Respiratory Health Benefits and Risks of Living at Moderate Altitude

Abstract

Grissom, Colin K., and Barbara E. Jones. Respiratory health benefits and risks of living at moderate altitude. High Alt Med Biol 19:109–115, 2018.—The respiratory system plays a critical role in the series of physiologic responses that occur at high altitude and allows individuals to adapt to and tolerate hypobaric hypoxia. Persons with underlying lung disease may have complications, but sometimes derive benefits, related to residence at high altitude. This review will focus on health benefits and risks of patients with underlying asthma, chronic obstructive pulmonary disease, pulmonary hypertension, or obstructive sleep apnea, who live at altitudes of 1500 to 4500 m. We will also discuss maladaptive responses of the respiratory system at high altitude in previously healthy persons, including development of pulmonary hypertension and sleep-disordered breathing.

Introduction

Over 385 million people permanently reside at elevations above 1500 m worldwide (Cohen and Small, 1998), and over 140 million people reside above 2500 m worldwide (West et al., 2004). These permanent residents of high altitude are chronically exposed to hypobaric hypoxia. The respiratory system plays a critical role in the series of physiologic responses that allows individuals to adapt to and tolerate low oxygen tensions in tissues and organs at high altitude. Patients with underlying lung disease may be at an increased risk for complications at high altitude and maladaptive responses can predispose persons without lung disease to chronic high-altitude illness. This review considers these issues for residents of moderately high altitude between 1500 and 4500 m. The highest permanent human habitation is at about 5500 m. Sojourns by humans above this altitude are tolerated only for weeks to months and is not a subject of this review. We will review maladaptive responses that can lead to subacute and chronic mountain sickness (CMS) at moderate high altitude and the health benefits and complications of moderate high altitude in patients who have underlying lung disease, including asthma, chronic obstructive lung disease, pulmonary hypertension, and obstructive sleep apnea (OSA).

Environmental Factors at High Altitude

Several important features of the high-altitude environment can affect both healthy individuals and those with preexisting lung disease. Barometric pressure decreases in a nonlinear manner with increasing elevation (West, 2012). As a result of the lower barometric pressure, the inspired partial pressure oxygen (P_iO₂) falls, leading, in turn, to decreased alveolar and arterial oxygen tensions (P_AO₂ and P_aO₂, respectively).

With an increasing altitude, humidity and temperature also decrease. These factors may contribute to airway reactivity, insensible water losses, ventilatory changes, and alterations in pulmonary hemodynamics. High altitude also reduces allergen burden, including dust mites, a common trigger for asthma (Spieksma et al., 1971). Changes in air quality are equivocal at a high altitude: while air quality may be much better in some high-altitude regions (Leuenberger et al., 1998), mountain valley systems can trap pollution from urban areas, and heavily traveled regions near roads may be prone to accumulation of heavy-duty automotive emissions (Bishop et al., 2001). Local air quality at high altitude in developing countries is often poor due to smoke from wood- and animal dung-burning stoves (Luks and Swenson, 2007).

Changes in Pulmonary Physiology at High Altitude

Exposure to hypoxia causes several critical changes in respiratory physiology that affect all individuals at high altitude regardless of whether they have underlying lung disease. Ascent to high altitude leads to an increase in minute ventilation due to the hypoxic ventilatory response that increases P_AO₂ and P_aO₂ and decreases the arterial partial pressure of carbon dioxide (P_aCO₂) (Stream et al., 2009; West, 2012). Permanent residents of high altitude have a chronic respiratory alkalosis with higher minute ventilation and lower PaCO₂ than sea-level residents (Crapo et al., 1999). Respiratory alkalosis leads to a leftward shift of the oxyhemoglobin dissociation curve, which improves alveolar oxygen uptake, but may impair oxygen delivery to the tissues. This leftward shift is balanced by an increased production of 2,3-diphosphoglycerate by red blood cells at a high altitude, which causes a compensatory rightward shift in the curve and enhances unloading of oxygen at the tissue level even under hypoxic conditions (Liu et al., 2016), so that on balance, the in vivo partial pressure of oxygen at 50% saturation of hemoglobin remains about the same as that at sea level (Wagner et al., 2007).

Hypoxic pulmonary vasoconstriction is another important physiologic response to high altitude. Mediated by a decreased alveolar oxygen tension, this response increases pulmonary vascular resistance and pulmonary artery pressure, and varies widely among individuals (Groves et al., 1987; Bartsch and Gibbs, 2007). The degree of this response plays a critical role in the pathophysiology of both acute and chronic forms of high-altitude illness (Kawashima et al., 1989).

Asthma

In patients with asthma, studies demonstrate the benefit of permanent high-altitude residence (Vargas et al., 1999) in reducing exacerbations, and long-term high-altitude residence (>12 weeks) for improving symptoms, lung function, and exercise performance (Rijssenbeek-Nouwens et al., 2012). Children who are permanent residents of high altitude at 3658 m in Tibet have a lower prevalence of asthma (Droma et al., 2007). A meta-analysis of 21 published studies of spirometry in asthmatic patients concluded that stays at high altitude of 2 to 12 weeks improve lung function (Vinnikov et al., 2016). This has been attributed to the reduced allergen burden, resulting in decreased airway inflammation (Peroni et al., 1994; Simon et al., 1994; Grootendorst et al., 2001; Karagiannidis et al., 2006). Another study found that high altitude improves clinical and functional parameters, and decreases oral corticosteroid requirements, in patients with severe refractory asthma, irrespective of allergic sensitization (Rijssenbeek-Nouwens et al., 2012). Thus, improvements in asthma at high altitude may be related to other factors beyond allergen concentration.

Data regarding the effect of hypoxia on airway reactivity are conflicting, as studies report either an increase (Denjean et al., 1988; Dagg et al., 1997) or no change (Saito et al., 1999) in bronchial responsiveness to a methacholine challenge. Minute ventilation incrementally increases with exposure to hypoxia at higher altitudes beginning at about 1500 m (Crapo et al., 1999), leading to hypocapnia, which may increase airway resistance in asthmatic patients (van den Elshout et al., 1991). Lower air temperature may also affect persons with asthma; numerous studies demonstrate that cold air increases the airway reactivity in asthmatics more than in healthy control subjects (Ahmed and Danta, 1988; Kaminsky et al., 1995; Zeitoun et al., 2004). Athletes who exercise and maintain high minute ventilation rates in cold air at a high altitude have a higher prevalence of exercise-induced asthma, including cross-country skiers (Larsson et al., 1993; Pohjantahti et al., 2005) and ski mountaineers (Durand et al., 2005). Individuals whose asthmatic trigger is cold air at lower humidity may be more prone to asthma exacerbation at a high altitude, especially during exercise.

While hypoxia, cold air, and hypocapnia may affect airway reactivity in asthmatic patients, it is important to remember that most studies examined the effect of these factors in isolation under experimental conditions. The number of reports involving asthmatics at a terrestrial high altitude, where these environmental factors all work simultaneously, is limited. Two studies have reported a decreased bronchial reactivity to hypotonic aerosol in patients with mild, well-controlled asthma after ascent to 4559 and 5050 m (Allegra et al., 1995; Cogo et al., 1997), while another study showed a decrease in the peak expiratory flow rate (PEFR) in asthmatics after ascent to 2600 to 4000 m (Louie and Pare, 2004).

Treatment of asthma at a high altitude is similar to sea level, but individuals with asthma and a strong exercise component to their symptoms should use short-acting bronchodilators before activity and may consider adding a leukotriene receptor blocker or a mast cell stabilizer (Patz et al., 2006). In addition, a scarf, face mask, or balaclava can warm and humidify inhaled air in particularly cold, dry environments. If patients wish to monitor their symptoms objectively, they should use a fixed-orifice peak flow meter, as variable-orifice meters may not function well at a high altitude (Pollard et al., 1996).

Asthmatic residents of high altitude may gain benefit from living at a high altitude, particularly if their asthma is primarily triggered by environmental allergens that decrease with an increasing altitude. There will, however, be a wide variation in responses among asthmatics living at altitudes depending on their geographic location in a tropical or temperate climate, or their relative altitude of residence. For example, the environmental allergen burden may be higher at a given altitude in a tropical climate compared to a temperate climate, and asthmatics who have improved symptoms living at 2000 m compared to sea level due to decreased allergens might still experience symptoms due to breathing cold dry air after ascent to 4500 m.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by an impaired gas exchange, airway obstruction, and increased work of breathing. Exposure to hypobaric hypoxia at moderately high altitude may alter these factors and exacerbate the baseline disease state.

COPD patients experience worsening hypoxemia when exposed to a hypobaric hypoxic environment. In a study of eight COPD patients (mean FEV₁ [forced expiratory volume in one second] 1.27 L, 42% predicted) within 3 hours of ascent to 1920 m, P_aO₂ decreased from 66 ± 7 to 52 ± 7 mmHg (Graham and Houston, 1978). In another study of 18 COPD patients (mean FEV₁ 1.11 L, 42% predicted) after acute ascent to 2086 m, P_aO₂ decreased from 75 ± 9 to 51 ± 6 mmHg, which was partially reversed to a P_aO₂ of 64 ± 9 mmHg on 2 L/min flow of supplemental oxygen (Kelly et al., 2009a, 2009b). In a hypobaric chamber study of patients with severe COPD, but without chronic hypercapnia, exposed to 2438 m for 2 hours, mean PaO₂ decreased from 72 ± 9 to 47 ± 6 mmHg (Dillard et al., 1998). Some patients with COPD who do not require supplemental oxygen at sea level will require supplemental oxygen at high altitude if P_aO₂ decreases to ≤55 mmHg or if SpO₂ decreases to ≤88%, as supplemental oxygen treatment for patients below these thresholds has been shown to improve survival (Anonymous, 1980; Qaseem et al., 2011). In patients with COPD, worsening hypoxemia at high altitude may augment pulmonary hypertension, contribute to development of cor pulmonale, and increase mortality (Pierson, 2000). In one study, emphysema deaths at higher altitudes above 2100 m in Colorado, compared to deaths below 1370 m, occurred after a shorter duration of illness and were more commonly due to cor pulmonale rather than pneumonia (Moore et al., 1982). Patients with COPD and known cor pulmonale, who have a resting P_aO₂ ≤60 mmHg, or SpO₂ ≤90%, should be treated with supplemental oxygen according to guideline recommendations (Qaseem et al., 2011).

Pulmonary vasodilators (prostacyclin, endothelin receptor antagonists, sildenafil, and nitric oxide) have been shown to reduce pulmonary vascular resistance and improve cardiac index in patients with COPD (Weitzenblum and Chaouat, 2009; Rowan et al., 2016), but may alter ventilation perfusion mismatch and worsen hypoxemia (Calcaianu et al., 2016). Use of pulmonary vasodilators for standard treatment of cor pulmonale complicating COPD is not generally recommended, however, because controlled clinical studies demonstrating a survival benefit are lacking (Weitzenblum and Chaouat, 2009; Rowan et al., 2016). Supplemental oxygen is the only proven therapy in patients with COPD, hypoxemia, and pulmonary hypertension that may increase survival (Anonymous, 1980, 1981).

Epidemiological data indicate that mortality from COPD increases with altitude (Moore et al., 1982; Burtscher, 2014). In a study of COPD mortality in states in the United States, for every 95 m increase in resident altitude, COPD mortality increased by 1 in 100,000 (Cote et al., 1993). In another study, COPD mortality increased by 3–4 per 10,000 in U.S. counties above 1000 m compared to counties below 100 m (Ezzati et al., 2012). These results suggest that long-term residence at high altitude increases mortality in patients with COPD and raises the consideration that migrating to a lower altitude may increase survival.

High-altitude exposure may also alter lung mechanics in COPD patients. No studies have investigated changes in pulmonary function at terrestrial high altitude when multiple factors may influence airflow obstruction concurrently. Several studies have examined the effect of environmental factors in isolation under experimental conditions, and results are conflicting. The lower air density at high altitude may improve air flow dynamics, although some investigators have shown that hypoxemia and cold air exposure worsen air flow obstruction (Libby et al., 1981; Koskela et al., 1996). One study of patients with obstructive lung disease reported an increase in PEFR and maximum voluntary ventilation, but a decrease in vital capacity after ascent to 5486 m (Finkelstein et al., 1965), while another study found that ambulatory patients with severe COPD, but without chronic hypercapnia, had a decrease in forced vital capacity (FVC), but no change in PEFR after ascent to 2438 m (Dillard et al., 1998).

Patients with COPD have exercise limitation due to ventilatory and gas exchange impairment. Ventilatory requirements during exercise at low altitude are often higher than expected because of increased work of breathing, increased dead space ventilation, and impaired gas exchange (Spruit et al., 2013). At a high altitude, minute ventilation is increased at rest in response to hypobaric hypoxia, and during exercise, additional ventilatory demand occurs because minute ventilation is higher than at sea level for any given work rate (West et al., 1983). In patients with severe COPD and low maximum voluntary ventilation, minute ventilation during exertion may rise to the level of maximum voluntary ventilation, leading to severe functional limitation at a high altitude. In a study of 18 patients with COPD, who acutely ascended to 2086 m, a 6-minute walk test distance at a high altitude was 52% shorter than at sea level and was associated with significant hypoxemia (P_aO₂ after exercise was 41 ± 7 mmHg, decreased from 51 ± 6 mmHg at rest) (Kelly et al., 2009a).

Pulmonary Hypertension, Subacute Mountain Sickness, and CMS

The long-term effects of high altitude on the pulmonary circulation are complex. Hypoxic pulmonary vasoconstriction is intrinsic to the pulmonary arterial smooth muscle cells and leads to an increased pulmonary artery pressure. Hypoxia increases pulmonary artery pressure through endothelin and sympathetic activation. Increased nitric oxide synthesis and hyperventilation (leading to increased P_AO₂) may attenuate hypoxic pulmonary vasoconstriction (Bartsch and Gibbs, 2007). These effects are highly variable, making it difficult to predict how a given individual will respond to high altitude over time. Population autopsy studies reveal greater muscularization in the pulmonary circulation of individuals living at 3700 to 4500 m, suggesting that pulmonary hypertension, and the smooth muscle remodeling within the pulmonary arteries, persists in high altitude dwellers over a lifetime (Penaloza and Arias-Stella, 2007). Studies of different populations at similar altitudes demonstrate substantial variation in pulmonary artery pressures (Penaloza and Arias-Stella, 2007), indicating a genetic component (Simonson et al., 2010; Simonson, 2015).

High-altitude pulmonary edema (HAPE) is the most immediately life-threatening maladaptive response associated with pulmonary hypertension occurring after acute ascent and is reviewed elsewhere (Swenson and Bartsch, 2012). Two distinct populations are affected by HAPE. The first population pertains to ascent of unacclimatized lowlanders to high altitude. The second population involves well-acclimatized high-altitude residents, especially children, who are returning from low-altitude stays and develop HAPE, and is known as reentry HAPE. Clinical observations suggest that acetazolamide may prevent reentry HAPE. Alternatively, other proven pharmacologic agents for prophylaxis of HAPE may be used to prevent reentry HAPE, including calcium channel blockers and phosphodiesterase-5 inhibitors (Luks et al., 2014), which mitigate hypoxia-induced pulmonary vasoconstriction that is associated with the development of HAPE.

Pulmonary hypertension after prolonged stay at a high altitude is due to a persistent increase in pulmonary vascular resistance (Maggiorini, 2003; Bartsch and Gibbs, 2007) that is not reversible with the administration of oxygen (Groves et al., 1987), suggesting that structural, rather than functional, changes are part of the pathophysiologic mechanism. A separate group is patients with underlying pulmonary hypertension classified by the World Health Organization Group 1 pulmonary arterial hypertension or Groups 2 to 4 pulmonary hypertension. Those patients with identifiable causes of pulmonary hypertension other than hypobaric hypoxia, who have a mean pulmonary artery pressure ≥35 mmHg or a right ventricular systolic pressure ≥50 mmHg at low altitude, may not tolerate high altitude well and require careful attention to treatment with supplementary oxygen and pulmonary vasodilators, and should consider residence at lower altitudes (Luks, 2009).

Cardiac subacute mountain sickness, adult or infantile subacute mountain sickness, and high-altitude pulmonary hypertension with heart failure are all names for the phenomenon of pulmonary hypertension and right-sided heart failure after exposure to altitude for weeks to months duration (Maggiorini and Leon-Velarde, 2003; Wilkins et al., 2015). It is distinct from HAPE or acute mountain sickness, and is due to pulmonary hypertension secondary to hypoxia with remodeling of the pulmonary vasculature. Patients experience shortness of breath, cough, hypoxemia out of proportion to normal individuals at a high altitude, and peripheral edema due to right ventricular failure. The primary treatment is descent to a lower altitude (Anand et al., 1990).

Exposure to altitudes for years may result in CMS, a syndrome characterized by right-sided heart failure, moderate-to-severe pulmonary hypertension, and polycythemia. The first description of CMS was by Monge, who also noted hypoventilation and severe hypoxemia in Andean residents (Monge and Whittembury, 1976). Subsequent reports of CMS have described individuals without hypoventilation, and others without polycythemia. Patients with hypoventilation, polycythemia, and right-sided heart failure can develop life-threatening complications such as stroke and myocardial infarction.

High-altitude pulmonary hypertension, subacute mountain sickness, and CMS are all reversible conditions with return to low altitude (Wilkins et al., 2015; Villafuerte and Corante, 2016). If descent is not possible, however, such as for individuals whose livelihood depends upon residence at altitude, treatment may include supplemental oxygen, phlebotomy for polycythemia, or acetazolamide (which reduces hypoxemia, polycythemia, and pulmonary hypertension) (Richalet et al., 2008). For those patients with polycythemia, primary prevention of cardiovascular events with aspirin should also be strongly considered.

Sleep-Disordered Breathing and OSA

Altitude can have dramatic short- and long-term effects on the regulation of breathing during sleep. In healthy persons, the increased ventilatory drive induced by exposure to hypobaric hypoxia promotes high-altitude periodic breathing, an alternating pattern of hyperventilation and central apneas/hypopneas associated with cyclic oscillation of oxygen saturation and sleep disturbances (Bloch et al., 2015). Periodic breathing at high altitude can occur as low as 1600 m (Latshang et al., 2013), is nearly universal at altitudes higher than 4000 m (Stream et al., 2009), and typically persists after acclimatization. There is significant individual variability in periodic breathing, felt to be related to variability in the hypoxic ventilatory response. In one study after acute ascent to 4300 m, periodic breathing during sleep was highly variable and diminished over time at altitude (White et al., 1987). In another study, acute ascent to 3600 m resulted in sleep periodic breathing and reduced rapid eye movement (REM) sleep in young athletes. Over 2 weeks, REM sleep increased to low-altitude baseline levels, but sleep periodic breathing persisted (Sargent et al., 2013). Strenuous exercise at high altitude has been found to exacerbate sleep periodic breathing (Morrison et al., 2016). Treatment with acetazolamide has demonstrated effectiveness in reducing sleep periodic breathing (Fischer et al., 2004); oxygen, continuous positive airway pressure (CPAP), and sleep aids such as zolpidem (Beaumont et al., 1996) that do not affect respiratory drive have all demonstrated effectiveness in improving sleep quality.

Individuals living at altitude with OSA can have profound, persistent abnormalities that require recognition and treatment. Sleep studies of patients with known OSA ascending to altitude have shown a decrease in obstructive apnea/hypopnea episodes, but an increase in the number of central apnea episodes (Burgess et al., 2006). This phenomenon increases incrementally with higher altitudes (Patz et al., 2006; Nussbaumer-Ochsner et al., 2010). OSA patients living at moderate altitude also experience more central sleep apnea (CSA) events than patients at lower altitudes (Pagel et al., 2011), suggesting that this problem persists despite acclimatization. While the ultimate long-term health effects of untreated CSA are not known, patients with OSA and short-term altitude exposure randomized to no treatment performed more poorly in driving simulator tests, had increased blood pressure, cardiac arrhythmias, weight gain, and leg edema than patients treated with CPAP (Nussbaumer-Ochsner et al., 2010). Thus, evaluation of OSA at altitude and adjustment of therapy is likely important to preventing long-term health consequences. The combination of CPAP and acetazolamide has been shown to dramatically reduce the number of central sleep apnea events during short stays at altitude (Latshang et al., 2012). A study of 10 residents of moderate altitude (1320 m) undergoing a sleep study at simulated altitude of 2750 m on their home CPAP settings found an increase in hypopnea events, and two of the subjects required supplemental oxygen (Nishida et al., 2015). This suggests that sleep studies performed at lower altitudes than the patient's residence may be underestimating the settings needed for adequate therapy. Thus, for patients living at altitude, it is advisable to obtain polysomnography at an altitude as close as possible to that of the individual's residence, and to use auto-titrating CPAP (Bloch et al., 2015).

Conclusion

Residents of high altitude who have lung disease may experience complications, but sometimes derive benefits, attributable to the high-altitude environment. Patients with asthma may have fewer symptoms, fewer exacerbations, and improved lung function at high altitude, especially if their primary asthma trigger is allergens in the environment that decrease at high altitude. Asthmatics whose trigger is breathing cold, dry air, especially during exercise, however, may experience more symptoms at high altitude. Patients with moderate-to-severe COPD who reside at high altitude have a higher mortality, probably due to worsening hypoxemia and development of cor pulmonale. Patients with COPD may develop worsening hypoxemia and require treatment with supplemental oxygen at a high altitude. Patients with pulmonary hypertension due to causes other than hypobaric hypoxia do not tolerate high altitude well and require careful attention to treatment with supplemental oxygen and pulmonary vasodilators. Even in long-term residents of high altitude without pulmonary hypertension, global hypoxic pulmonary vasoconstriction can result in worsening pulmonary hypertension and right-sided heart failure, and is the prominent pathophysiology of subacute mountain sickness that occurs after weeks or months at high altitude. Treatment usually requires descent to a lower altitude. CMS may occur after years at high altitude and includes polycythemia as well as pulmonary hypertension and right-sided heart failure. Patients with sleep-disordered breathing and OSA may have increased central apneas at high altitude and can be treated with nocturnal CPAP by mask, with consideration for adding acetazolamide or supplemental oxygen if indicated.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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