, Switzerland) against HAPE is the avoidance of an excessive hypoxic pulmonary hypertension by keeping a moderate ascent rate and avoiding strenuous exercise. The preferred pulmonary vasodilator is Table 3 Management and prevention of high-altitude disease.

Treatment Prevention Acute Mountain Sickness Mild Stop ascent, minimise physical Gradual ascent to promote of arterial oxygen saturation to rise to >90% exertion, rest and acclimatise at acclimatisation: once above an the same altitude. Symptomatic altitude of 2,500 m, don't ascend within 5 min of giving high-flow oxygen, should treatment if necessary more than 300–600 m per day. descend to low altitude. If descent is impossible (analgesics, ). Spend one night at intermediate and oxygen unavailable, the hyperbaric bag may Moderate Acclimatise, stay at same altitude altitude. Avoid overexertion. be life-saving. Other pulmonary vasodilators, such for 1–2 days or return to lower Acetazolamide 125 mg twice daily, as inhaled prostaglandins, nitric oxide and phos- altitude. Acetazolamide (Diamox) starting 24 h before ascent; or phodiesterase inhibitors (), may be effec- 250 mg twice daily until descent. dexamethasone 4 mg twice daily tive but are impractical (inhlaled agents) or Severe Immediate descent by ≥500 m. If afflicted by side effects (headache with silde- descent is not possible and oxygen is available, give 2–4 per min of nafil). In contrast, (furosemide) and mor- oxygen by face mask or nasal phine, successfully employed in cardiogenic pul- cannula. If descent is not possible monary oedema, have not been proven to be and oxygen not available, give effective. These drugs may even have undesirable dexamethasone (initially 8 mg i.v., effects such as dehydration and respiratory followed by 4 mg orally every 6 h), , respectively. acetazolamide (250 mg twice daily) or both until symptoms resolve. Use a portable hyperbaric chamber if Prevention of high-altitude related available and clinically required. illness High-altitude Immediate descent or evacuation. As for acute mountain sickness Table 3 contains a summary on the prevention of cerebral oedema If descent is not possible, administer high-altitude related illnesses. The best and most oxygen (2–6 L per min) or use a important strategy to prevent any high-altitude hyperbaric chamber if available. Administer dexamethasone disease is gradual ascent to allow sufficient time (initially 8 mg i.v., followed by 4 mg for acclimatisation. Above an altitude of 2,500 orally every 6 h). Check for symptoms m, a daily ascent not exceeding 300 m has been and signs of a concomitant HAPE and recommended although no robust scientific evi- initiate adequate treatment. Consider dence is available to support this advice. An extra acetazolamide if descent is delayed. day can be added for acclimatisation for every High-altitude If available, give oxygen 2–6 L per Gradual ascent to promote increase of 600–1,200 m at this altitude. If there pulmonary min until oxygen saturation is acclimatisation: once >2,500 m, are signs of high-altitude disease and appropriate oedema >90% or use a hyperbaric chamber. ascend nomore than 300 m per day. Descend as soon as possible. Avoid overexertion. Consider taking acclimatisation is not possible for logistical rea- Depending on blood pressure, nifedipine 30–60 mg per day sons, preventive pharmacological treatment can administer nifedipine. 10–20 mg (extended-release formulation). be indicated. initially and an extended-release In AMS, acetazolamide is the preferred pro- formulation (nifedipine 30/60 mg) phylactic drug. It reduces symptoms of AMS and subsequently. Treat accompaning periodic breathing and promotes sleep at high acute mountain sickness with altitude. The recommended daily prophylactic dexamethasone 8 mg i.v. is 125 mg twice daily starting the evening Most common adverse effects before ascent above 2,500 m and continuing for Acetazolamide: paresthesias, altered taste of carbonated beverages, polyuria. several days or until return to low altitude. Side- Dexamethasone: hyperglycaemia, mood changes, rebound effect on withdrawal. effects include paraethesias and gastrointestinal Nifedipine: hypotension, reflex tachycardia.

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nifedipine, which effectively lowers pulmonary studies in normal subjects. The discussion below artery pressure. Nifedipine 30–60 mg per day, in addresses high-altitude tolerance in selected, an extend-release formulation, is a well- common respiratory diseases. For a more exten- established prophylactic medication. Dexametha- sive review the reader is referred to an article in sone and other vasodilators, like or the European Respiratory Journal [14]. An sildenafil, also reduce pulmonary artery pressure overview of problems of air travel for patients and have some prophylactic effect against HAPE with lung disease has been provided recently in [12]. Breathe [15]. The treatment for periodic breathing and sleep disturbances at high altitude is similar to that for control of the daytime symptoms of Chronic obstructive pulmonary AMS. Acetazolamide reduces periodic breathing, disease (COPD) the mean level and the stability of nocturnal oxy- Many COPD patients are exposed to high alti- gen saturation during sleep. Furthermore, awak- tude by long-term residence or during vacations enings are reduced and subjective sleep quality or flights. Patients with a marginal or reduced is improved. Pa,O2 at low altitude will drop their Pa,O2 to even were once thought to be lower levels during a stay at moderate or high contraindicated for high altitude insomnia due to altitude so that the use of supplemental oxygen their potential ventilatory depression. Recent is advisable to prevent pronounced hypoxaemia, studies show, however, that bezodiazepines in which could lead to excessive pulmonary low doses are relatively safe in this setting. hypertension and a risk of acute right heart fail- Temazepam (10 mg) taken before sleeping result- ure or HAPE. The individual need for supple- ed in a significant reduction of periodic breathing mental oxygen is difficult to predict and recom- and had no adverse effect on next-day reaction mendations are based on theoretical time, maintenance of wakefulness, cognition or considerations and small studies in hypobaric AMS [10]. Temazepam in combination with aceta- chambers or with experimental exposure to a zolamide may effectively improve sleep quality. low inspiratory PO2. From a practical point of view it seems reasonable that patients with Checklist for staying safe during severe COPD (forced expiratory volume in one high-altitude treks second (FEV1) <50% predicted) with an Sa,O2 of •Ascend slowly to allow acclimatisation. <95% at low altitude should have an individual •Build flexibility into trek schedules to allow assessment of the potential risks and the neces- for the requirements of the slowest in the sary precautions before travelling to altitude. group to acclimatise. Evaluation might include arterial blood gas anal- •Desend urgently in the event of HAPE or ysis and spirometry to have a better appreciation HACE even during the night. of their predicted PO2 at moderate altitude as •Never leave someone with HAPE or HACE has been recommended in pre-flight assessment alone. [15]. The intention is to prevent a fall of Pa,O2 at •Porters and other staff are equally altitude to <6.7 kPa (55 mmHg), the level where susceptible to altitude illness as other the steep portion of haemoglobin-oxygen disso- participants but they may be reluctant to ciation curve starts and pulmonary artery pres- report symptoms. Their welfare should be sure rises progressively. The Pa,O2 at an altitude a high priority. of 2,438 m (8,000 ft, corresponding to the allowed maximal cabin altitude of commercial airplanes) has been estimated from Pa,O2 at sea Patients with pre- level based on a regression equation which existing lung disease incorporates the patient's FEV1: predicted Pa,O2 [at altitude 2,438 m] = 0.453 (Pa,O2 {at sea at high altitude level}) + 0.386 (FEV1 % pred) + 2.440 [16]. If predicted Pa,O2 at altitude is <55 mmHg, In contrast to well-documented studies in healthy supplemental oxygen administration has been individuals, little is known about the potential suggested, although the clinical significance of risk of high-altitude exposure in patients with pre- temporary hypoxaemia at altitude is not clear. existing lung disease. Counselling these patients Other factors, such as physical activity, coexisting is therefore mainly based on expert opinions, medical conditions and the experience during anecdotal evidence and extrapolation from previous altitude exposures have to be taken

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into account when counselling patients. not been appropriately investigated. Studies in Educational questions Baseline medication should be continued and OSA patients dwelling near sea level exposed to 1. What does the 14-year- patients instructed regarding the therapy of a hypoxic air mixture corresponding to a simu- potential exacerbations (rescue , oral lated altitude of 2,750 m (inspiratory oxygen frac- old boy, described in the prednisone, ). Patients with COPD and tion of 0.16) revealed a reduction of obstructive vignette, suffer from? pre-existing pulmonary hypertension should be apnoea/hypopnoea but a high number of cen- a) Migraine. counselled against travelling to high altitude. If tral apnoea/hypopnoea events [18]. In another b) Acute mountain sickness. absolutely necessary they might take nifedipine study, OSA patients living at an altitude >2,400 c) Dehydration. slow release 20 mg twice daily to reduce the risk m in Colorado were referred for sleep studies to d) Flu-like illness. of developing HAPE or acute right heart failure. laboratories at sea level and at 1,370 m [19]. 2. What should be done in For patients with very severe airflow obstruction These investigations revealed a significant reduc- this case? (FEV1 <25% pred), acetazolamide should be tion in the number of apnoea/hypopnoea events a) Immediate evacuation by used with caution for AMS prophylaxis since CO2 at lower compared with higher altitudes, which helicopter. retention may lead to worsened dyspnoea or res- was predominantly related to a reduction in cen- b) Acetaminophen to treat piratory failure; the dose of acetazolamide should tral events. These data have led to the hypothesis the headaches and further not exceed 125 mg twice daily or an alternative that patients with OSA predominantly have cen- ascent the next day if symp- agent such as dexamethasone should be used. tral sleep apnoea when sleeping at high altitude. toms have improved. Further studies are required to corroborate the pre- liminary observations in OSA patients at altitude c) Acetazolamide, acclimati- Considering the reduced allergen burden with and to evaluate whether they require adaptation sation at lower altitude for increasing altitude (house-dust mites), improve- of their CPAP therapy or another treatment such 1–2 days and then further ment in bronchial hyperresponsiveness can be as acetazolamide. ascent. expected. However, inhalation of cold air may d) Acetazolamide and dex- worsen asthma symptoms, especially in combina- Diseases associated with pulmonary amethasone followed by tion with exercise or hypoxia-induced hyperventi- hypertension the same procedure as in lation. A survey in adventure travellers with known Pulmonary arterial pressure in patients with pre- answer c. asthma revealed that 88 of 203 subjects had existing pulmonary hypertension is further 3. What do you recommend asthma attacks during their journey, 40 reported increased at high altitude. Several case reports to this young mountaineer asthma worsening, 32 experienced the worst suggest that pre-existing pulmonary hypertension for his next alpine tour? asthma attack of their life and 11 suffered from a may exacerbate the pathophysiology of HAPE a) Taking acetazolamide life-threatening asthma attack during travel [17]. and, therefore, predispose to HAPE. In general, 500 mg the evening before Frequent use of inhaled bronchodilators (more patients with pre-existing pulmonary hyperten- than twice weekly) before travel, suggesting sion should be counselled against high-altitude ascent. poorly controlled asthma, and participation in travel. If high-altitude travel cannot be avoided, b) Ascending slowly, a maxi- intense physical exercise during treks were associ- patients must be informed about signs and symp- mum of 300 m per day ated with attacks during travel. Based on this toms of HAPE and for patients not on medical once above 2,500 m. experience, patients with uncontrolled, severe therapy, prophylaxis with nifedipine can be given c) Flying by helicopter to asthma should be cautioned against trekking and (nifedipine 20 mg SR) for the duration of their this altitude to minimise travelling to high altitude, in particular to remote stay. Supplemental oxygen should be recom- physical exertion. areas. Asthma patients with controlled disease mended, if available, to avoid hypoxic pulmonary d) Performing endurance should continue to take their usual vasoconstriction. training at least three times when travelling to high altitude, avoid strenuous a week. exercise in a cold environment and take a supply of rescue inhalers, oral prednisone and an antibi- Future perspectives otic to treat any asthma exacerbation and infec- tions. Although the lessons learned from high altitude physiology over the past few years have been Obstructive sleep apnoea syndrome exciting and extensive, there are still areas of As the prevalence of obstructive sleep apnoea syn- uncertainty [20]. The mechanisms underlying drome (OSA) is quite high, the number of patients high-altitude diseases, including genetic factors, with the disorder is also expected to be large remain to be investigated in further detail. The among high-altitude sojourners. Whether travel- physiological effects of high-altitude exposure on ling to, and staying at, high altitude exposes OSA patients with cardiac and pulmonary diseases patients to particular health risks that differ from and the prophylaxis and treatment of high- those described above for healthy subjects has altitude related illness in such patients are

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Suggested answers largely unknown. Many of these unanswered related illness is growing related to the popular- 1: b questions are evaluated worldwide by various ity of outdoor and mountaineering activities and Migraine, dehydration and groups through laboratory and field studies. This the continuing progress in transport means that exhaustion are all important research is of increasing importance as the num- facilitate the access to remote and high moun- ber of subjects affected with high-altitude tain areas. differential diagnoses of acute mountain sickness. The rapid ascent from References 568–3,450 m in <24 h, 1. Hackett PH, Roach RC. High-altitude illness. N Engl J Med 2001; 345: 107-114. 2. Basnyat B, Murdoch DR. High-altitude illness. Lancet 2003; 361: 1967-1974. headache and loss of 3. Maggiorini M, Muller A, Hofstetter D, Bartsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in appetite together with the the Swiss Alps. Aviat Space Environ Med 1998; 69: 1186-1192. 4. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat.Dublin Hospital Reports 1818; 2: poor sleeping quality sug- 216-223. gest AMS. 5. Stokes W. Fatty degeneration of the heart. In: The Diseases of the Heart and Aorta. Dublin, 1854; pp. 320-327. 6. Mosso A. Respiration on the mountains. In: Life of Man in the High Alps. London, Fischer Unwin, 1898; pp. 31-50. 2: b 7. Senn O, Clarenbach CF, Fischler M, et al. Do changes in lung function predict high-altitude pulmonary oedema at an early Immediate descent in mild stage? Med Sci Sports Exerc 2006; 38: 1565-1570. 8. Cremona G, Asnaghi R, Baderna P, et al. Pulmonary extravascular fluid accumulation in recreational climbers: a prospective forms of AMS is not neces- study. Lancet 2002; 359: 303-309. sary. 9. Khoo MC, Anholm JD, Ko SW, et al. Dynamics of periodic breathing and arousal during sleep at extreme altitude. Respir with acetaminophen when Physiol 1996; 103: 33-43. 10. Hackett PH, Roach RC. High altitude cerebral oedema. High Alt Med Biol 2004;5:136-146. headaches develop can be 11. Bartsch P, Mairbaurl H, Maggiorini M, Swenson ER. Physiological aspects of high-altitude pulmonary oedema. J Appl Physiol attempted. If headaches do 2005; 98: 1101-1110. 12. Maggiorini M, Brunner-La Rocca HP, Perth S. et al. Both tadalafil and dexamethasone may reduce the incidence of high- not respond to analgesics, altitude pulmonary oedema: a randomized trial. Ann Intern Med 2006; 145: 497-506. dexamethasone, 4 mg orally 13. Nickol AH, Leverment J, Richards P, et al. Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study. J Sleep Res 2006; 15: 445-454. should be taken. Poor sleep 14. Luks AM, Swenson ER. Travel to high altitude with pre-existing lung disease. Eur Respir J 2007; 29: 770-792. quality due to AMS may be 15. Robson AG, Innes JA. Problems of air travel for patients with lung disease. Breathe 2006; 3: 141-147. improved with acetazol- 16. Dillard TA, Berg BW, Rajagopal KR, Dooley JW, Mehm WJ. during air travel in patients with chronic obstructive pul- monary disease. Ann Intern Med 1989; 111: 362-367. amide. If nausea and vomit- 17. Golan Y, Onn A, Villa Y, et al. Asthma in adventure travelers: a prospective study evaluating the occurrence and risk factors for ing occur, dexamethasone acute exacerbations. Arch Intern Med 2002; 162: 2421-2426. 18. Burgess KR, Cooper J, Rice A, Wong K, Kinsman T, Hahn A. Effect of simulated altitude during sleep on moderate-severity OSA. can be given intravenously. Respirology 2006; 11: 62-69. Further ascent should be 19. Patz D, Spoon M, Corbin R, Patz M, Dover L, Swihart B, and White D. The effect of altitude descent on obstructive sleep . Chest 2006; 130: 1744-1750. delayed and more time for 20. Erba P, Anastasi D, Senn O, Maggionni M, Bloch KE. Acute mountain sickness is related to nocturnal hypoxaemia but not to acclimatisation allowed. hypoventlation. Eur Respir J 2004; 24: 303–308. 3: b Physical fitness does not pro- tect against high-altitude related illness. Drug prophy- laxis can be helpful. The dose of acetazolamide would be 125 mg twice daily starting one day before ascent.

Suggested further reading West JB, Schoene RB, Milledge JS. High altitude medicine and physi- ology. London, Hodder Education, 2007.

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