Coronary Artery Disease

A key concern in patients with coronary artery disease is whether the ambient hypoxia at high altitude will provoke myocardial ischemia, particularly during physical exertion. This question can be considered in several different contexts including patients with occult coronary artery disease, those with recognized stable disease and those who have undergone coronary revascularization.

Hypertension

The majority of studies demonstrate that individuals with mild hypertension who ascend to high altitude experience increased systemic blood pressure following ascent (Bilo et al. 2015; Palatini et al. 1989; Roach et al. 1995; Savonitto et al. 1992; Wu et al. 2007b), although a few studies have found only small, nonstatistically significant changes (D’Este et al. 1991; Somers et al. 1988). The increase in systolic pressure averages about 10–15 mmHg and is exacerbated by exertion (Lang et al. 2016; Savonitto et al. 1992). One of the noteworthy features of the observed responses, however, is the interindividual variability in the magnitude of observed changes, with some individuals experiencing minimal to no changes in blood pressure and others manifesting significant increases (Keyes et al. 2017; Roach et al. 1995). While there are no means to predict ahead of time which individuals will experience marked rises in their pressure, there is currently no evidence that severe hypertension following ascent is associated with increased risk of AMS or other adverse events, such as retinopathy, intracranial hemorrhage, or myocardial infarction.

Given these data, individuals with well-controlled hypertension can safely ascend to high altitude without the need for medication adjustments or blood pressure monitoring after arrival. Because the studies cited previously generally did not include individuals with severe hypertension, individuals with poorly controlled or labile blood pressure should monitor blood pressure following arrival and adjust their medications according to a plan arranged with their physician prior to their trip (Luks 2009b). Which medications are best for blunting blood pressure responses in hypertensive individuals is not clear. Studies have demonstrated that various agents, including angiotensin-­receptor blockers (Parati et al. 2014), beta-adrenergic blockers (Valentini et al. 2012), acetazolamide (Parati et al. 2013), and combination therapy with angiotensin- and calcium-­channel blockers (Bilo et al. 2015), can blunt but not eliminate the increase in systolic pressure with exposure to hypoxia, but most of these studies were performed in normotensive individuals and head-to-head studies have not established the most effective approach. Because elevated blood pressure may improve over time at high altitude, individuals who add or change blood pressure medications in response to a prearranged plan should continue to monitor their blood pressure and readjust medications as needed to avoid hypotension.

Heart Failure

A limited number of studies have examined the effect of high altitude exposure on patients with heart failure. Schmid et al. (2015) performed exercise tests on 29 patients with stable heart failure and peak V˙O₂ >50% predicted at 540 m and 3454 m and demonstrated a 22% decrease in mean peak V˙O₂ following ascent, while Agostoni et al. (2000) performed cardiopulmonary exercise tests on 38 heart failure patients at sea level and simulated altitudes of 1000 m, 1500 m, 2000 m, and 3000 m and noted a decrease in work rate with increasing altitude, with the greatest decrements seen in those patients with the greatest baseline exercise impairment (Figure 25.1). Erdman et al. (1998) noted decrements in exercise capacity in patients with ischemic cardiomyopathy similar to those seen in healthy controls following ascent to 2500 m. Importantly, none of these studies found evidence of significant complications such as arrhythmia, myocardial ischemia or pulmonary edema.

While these studies are reassuring, it should be noted that studies were limited to <3454 m, were shorter in duration than an individual might experience on a regular sojourn, and only included individuals with stable, well-controlled disease. These issues are important when one considers anecdotal evidence from physicians working at high altitude resorts that suggest some patients are predisposed to acute decompensation following arrival, possibly as a result of either hypoxia-induced alterations in sodium and fluid balance (Swenson 2001) or travel-related disruptions in medication adherence.

Given the studies noted above, travel to altitudes up to 3500 m is feasible in patients with stable, well-controlled disease, but should be avoided in patients with New York Heart Association (NYHA) class III or IV symptoms, high-grade ventricular arrhythmias, recent hospitalization, or evidence of worsening symptoms or fluid balance prior to their trip. Individuals who do not regularly exercise at low elevation should not engage in strenuous exercise after ascent. All patients should remain on their regular medications and arrange a plan with their physician to adjust their diuretics and other medications in response to changes in weight or blood pressure.

Arrhythmias

Studies performed with implantable cardiac monitors (Boos et al. 2017) and Holter monitors (Behn et al. 2014) and a variety of other reports have documented the occurrence of supraventricular and ventricular arrhythmias and other conduction disturbances in healthy individuals following ascent (Levine et al. 1997; Windsor et al. 2010; Woods et al. 2008), likely as a result of the sympathoadrenal responses to acute hypoxia. Given these findings, one might expect an increased incidence of arrhythmias in those with pre-existing arrhythmias, but data regarding this question are limited. In one of the few studies of this issue, Wu et al. (2007b) performed electrocardiograms (ECG) and 24-hour ambulatory ECG on 42 workers on the Qinghai-Tibet Railway with a variety of preexisting arrhythmias including sinus arrhythmia, premature atrial or ventricular beats, first degree atrioventricular (AV) block, and incomplete right bundle branch block. Assessments were made at one week and three months after exposure to 4500–5056 m and, aside from one case of asymptomatic Wolff-Parkinson-White syndrome, there were no reported exacerbations of underlying arrhythmia or other life-threatening conduction issues.

Given the lack of documented problems, it is likely safe for individuals with arrhythmias to continue to go to high altitude, provided their arrhythmia is under adequate control at the time of their sojourn. Patients should remain on their preexisting antiarrhythmic medications during their trip. Patients using oral anticoagulants for atrial fibrillation should remain on these medications unless planning to engage in high risk activities, in which case a discussion with their physician is necessary to weigh the benefits of anticoagulation versus the risks of bleeding in a remote area with limited resources for reversing anticoagulation. Because there are minimal issues regarding the use of the newer direct oral anticoagulants (DOAC) at high altitude, individuals who normally use warfarin may consider changing to a DOAC for their planned trip due to the fact that the INR can change during prolonged stays at high altitude despite stable warfarin dosing (Van Patot et al. 2006), anticipated changes in diet, vitamin K intake, and the potential for adverse interactions with dexamethasone, commonly used for prevention and treatment of AMS, that lead to increases the INR (DeLoughery 2015).

Adult Congenital Heart Disease

With improvements in medical care, many patients with congenital heart disease are living into adulthood, engaging in a wider variety of activities, and may, as a result, travel to high altitude. Drawing conclusions about high altitude activity in this patient population is challenging given the wide variety of congenital defects and surgical repairs. From a theoretical standpoint, those patients at potential risk for problems include those whose defects are associated with pulmonary hypertension, which, as discussed later in this chapter, may increase the risk of high altitude pulmonary edema, those individuals with significant right-to-left shunts and baseline hypoxemia, and Fontan circulation patients who lack a contractile subpulmonary ventricle.

The limited evidence suggests that individuals with unilateral absence of a pulmonary artery (Hackett et al. 1980; Rios et al. 1985) or Down syndrome, a disorder associated with various cardiac abnormalities (Durmowicz 2001), may be associated with an increased risk of HAPE while patients who have undergone a Fontan procedure for correction of tricuspid atresia may actually tolerate submaximal (Garcia et al. 1999) and maximal (Staempfli et al. 2016) exercise at altitudes as high as 3454 m despite the lack of a functional right ventricle. While studies have not specifically addressed this issue, individuals with cyanotic congenital defects will experience exaggerated hypoxemia at high altitude compared to healthy individuals, with the degree of hypoxemia varying as a function of the magnitude of the shunt. A single study suggests that patients with patent foramen ovale (PFO) may be at increased risk for HAPE (Allemann et al. 2006). A causal link between the two entities has not been established, however, and given the known exaggerated hypoxic pulmonary vasoconstriction in HAPE-susceptible individuals (Dehnert et al. 2005), it is possible the foramen ovale remains open due to excessive pulmonary artery pressure responses to hypoxia and exercise and is therefore simply a problem associated with HAPE, rather than a cause of that entity.

Given the paucity of data in this area, individuals with complex congenital heart disease should undergo thorough evaluation prior to any planned high altitude travel, including echocardiography, to assess pulmonary artery pressures and cardiopulmonary exercise testing to assess the overall adequacy of cardiac function (Luks et al. 2010). Consideration can also be given to pretravel high altitude simulation testing (Dine and Kreider 2008), although this test will only give information about short-term exposures and may not reflect what will happen on a long trip.

Pacemakers and Defibrillators

Patients with various forms of cardiac disease often have either permanent pacemakers and/or implantable cardiac defibrillators (ICDs). Little information exists regarding how these devices function at high altitude. Weilenmann et al. (2000) studied 13 patients with single chamber pacemakers and found no changes in ventricular stimulation thresholds at a simulated altitude of 4000 m, although the duration of exposure was only 30 minutes and may not accurately reflect the risks associated with longer exposures. Kobza et al. (2008) surveyed 217 patients with ICDs who traveled to altitudes above 2000 m and found that 4% experienced an ICD shock during their sojourn. Due to the study design, however, it is difficult to determine if the shocks were due to alterations in the device’s defibrillation threshold or due to the patient’s underlying cardiac condition. Given this limited body of evidence, it would be prudent for patients with implanted devices to have them interrogated prior to any long trips into remote areas far away from medical care.

Asthma

Given the prevalence of asthma in the general population, particularly among young otherwise healthy individuals who engage in active pursuits, it is likely that providers will be asked to evaluate the safety of high altitude travel in this patient population.

A variety of factors may affect asthma control at high altitude. While some, such as the lower air density, increased sympathoadrenal activity, and decreased number of dust mites, may improve various biologic and clinical markers of disease activity (Boner et al. 1993; Grootendorst et al. 2001; Spieksma et al. 1971; van Velzen et al. 1996), other factors such as hypoxia (Dagg et al. 1997; Denjean et al. 1988), hypocapnia (van den Elshout et al. 1991), and decreased air temperature (Kaminsky et al. 1995) may increase airway resistance or trigger airway reactivity and potentially worsen asthma control.

Most studies on these factors try to isolate the effect of that factor on asthma control. The reality, however, is that when a patient travels to high altitude, multiple factors may be simultaneously present. For this reason, clinical studies of asthma patients at high altitude provide more useful information to guide the pretravel assessment. Golan et al. (2002) reported that 20% of adventure travelers with asthma, including many engaging in high altitude trekking, had their “worst ever” asthma during the trip. This study, however, did not control for the altitudes attained during high altitude travel nor the fact that travel to such regions often requires that individuals spend time in urban centers with very poor air quality. Other field studies suggest the risks of high altitude travel may be quite manageable. Cogo et al. (1997) and Allegra et al. (1995), for example, studied individuals with mild asthma and reported decreased bronchial hyperreactivity to hypo-osmolar aerosol or methacholine at 4559 m and 5050 m when compared to sea level, while other studies have also documented that patients with mild, well-controlled asthma can ascend to at least as high as 6410 m without exacerbations of their disease and with no increase in the rate of AMS compared to climbers without asthma (Huismans et al. 2010; Stokes et al. 2008).

While these studies suggest individuals with well-­controlled asthma tolerate high altitude travel without problems, several studies suggest that caution is still warranted. Louie and Pare (2004), for example, reported a small decrease in peak expiratory flow of 76 ± 67 L/min during a trek to 5050 m in Nepal, while Seys et al. (2013) noted a slight increase in asthma symptoms during an expedition to Aconcagua (6965 m) as well as decreased prebronchodilator FEV₁ and increased markers of airway inflammation following the climb. Several studies have also reported an increased incidence of asthma or exercise-induced bronchoconstriction in cross-country skiers and ski mountaineers, two groups of athletes whose activity requires high minute ventilation in cold environments and often at high altitude (Durand et al. 2005; Larsson et al. 1993). Limited evidence suggests airway hyperreactivity in athletes at high altitude may be blocked in part by nifedipine (Henderson et al. 1983), acetazolamide (O’Donnell et al. 1992), and cromolyn sodium (Juniper et al. 1986), but these interventions not been examined in large clinical studies.

Patients with mild-intermittent or mild-persistent asthma can safely ascend to high altitude provided their disease is under good control at the time of their trip. Patients with more severe disease or who are in an active exacerbation at the time of their trip should avoid high altitude travel, particularly into remote regions away from medical care. Individuals should remain on preexisting medications and carry an adequate supply of rescue inhalers and oral prednisone to treat an exacerbation. Individuals using metered-dose inhalers should be careful to keep the inhalers warm in cold environments. While some evidence suggests the number of puffs delivered per inhaler may be decreased at elevations above 3000 m (Roggla and Moser 2006), more recent data indicate that the dose by either metered-dose or dry-powder inhalers appears largely unchanged up to elevations of 4300 m (Titosky et al. 2014). Individuals can monitor peak expiratory flow during their trip but should be aware that variable orifice peak flow meters may underestimate peak flows at high altitude or in cold environments (Pollard et al. 1996; Thomas et al. 1990) and should rely more on the trends in their measurements rather than the absolute values.

Chronic Obstructive Pulmonary Disease (COPD)

Despite the high prevalence of this disease, until recently, little has been known about how patients with COPD fare following ascent to high altitude. Most information had to be gleaned from chamber studies or studies simulating flight on commercial aircraft. A series of recent studies conducted at terrestrial high altitude, however, have provided some initial insights into issues of concern in these patients following ascent.

Changes in exercise capacity

In their study of 40 patients with a median FEV₁ of 57% predicted taken to 1650 m and 2590 m, Furian et al. (2018a) found that the six-minute walk distance decreased from 534 ± 93 m at 490 m in elevation to 512 ± 93 m on the first day at 1650 m and 491 ± 93 m on the first day at 2590 m. Slight increases were seen in the six-minute walk distance on the second day at both 1650 m and 2590 m, but a similar increase was also seen on the second day of testing at 490 m, suggesting the change from the first to the second day at each altitude may be due to learning effect rather than any real changes in exercise capacity. In a subset of 31 patients who completed cardiopulmonary exercise tests, the authors found that the maximum work rate fell significantly from 92 (IQR 73–120) to 82 watts (IQR 63–120) while the V.O_2max fell significantly from 1.21 L min⁻¹ (IQR 0.90–1.43) to 1.06 L min⁻¹ (IQR 0.88–1.47). Interestingly, while perceived dyspnea increased at high altitude on the six-minute walk test, no changes in dyspnea ratings were noted on the cardiopulmonary exercise test following ascent. Finally, exercise endurance, measured by time to exhaustion during constant-load bicycle exercise at equivalent work rates, was reduced at 2590 m compared to 490 m (Furian et al. 2018b) (Figure 25.2).

In considering these changes in exercise capacity, however, it is important to note that exercise is impaired in all individuals who ascend to high altitude, regardless of their underlying health status. Because these studies did not include a control group of healthy individuals, it is impossible to determine how the observed rates of decline compare to that expected in the general population.

Diffuse Parenchymal Lung Diseases

Only two studies have examined the effect of simulated high altitude on patients with diffuse parenchymal lung diseases (often referred to as interstitial lung disease) with each study noting a decline in P_aO₂ to around 50 mmHg with exposure to the equivalent of 2440 m (∼8000 ft) at rest and more significant declines with mild exercise such as walking on flat ground for 50 m (Christensen et al. 2002; Seccombe et al. 2004). It is unclear whether the exaggerated hypoxemia predisposes to complications at high altitude such as acute mountain sickness. Patients with severe diffuse parenchymal lung disease often develop pulmonary hypertension, however, which, as discussed further, may increase the risk of high altitude pulmonary edema. Furthermore, these patients have reduced lung compliance, which may increase the work of breathing in response to hypoxia at high altitude. Patients with severe restrictive physiology (total lung capacity [TLC] <50% predicted) or a pre-existing oxygen requirement should likely avoid high altitude travel altogether, while those with less severe disease can travel to high altitude with adequate pretravel assessment. The regression equation provided by Christensen et al. (2002) can be used to help assess the need for supplemental oxygen during a planned trip. The same issues noted above regarding securing oxygen for high altitude travel apply to these patients as well.

Cystic Fibrosis

As with congenital heart disease patients, more and more patients with cystic fibrosis (CF) are living well into adulthood and may seek travel opportunities that involve going to high altitude. As with the COPD and diffuse parenchymal lung diseases, the available evidence suggests that exposure to moderate altitudes of 2000–3000 m is associated with a significant decrease in arterial oxygenation, with more precipitous declines seen in individuals with severe disease or following exercise (Fischer et al. 2005; Rose et al. 2000; Ryujin et al. 2001; Thews et al. 2004). Despite the severe hypoxemia, however, these individuals generally had either no or minor symptoms (Kamin et al. 2006). This finding must be viewed with caution as the hypoxic exposures were of only short duration and may not adequately predict what would happen with longer exposures typical of a high altitude vacation or climbing expedition. A report of two cystic fibrosis patients with baseline FEV₁ ∼1 L who developed pulmonary hypertension and cor pulmonale during a high altitude trip provides some evidence that patients with severe disease can, in fact, develop severe problems following ascent (Speechly-Dick et al. 1992).

Patients with severe CF (FEV₁ ≤1 L or <30% predicted) should avoid high altitude travel, but other patients can likely travel safely provided their disease is under good control at the time of their trip. They should continue their pre-existing airway clearance regimen, prophylactic antibiotics, and mucolytic therapy during their travels. Studies have proposed using the baseline partial pressure of oxygen (Fischer et al. 2005) or more complicated prediction equations (Kamin et al. 2006) to identify which patients will develop severe hypoxemia at high altitude and may require supplemental oxygen. The same issues noted above regarding use of supplemental oxygen in patients with COPD apply in this case as well and a more feasible approach for many patients with CF would be to monitor oxygen saturation following arrival and respond according to a preset plan if they have severe hypoxemia and/or worsening symptoms.

Pulmonary Hypertension

Only a few studies have examined the effects of acute hypoxia on patients with pulmonary hypertension. Seccombe et al. (2017) exposed seven healthy controls and 14 patients with NYHA class II or III pulmonary arterial hypertension (PAH) to an F_IO₂ of 0.15 for 20 minutes at rest and during mild exertion and found that estimated systolic pulmonary artery (PA) pressure increased from 56 ± 14 mmHg at rest to 75 ± 17 mmHg during hypoxia with exertion in the patients with PAH (Figure 25.3). The patients with PAH had lower oxygen saturation than the controls (90 ± 4% vs. 94 ± 2% at rest; 91 ± 2% vs. 94 ± 2% with exercise) but did not manifest evidence of worsening right ventricular function or other significant complications. In another study, Groth et al. (2018) exposed 28 patients with PAH or chronic thromboembolic pulmonary hypertension and 16 healthy controls to 10 minutes of acute hypoxia (F_IO₂ of 0.16, ∼2600 m) during right heart catheterization and noted no significant changes in mean pulmonary artery or systemic blood pressure, pulmonary vascular resistance, or cardiac output in either group as well as no significant difference in vascular reactivity between the two groups.

Despite the lack of complications in these studies, which involved a very short duration of hypoxic exposure, there is still reason to suspect that HPV may predispose to problems following longer exposures. The literature contains a large number of reports of patients with pulmonary hypertension due to a variety of factors including unilateral absence of a pulmonary artery (Hackett et al. 1980; Rios et al. 1985), congenital heart disease (Durmowicz 2001), granulomatous mediastinitis (Torrington 1989), sarcoidosis (Brill et al. 2012), anorexigen use (Naeije et al. 1996), and portal hypertension (Bogaard et al. 2007) who developed HAPE following ascent to a variety of different elevations. Importantly, some of the reported cases occurred at elevations as low as 1500–2000 m, lower than the altitudes at which HAPE is seen in otherwise healthy individuals. It is not clear from these reports exactly what level of pulmonary hypertension is necessary to increase the risk of HAPE and no cases of this phenomenon have been described in patients with idiopathic pulmonary arterial hypertension. Even if these individuals do not develop overt edema, they may still be at risk for worsening right heart function due to the rise in pulmonary artery pressure and subsequent increase in right ventricular afterload. This problem was not seen in the studies noted previously (Groth et al. 2018; Seccombe et al. 2017), but their 10–20 minute exposures were short relative to the length of time travelers often spend at high altitude and it is conceivable that problems may develop with a longer exposure, particularly if there is significant physical activity. The altitude to which subjects were exposed in these studies was also low compared to altitudes individuals may reach during travel to the mountains.

Patients with milder disease (e.g., NYHA class I or II) can likely travel to high altitude, but should consider using systemic vasodilator therapy, such as nifedipine or a phosphodiesterase inhibitor, if not already on such therapy, as well as closely monitoring symptoms and oxygen saturation after arrival. Those with poorly controlled disease (e.g., NYHA class III or IV symptoms) or who require continuous intravenous vasodilator therapy should avoid high altitude altogether. If high altitude travel is necessary in those cases, strong consideration should be given to using supplemental oxygen to blunt the rise in pulmonary artery pressures.

Pulmonary Embolism

A prior history of pulmonary thromboembolic disease presents a difficult clinical dilemma. As discussed in Chapter 23, there are case reports of thromboembolic disease at high altitude, but many of those cases occurred in patients with hypercoagulable states (Ashraf et al. 2006; Boulos et al. 1999) and there is little consistent evidence that travel to high altitude predisposes people to either hypercoagulability or recurrent thromboembolism. Nevertheless, it seems reasonable to evaluate patients with prior pulmonary embolism carefully. Those with no known predisposing conditions and who lack pulmonary hypertension can travel to high altitude for recreation, while those with pulmonary hypertension should be managed according to the principles outlined in the preceding section. Individuals who finished their course of anticoagulation for a prior episode of venous thromboembolism should not start anticoagulation for the trip to high altitude, while patients currently using anticoagulation should continue their regimen, with consideration given to changing from warfarin to a direct oral anticoagulant for the sojourn. All individuals should remain well hydrated and avoid periods of immobility, as can happen when tent-bound in prolonged storms.

Sleep Disordered Breathing

Patients with obstructive sleep apnea (OSA) will experience an increase in the total apnea hypopnea index (AHI) following ascent to high elevation. Burgess et al. (2006) observed individuals with moderate severity OSA during sleep in normobaric hypoxia and demonstrated that while the obstructive AHI fell from 25.5 ± 14.4 at 60 m to 0.5 ± 0.7 at 2750 m, the central AHI increased markedly from 0.4 ± 0.5 at 60 m to 78.8 ± 29.7 at 2750 m. Nussbaumer-Oschner et al. (2010) took patients with OSA of similar severity to terrestrial high altitude and noted no significant change in the number of obstructive events, but a marked increase in the number of central events, such that the median AHI rose from 47.5 at 490 m to 90.9 on the second night at 2590 m (Figure 25.4). The increase in the AHI may have important implications for these individuals following ascent, as it not only is associated with lower nocturnal oxygen saturation but also impaired tracking performance during simulated driving at high altitude compared to lower elevation, increased systolic blood pressure, and increased cardiac arrhythmias (Nussbaumer-Ochsner et al. 2010). These latter two findings are likely related to increased sympathetic stimulation from the increased arousals and exaggerated hypoxemia.

Because obstructive events persist following ascent, patients with OSA should consider bringing their CPAP machines on their sojourn. The size of the machines and accessibility of electrical power have generally limited the number of settings in which CPAP is feasible, but the increasing availability of lightweight, portable, battery-powered devices may increase the number of settings amenable to CPAP use (Lebret et al. 2018). Consideration should also be given to adding acetazolamide to CPAP, as the combination decreases the number of central apneas and the AHI and improves nocturnal oxygenation when compared to autotitrating CPAP alone (Latshang et al. 2012). Even if CPAP is not feasible due to a lack of electrical power or other logistical issues, acetazolamide alone is effective at improving oxygenation, AHI, and sleep quality and warrants strong consideration (Nussbaumer-Ochsner et al. 2012a).

Ventilatory Control Disorders

Because ventilatory responses play a key role in acclimatization and adaptation to high altitude, individuals with ventilatory control disorders warrant careful consideration prior to high altitude travel. Limited data in the literature suggest there are several groups of patients who might be at risk for problems. Because carotid endarterectomy can damage or obliterate the carotid body, patients who have undergone bilateral endarterectomy or carotid body ablation, an old treatment for refractory asthma, may be at risk for impaired hypoxic ventilatory responses (Honda et al. 1979; Roeggla et al. 1995) and, as a result, exaggerated hypoxemia following ascent. Similar problems may also be seen in Parkinson’s disease and myotonic dystrophy, as these disorders have been shown to be associated with impaired hypoxic ventilatory responses at sea level (Carroll et al. 1977; Serebrovskaya et al. 1998). Finally, patients with skeletal or neuromuscular disorders, such as severe kyphoscoliosis, diaphragmatic paralysis, Duchenne’s muscular dystrophy, or amyotrophic lateral sclerosis may not be able to adequately raise their minute ventilation in response to the hypoxia at high altitude, despite having adequate carotid body responses. Even if they do not have problems with ventilation while awake, patients with bilateral diaphragmatic paralysis can develop arterial hypoxemia when supine (Kumar et al. 2004; Sandham et al. 1977) and, as a result, may experience significant hypoxemia during sleep at high altitude.

Anemia

Anemia will impair oxygen delivery and exercise performance at high altitude, but there are no data regarding the degree of anemia sufficient to provoke these problems and no data indicating that anemia increases the risk of acute altitude illness. Individuals with anemia of known cause may consider checking their hematocrit prior to high altitude travel and pretravel transfusion depending on the anticipated duration of stay and level of exertion at high altitude, although the literature provides no guidance on the appropriate transfusion threshold for such situations. Individuals with low iron stores, such as premenopausal females, may consider iron supplementation prior to and during their trip as low iron stores affect erythropoietic responses to hypoxia (Richalet et al. 1994). Those individuals in whom the cause of anemia has not been identified should complete a diagnostic work up prior to their trip to rule out ongoing bleeding or a hemolytic process.

Patients using erythropoiesis stimulating agents (ESA), such as erythropoietin or darbepoetin, for chronic anemia in the setting of chronic kidney disease may require reduced doses during prolonged stays at high altitude, as a retrospective analyses dialysis-dependent patients in the United States found that patients living above 1300–1800 m required lower doses of these agents compared to those living at lower elevations (Brookhart et al. 2008; Sibbel et al. 2017). Any patient using ESAs during a prolonged stay at high altitude should have close follow up of their hematocrit.

Sickle Cell Anemia and Sickle Cell Trait

High altitude travel should be avoided in patients with sickle cell anemia, as hypoxia during either airplane flight or travel to the mountains can increase sickling and provoke vaso-occlusive crises (Claster et al. 1981; Mahony and Githens 1979). Claster et al. (1981) showed that 37.9% of patients with sickle cell disease and 56.6% of those with hemoglobin SC or Hb S-β-thalassemia developed vaso-occlusive crises with travel to a modest elevation of 1900 m. Even patients with sickle cell trait (Hb AS) may be at risk for problems, as multiple reports document splenic crises and splenic infarction in these patients following acute altitude exposure (Goodman et al. 2014; Kumar et al. 2019; Sheikha 2005; Tiernan 1999). Patients with Hb AS can likely still travel to high altitude, but must be vigilant about maintaining hydration and seek medical attention and/or descend with the onset of left upper-quadrant pain or left-sided pleuritic pain. Conservative management at low altitude is usually sufficient to resolve the problem (Goodman et al. 2014).

Polycythemia Vera

While higher hemoglobin concentrations theoretically would improve oxygen delivery at high altitude, high altitude travel increases the risk of dehydration due to the lower humidity and altitude-induced diuresis. In individuals with polycythemia vera (PV), this could raise hemoglobin concentration further, thereby worsening blood viscosity, impairing oxygen delivery, and increasing risk of thrombosis (Spivak 2002). Patients with PV are at increased risk for gastroduodenal erosions (Torgano et al. 2002), but whether this risk is further increased by hypobaric hypoxia is unknown. Given these uncertainties, patients with PV can travel to high altitude but should maintain adequate hydration and mobility, and consider low-dose aspirin to reduce the risk of thrombosis. Patients with known gastroduodenal erosions should avoid aspirin, as well as dexamethasone, as either medication increases the risk of upper gastrointestinal bleeding.

Acclimatization to High Altitude

Multiple studies performed as part of climbing expeditions suggest that major physiologic responses to hypoxia, risk of acute altitude illness, and summit success rates are similar between healthy individuals and individuals with well-­controlled type I diabetes. Pavan et al. (2004), for example, studied well-controlled patients with type I diabetes at 3700 m and 5800 m on Cho Oyu and found no difference in bicarbonate, hematocrit, and the arterial partial pressures of oxygen and carbon dioxide. Other studies have reported no difference in the incidence of AMS or Lake Louise AMS scores between climbers with and without diabetes during ascents of Aconcagua (6962 m), Cho Oyu (8201 m), and Kilimanjaro (5895 m) (Kalson et al. 2007; Moore et al. 2001; Pavan et al. 2003). In one of the few studies examining patients with type II diabetes, Del Mol et al. (2012) reported low AMS scores during a 12-day trek to the summit of Mount Toubkal (4167 m) among 13 patients with well-controlled disease and no history of diabetes-related complications.

Insulin Requirements and Glycemic Control

Multiple factors impact glycemic control at high altitude, including changes in diet, altitude-related anorexia, the degree of exertion, sympathetic nervous system responses to hypoxia, and other forms of altitude-related stress. Comparing results across the studies is difficult because ascent rates, levels of exertion, altitudes attained, and dietary factors vary significantly between the available studies. Most studies also involve ascent to altitudes >5800 m and may not be applicable to the broader population of travelers who are only visiting lower elevations and not engaging in the same level of exertion seen in climbing. Most studies on insulin requirements report increased requirements during high altitude travel (Admetlla et al. 2001; de Mol et al. 2011; Pavan et al. 2003), while a single study found decreased requirements (Moore et al. 2001). Given the uncertainties about insulin requirements, individuals with diabetes should monitor blood glucose levels more frequently than at home and alter their insulin dosing accordingly. Further discussion of these issues is available in a comprehensive review on this topic (Richards and Hillebrandt 2013).

Glucometer Function

Many early studies reported issues with glucometer accuracy at high altitude (Fink et al. 2002; Gautier et al. 1996; Pecchio et al. 2000), possibly due to the fact that monitors used in these studies were glucose oxidase-based systems (GOX) that rely on oxygen for their measurements. Many of the more recent generation devices rely on a non-oxygen dependent glucose dehydrogenase (GDH) reaction, which, from a theoretical standpoint, should be less susceptible to the effects of hypobaric hypoxia. Despite this theoretical benefit, it is unclear whether these monitors perform better at high altitude. While Oberg and Ostenson (2005) found that GDH meters outperformed GOX systems at simulated altitudes of 2500 m and 4500 m and de Mol et al. (2010) demonstrated better precision and accuracy among GDH systems during a climb of Mount Kilimanjaro, Olateju et al. (2012) found no difference in performance at a simulated altitude of 2340 m. Bilen et al. (2007) compared measurements from GDH and GOX systems at 2000 m with simultaneously drawn venous plasma glucose values measured in the reference laboratory and found that measurements from GDH systems were higher than the reference lab values, while the GOX systems showed no statistically significant difference.

On average, the differences in measured values tend to be relatively small and, as a result, likely not of major clinical significance. However, when readings fall near the low end of the normal range, small errors carry more significance, as travelers may be slow to recognize true hypoglycemia. For this reason, travelers with diabetes mellitus should react more readily to values near the low end of the normal range rather than using their usual thresholds for intervening to prevent hypoglycemia.

Insulin Pumps

Many patients with diabetes now use insulin pumps for blood glucose regulation rather than intermittent subcutaneous injections. King et al. (2011) examined pump function in hypobaric hypoxia and found that bubbles formed and expanded within the system during commercial flight and in a hypobaric chamber, while another study showed evidence of bubble formation with ascent to only 300 m (Lopez et al. 2014). The concern with bubble formation is that it could lead to excess insulin administration and, as a result, hypoglycemic episodes. This issue was not borne out, however, in an observational study of 19 patients with type I diabetes mellitus ascending to 5670 m (Matejko et al. 2017b). The participants used a variety of insulin pumps and continuous monitoring systems and had no episodes of ketoacidosis, alarms, or other problems with their pumps and no episodes of severe hypoglycemia, although mild hypoglycemia did occur at a frequency of 1.6 episodes every three days. Predictive low glucose management technology, designed to prevent severe hypoglycemia, was turned on 3.3 times per patient per day when the suspend-before-low threshold was set at 70 mg dL⁻¹. Importantly, the altitude attained by the participants was higher than the 3000 m altitude threshold for which the monitors were registered to work according to their product manuals. Another case report (Matejko et al. 2017a) documents the outcome for a single individual with type I diabetes mellitus who successfully climbed Aconcagua (6962 m) using an insulin pump with predictive low glucose management technology, and suffered only a single episode of hypoglycemia. These latter reports suggest that pumps and monitors function appropriately up to a certain altitude, but given the limited amount of data on this question, individuals should travel with a back-up plan for monitoring glucose and administering insulin, particularly if traveling in very cold conditions or to altitudes above 3000 m.

Retinal Disease

Retinal hemorrhage is a common complication of travel at moderate-extreme altitudes in normal individuals (Bosch et al. 2012). Two studies specifically examined this issue with regard to patients with diabetes, a group at increased risk for retinal disease. Moore et al. (2001) used ophthalmoscopy and found asymptomatic hemorrhage in two of 15 climbers with diabetes during an ascent of Kilimanjaro (5895 m) while Leal et al. (2008) used retinography and noted development of asymptomatic hemorrhage in one out of seven climbers ascending to 7100 m, one of whom had known diabetic retinopathy. These studies lacked control groups and, as a result, do not firmly establish the risk that patients with diabetes face relative to the general population traveling to these altitudes. Given the ongoing uncertainty on this issue, there is no reason to restrict high altitude travel in patients with retinal disease, except in cases of severe diabetic retinopathy (Mader and Tabin 2003). Aspirin and other nonsteroidal anti-inflammatory drugs do not appear to increase the risk of retinal hemorrhage at low elevations, but this has not been studied at altitude. As a result, it may be prudent to rely on acetaminophen as the first-line agent to treat AMS symptoms in patients with known diabetic retinopathy.

Gastrointestinal Bleeding and Peptic Ulcer Disease

Patients with prior gastrointestinal bleeding due to, for example, peptic ulcer disease or gastritis should exercise caution when traveling to high altitude as several reports indirectly suggest the risk of gastrointestinal bleeding may be increased at high altitude. Wu et al. (2007a), for example, studied 13,502 workers between 3500 m and 4900 m on the Qinghai-Tibetan railway and found a 0.49% incidence of hematemesis, melena, or hematochezia. Endoscopy was performed on all affected individuals and revealed evidence of gastric and duodenal ulcers, gastric erosions, and hemorrhagic gastritis. In a separate report, they also noted development of gastrointestinal bleeding in several individuals using alcohol and/or aspirin in conjunction with dexamethasone following ascent (Wu and Liu 2006). More recently, Fruehauf et al. (2019) performed endoscopy on 26 asymptomatic mountaineers with normal pre-expedition endoscopy ascending to 4559 m over 22 hours and noted gastric or duodenal erosions/ulcers, hemorrhagic gastritis or duodenitis, and reflux esophagitis in 26% of individuals on day 2 and 61% of individuals on day 4 at high altitude. On day 4, 21.7% had evidence of ulcer disease, although none of the climbers experienced active gastrointestinal bleeding. Interpretation of the findings in the latter study is a bit challenging, however, due to the fact that several of the climbers received either dexamethasone, nonsteroidal anti-inflammatory agents, or proton-pump inhibitors during the course of their ascent.

These studies do not establish a definitive link between acute hypoxia and gastrointestinal bleeding or peptic ulcer disease, but along with a report of gastric perforations in Indian soldiers posted to elevations >4500 m (Pawar et al. 2018), suggest that patients with poorly controlled esophagitis, gastritis, or peptic ulcer disease may be at risk for bleeding or perforation following ascent. Individuals with these problems should be careful when using medication known to increase the risk of gastrointestinal bleeding or perforation, such as nonsteroid anti-inflammatory agents or dexamethasone, to treat or prevent symptoms of altitude illness or arthralgias, minimize alcohol consumption, and consider the possibility of occult bleeding in the event of unexplained dyspnea, fatigue, or weakness or the possibility of perforation in the event of sudden onset of abdominal pain.

Inflammatory Bowel Disease

A single retrospective study has examined effects of acute hypoxia on patients with inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis. Vavricka et al. (2014) surveyed 103 patients with IBD with and without flares during a 12-month observation period and found that those individuals experiencing disease flares were more likely to have flown on commercial aircraft or traveled above 2000 m within four weeks of the flare than those individuals who remained in remission. This study, which did not identify the length of time spent above 2000 m in those who suffered flares, suggests that individuals may be okay during the actual sojourn but face risks upon return to lower elevation. Those patients who travel to high altitude during a quiescent phase should carefully plan their diet and medications, research the availability of local healthcare resources and evacuation strategies prior to their trip, and travel with medications suitable for treating exacerbations. Depending on the region to which they are traveling, they should also work closely with their physician to ensure they are appropriately vaccinated and take steps to decrease the risk of infection given that many are on immunosuppressive therapy (Esteve et al. 2011). Patients with IBD who are experiencing an active exacerbation should avoid high altitude travel.

Chronic Liver Disease

There are no data regarding patients with chronic liver disease at high altitude, although from a theoretical standpoint, two groups of patients with cirrhosis may be at risk for problems in this environment (Luks and Swenson 2015). Those patients with portopulmonary hypertension may be at risk for high altitude pulmonary edema or worsening right heart function, as discussed earlier in this chapter, while those patients with hepatopulmonary syndrome may have significant hypoxemia due to worsening gas exchange in low ambient oxygen conditions. Regardless of whether or not they have these disorders, all patients with chronic liver disease should avoid acetazolamide for prevention or treatment of AMS as the medication can provoke hyperammonemia and worsening encephalopathy in these patients (Luks and Swenson 2008).

Other Gastrointestinal Conditions

Preexisting gastrointestinal tract conditions such as hemorrhoids, perianal hematomas, perianal and ischiorectal abscesses, and anal fissures should be addressed prior to any prolonged high altitude expedition, as management once in the field may be challenging. Hernias should also be repaired prior to a climbing expedition as the heavy lifting often required on such trips could lead to enlargement of the hernia and potentially increase the risk of incarceration and strangulation, problems that could have severe consequences in a remote area away from medical care.