Travel to High Altitude Following Solid Organ Transplantation

Abstract

Luks, Andrew M. Clinician's corner: travel to high altitude following solid organ transplantation. High Alt Med Biol. 17:147–156, 2016.—As they regain active lifestyles following successful organ transplantation, transplant recipients may travel to high altitude for a variety of activities, including skiing, climbing, and trekking. This review is intended to provide information for medical providers who may encounter transplant patients seeking advice before planned high altitude travel or care for medical issues that develop during the actual sojourn. There is currently limited information in the literature about outcomes during high-altitude travel following solid organ transplantation, but the available evidence suggests that the physiologic responses to hypobaric hypoxia are comparable to those seen in nontransplanted individuals and well-selected transplant recipients with no evidence of organ rejection can tolerate ascents as high as 6200 m. All transplant recipients planning high-altitude travel should undergo pretravel assessment and counseling with an emphasis on the recognition, prevention, and treatment of altitude illness, as well as the importance of preventing infection and limiting sun exposure. Transplant recipients can use the standard medications for altitude illness prophylaxis and treatment, but the choice and dose of medication should take into account the patient's preexisting medication regimen and current renal function. With careful attention to these and other details, the healthy transplant recipient can safely experience the rewards of traveling in the mountains.

Introduction

With improvements in the quality of medical care, increasing numbers of people with underlying medical issues are partaking in adventure travel, including travel to high altitude (elevations >2440 m, 8000 ft). One group of individuals who might engage in such activities are solid organ transplant (SOT) recipients who, given improvements in physical well-being following transplantation, may be interested in resuming an active lifestyle after a period of severe limitation due to their underlying illness. Travel to high altitude carries many potential rewards for these patients, particularly given their difficult prior medical experiences, but there are also important risks, including that of developing acute altitude illnesses such as acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), as well as the risk of enteric, vector- borne, and blood-borne infection associated with international travel.

The purpose of this review is to provide information that can be used by a variety of providers to address issues surrounding their planned travel, including transplant physicians, medical advisers for guiding companies, and medical providers who may encounter these individuals in the mountains. The review begins by considering the high-altitude travel environment, major physiologic responses to hypoxia, and the existing evidence regarding high-altitude travel following transplantation. This is followed by a discussion of issues to consider during pretravel evaluation and counseling, as well as factors that affect the choice of medications for altitude illness prevention and treatment. The focus throughout will be on the unacclimatized lowlander traveling to high altitude for days to weeks rather than the care and outcomes for patients living at high altitude following transplant.

The High-Altitude Travel Environment

The defining environmental feature at high altitude is the nonlinear decrease in barometric pressure with increasing elevation, which leads to a series of physiologic responses described further below. Other important features include the decrease in ambient temperature and humidity and the increase in ultraviolet light (UV) exposure, which increase risk for various problems, including hypothermia, dehydration, sunburn, and ultraviolet keratitis.

In addition to these well-known issues, there are several other features of traveling to high altitude that warrant attention in the SOT recipient especially with regard to their immunosuppressive antirejection medications. While some people travel to the mountains alone or as part of small teams, many high-altitude climbs or trekking expeditions involve traveling in large groups during which individuals dine and are lodged in close proximity to other travelers, which eases the spread of infection. Hygiene issues, including the cleanliness of water sources, are also a large concern in many major high-altitude climbing and trekking zones such as the Himalaya, Andes Mountains, and Kilimanjaro, while travel to these areas typically requires transiting through major cities such as Kathmandu, Bangkok, or Delhi with not only hygiene issues but also air quality concerns. As described further below, these environmental concerns require attention during pretravel preparations and the trip itself.

Physiologic Responses to Acute Hypoxia

The fall in barometric pressure following ascent to high altitude leads to decreases in the alveolar, arterial, tissue, and mixed venous PO₂, which, in turn, provoke a series of physiologic responses across multiple organ systems (Luks, 2014, 2016). In considering the risks associated with high-altitude travel following SOT, it is worth considering whether and how the major responses are affected by the various forms of transplantation.

Ventilatory response to hypoxia

The decrease in arterial PO₂ normally triggers increased peripheral chemoreceptor output and an increase in minute ventilation, the magnitude of which varies significantly between individuals. This response is preserved following lung transplantation (Sanders et al., 1989) and may even be accentuated following heart transplantation (Ciarka et al., 2006).

Hypoxic pulmonary vasoconstriction

The decrease in alveolar PO₂ triggers hypoxic pulmonary vasoconstriction and an increase in pulmonary artery (PA) pressure. This response, whose magnitude also varies significantly between individuals, is preserved following heart-lung transplantation (Robin et al., 1987). Whether the denervation with lung transplantation possibly reduces HPV is unknown, but studies of lung denervation in patients with pulmonary hypertension suggest a possible benefit in this regard (Chen et al., 2015).

Increased sympathetic nervous system activity

Sympathetic nervous system activity increases during acute hypoxia leading to an increase in heart rate as well as variable increases in systemic blood pressure (Luks, 2009b). The sympathetic response still occurs in transplant recipients, but heart transplant patients do not experience the same increase in heart rate with hypoxia or exercise as other individuals due to the fact that the heart is permanently denervated (Cotts and Oren, 1997; Ciarka et al., 2006). They do respond to circulating catecholamines (Cannom et al., 1975), but the response to neutrally mediated signals is abolished. Blood pressure responses are unaffected (Ciarka et al., 2006).

Erythropoietin secretion

Serum erythropoietin concentrations increase within 24–48 hours of ascent to high altitude (Milledge and Cotes, 1985) and over time lead to increased red blood cell production and hemoglobin concentration, which help preserve tissue oxygen delivery. Because erythropoietin secretion normalizes following kidney transplant in those with normal graft function (Besarab et al., 1987; Sun et al., 1989), kidney transplant patients would be expected to mount the normal erythropoietic response to acute hypoxia.

Fluid homeostasis

Acute hypoxia triggers both diuresis and natriuresis in the first several days at high altitude. While this response has not been studied in kidney transplant recipients, other work has demonstrated that the response is mediated by the peripheral chemoreceptors (Swenson et al., 1995) and, as a result, should be preserved even in the denervated kidney, as has been demonstrated in animal studies.

Exercise capacity

Following ascent to high altitude, maximum exercise capacity declines (Cymerman et al., 1989; Wagner, 2000), while for any given work rate, heart rate and total ventilation are higher than at sea level (Pugh et al., 1964). For travelers, including those in good physical condition, this manifests as increased breathlessness with exertion, even when exercising at workloads comparable to those maintained at sea level. Given that maximum exercise capacity is decreased following all forms of common organ transplantation (Williams and McKenna, 2012), one could hypothesize that transplant recipients might be at risk for significant decrement in exercise capacity at high altitude, but this issue has never been formally studied and no firm conclusions can be drawn. The fact that transplant patients have been shown to successfully summit peaks such as Kilimanjaro (5595 m) and Island Peak (6189 m) (Pirenne et al., 2004; Suh et al., 2015; van Adrichem et al., 2015) (discussed further below) would suggest that healthy patients, far enough out from their transplant, retain the exercise capacity necessary to perform high levels of physical work in this environment.

Available Data Regarding SOT Patients at High Altitude

One of the challenges in counseling SOT patients about the risk of high-altitude travel is the paucity of evidence regarding performance at terrestrial high altitude following transplantation. Only three reports have been published, documenting the experience of a total of 24 organ transplant patients at high altitude (23 solid organ, 1 peripheral blood stem cell transplantation) (Pirenne et al., 2004; Suh et al., 2015; van Adrichem et al., 2015). Summary information from these reports is provided in Table 1. Botella de Maglia and Escrivà have also described the experience of a single lung transplant patient who ascended to 4164 m in the Alps (Botella de Maglia and Fuster Escriva, 2007), while Hillebrandt described a pretravel evaluation for a renal transplant patient who had previously trekked to 4000 m in Nepal, climbed Mont Blanc du Tacul (4248 m), and planned to ascend to Mont Blanc (4808 m), but provided no data regarding the outcome of the latter climb (Hillebrandt, 2003).

Table 1.

Data From Case Series of Transplant Patients at High Altitude

Study and location	Transplant patients on expedition (type: No.)	Transplant medications (regimen: No. of patients)	Pretrip training program	Altitude illness prophylaxis in transplant patients	Symptom scores	Summit success rate
Pirenne et al. (2004), Kilimanjaro (5595 m)	Liver: 6	Tacrolimus: 2; Tacrolimus + Azathioprine: 4	6-month program: aerobic training three times per week at increasing intensity	Salmeterol: 125 μg twice daily; Dexamethasone 1.5 mg every 4 hours; Piracetam: 4.8 g daily	No significant differences in AMS scores or Borg dyspnea scores between transplant patients and controls	All transplant patients reached 4550 m; 83% of transplant patients reached the summit vs. 84% of controls
van Adrichem et al. (2015), Kilimanjaro (5595 m)	Heart: 2; Kidney: 2; Liver: 1; Lung: 4; Small Bowel: 1; Stem Cell: 1	Not specified	6-month program: individually designed program of at least three sessions per week, including strength and endurance training	Acetazolamide: 125 mg twice daily^a	No difference in AMS scores or Borg dyspnea scores between transplant patients and controls	All transplant patients reached 5000 m; 73% of transplant patients reached the summit vs. 93% of controls
Suh et al. (2015), Island Peak (6189 m)	Kidney: 1; Liver: 6	Tacrolimus: 5; Cyclosporine: 2	3-month program: 11 weekend sessions with hiking and climbing as well as personal training during the week	Udenafil 100 mg dailyPiracetam 400 mg three times daily	No difference in AMS scores between transplant patients and controls	All transplant patients reached 5150 m; 29% of transplant patients reached the summit vs. 66% of controls^b

One transplant patient did not take acetazolamide.

Three transplant patients descended due to illness; only two of four healthy transplant patients were selected to go to the summit by trip leaders.

AMS, acute mountain sickness.

While it is difficult to draw firm conclusions from these reports about the outcomes of high-altitude travel following SOT, the data in these reports suggest that the incidence of acute altitude illness is similar between the transplant recipients and nontransplant controls as Lake Louise AMS scores were similar between these two groups in each of the reports, and summit success rates, which provide some information regarding altitude tolerance, were also similar between the SOT recipients and nontransplant controls in the reports by Pirenne et al. (2004) and van Adrichem et al. (2015) (statistical comparisons were not performed in these reports). The transplant recipients did have a lower summit success rate in the report by Suh et al. (2015), but their expedition was on a more technically challenging peak than in the other reports, and the expedition leader selected the individuals who were given a chance to go the summit on the final day of the climb. There is no information in the reports to suggest that transplant recipients are at higher risk of severe altitude illness; no clear cases of HAPE or HACE were documented among the transplant recipients in these reports, although one transplant recipient in the study by Suh et al. (2015) descended due to severe headache, vomiting, and marked hypoxemia.

With regard to other outcomes during the expeditions, there were no significant differences in blood pressure and heart rate responses, as well as oxygen saturation between the SOT recipients and the nontransplant controls with the exception of higher diastolic blood pressures noted in the SOT recipients in the study by Pirenne et al. (2004). Limited information was also provided regarding changes in laboratory parameters. Van Adrichem et al. (2015) noted no difference in capillary blood gas values (pH, PCO₂, PO₂, bicarbonate, and lactate) at 4030 m between the SOT recipients and the nontransplant controls, while Suh et al. (2015) reported that estimated glomerular filtration rates remained above 60 mL/min/1.73 m² without significant changes in immunosuppressive drug concentrations during the ascent. The latter information was not assessed in the other studies.

In considering this information regarding high-altitude tolerance following SOT, it is important to note several features of these reports. First, all of the transplant recipients were a minimum of 12 months out from their transplant with no evidence of either acute or chronic rejection or significant cardiopulmonary limitation. Second, all of the transplant patients completed a training regimen lasting between 3 and 6 months before their expedition and, finally, all subjects were on various forms of pharmacologic prophylaxis against acute altitude illness (Table 1). While the latter information suggests that transplant recipients can tolerate the medications used for altitude illness prophylaxis, the data in these reports neither serve as proof of efficacy or safety in these patients nor do they serve as the basis for a blanket recommendation that all transplant recipients use pharmacologic prophylaxis with ascent to high altitude.

Pretravel Assessment and Counseling

Due to the limited evidence regarding high-altitude travel following organ transplantation and the complicated medical histories of many of these patients, careful pretravel assessment and counseling is warranted before any planned high-altitude travel. One challenge with this is the fact that not all transplant recipients may present for help before their planned sojourn. Boggild et al. (2004), for example, surveyed 267 transplant recipients at a transplant clinic and found that only 66% of those who traveled outside Canada and the United States presented for pretravel advice. For this reason, it may be important to remind transplant recipients during clinic visits early in their posttransplant course of the need to obtain pretravel evaluation when they plan trips in the future.

Pretravel assessment

All transplant recipients should be assessed by their transplant physician to ensure they have normal graft function and no evidence of acute or chronic rejection before the planned trip. Given that the risk of acute rejection for most SOT recipients is highest within the first year following transplant, providers should counsel patients to avoid high-altitude travel for at least 12 months following transplant.

The extent of the suitable pretravel assessment and, in particular, whether to include testing such as exercise testing, echocardiography, or other studies will vary based on the clinical circumstances. Because heart transplant patients are at risk for cardiac allograft vasculopathy (also known as transplant coronary artery disease) after their first year following transplant and these patients do not develop typical signs of angina pectoris due to cardiac denervation, exercise stress testing is indicated to identify silent ischemia (Schmauss and Weis, 2008). Exercise testing should also be strongly considered in patients with comorbid conditions that predispose to coronary artery disease, as would be the case, for example, in a patient who received a kidney transplant for diabetes mellitus or hypertension. Travel should be deferred in patients with evidence of exercise-induced ischemia until further evaluation and management is pursued. Travel should also be deferred in any heart transplant recipient with worsening exercise performance or echocardiographic evidence of declining ventricular function until further evaluation is completed.

If not already performed as part of routine posttransplant care, echocardiography can be considered in heart and lung transplant patients to estimate PA pressure, as those individuals with persistent elevation in PA pressure following transplant may be at risk for complications following ascent when the expected hypoxic pulmonary vasoconstriction causes further increases in PA pressure (Luks, 2009a). Patients who had portopulmonary hypertension before liver transplantation also warrant echocardiography to ensure that their PA pressure has improved since transplant. Patients with mean PA pressure >35 mm Hg or systolic pressure >50 mm Hg should probably avoid travel to altitudes above 2000 m without supplemental oxygen (Luks, 2009a).

Lung transplant patients should also undergo spirometry before high-altitude travel. In the absence of postprocedure complications, bilateral lung transplant patients generally have normalization of pulmonary function by 3–6 months following their procedure, while single lung transplant patients experience incomplete improvement (Kotloff and Keshavjee, 2016). Because there is no clear threshold for the forced expiratory volume in 1 second (FEV₁), below which patients should forego planned high-altitude travel, a prudent approach would be to defer high-altitude travel in any patient who has had a decline in their spirometry relative to their recent baseline, a situation which typically prompts evaluation for rejection and/or infection. Travel should also likely be deferred in patients who have not seen the expected improvement in lung function, who continue to require supplemental oxygen, who have decrements in exercise performance beyond that expected in healthy transplant recipients, or who have evidence of bronchiolitis obliterans syndrome, the manifestation of chronic rejection.

Counseling

Pretravel counseling should focus on several key issues.

Recognizing the normal responses to high altitude

Even if they do not develop acute altitude illness, high-altitude travelers often feel different at high altitude than they do at sea level due to the manifestations of the normal physiologic responses to acute hypoxia described above. These differences should be reviewed as part of pretravel counseling (Table 2), as this will prevent individuals from attributing these differences to acute altitude illness and potentially initiating treatment when, in fact, they are experiencing normal sensations that do not warrant intervention. This will also allow them to better recognize when they or a traveling companion becomes ill.

Table 2.

Changes in How Individuals Feel Following Ascent to High Altitude

Increased heart rate at rest and with exercise

Increased breathing frequency and tidal volume

Breathlessness with exertion that resolves quickly (one-half to 2 minutes) with rest

Increased frequency of urination

Poor sleep (Cheyne stokes respirations, frequent arousals, insomnia, vivid dreams)

Transient lightheadedness upon assuming upright position

Recognition, prevention, and treatment of acute altitude illness

As with any other high-altitude traveler, the SOT recipient traveling to high altitude should be instructed how to recognize, prevent, and treat the three main forms of acute altitude illness, AMS, HACE, and HAPE. The clinical features and management of these entities have been described in depth elsewhere (Bartsch et al., 2003; Hackett and Roach, 2004; Bartsch and Swenson, 2013) and are summarized in Tables 3 and 4.

Table 3.

Clinical Features and Management of Acute High Altitude Illnesses

Acute altitude illness	Clinical features	Prevention	Treatment
AMS	Onset of symptoms within 6–10 hours of ascent Headache plus one or more of the following: nausea, vomiting, lethargy, sustained light-headedness Normal neurologic examination and normal mental status	Slow ascent (above 3000 m), limit increases in sleeping elevation to 500 m/day Avoid overexertion Acetazolamide or dexamethasone with moderate to high-risk ascent profiles	Stop ascending Acetaminophen or NSAIDs for headache; Antiemetics; Acetazolamide or dexamethasone Descend if symptoms do not improve in 1–2 days or worsen on appropriate treatment. Further ascent possible if symptoms resolve.
HACE	Preexisting AMS or HAPE symptoms (not universally present) Ataxia, altered mental status, severe lassitude, somnolence, coma Focal neurologic deficits uncommon Potentially fatal if not recognized and treated promptly	Slow ascent Avoid overexertion Acetazolamide or dexamethasone with moderate to high-risk ascent profiles	Descend until symptoms resolve If descent not possible, supplemental oxygen or a portable hyperbaric chamber Dexamethasone No further ascent until asymptomatic while off treatment medications
HAPE	Onset within 2–5 days of ascent Can occur without preceding AMS symptoms Mild disease: dyspnea out of proportion to that expected among normals at a given elevation; decreased exercise performance, dry cough Severe disease: dyspnea with mild exertion or at rest; cough with pink, frothy sputum; cyanosis May see concurrent signs or symptoms of AMS or HACE Potentially fatal if not recognized promptly	Slow ascent Avoid overexertion Nifedipine or tadalafil for individuals with prior history of HAPE Consider adding salmeterol to pulmonary vasodilator agent	Descend until symptoms resolve; avoid over-exertion on descent If descent not possible, supplemental oxygen or a portable hyperbaric chamber Nifedipine or phosphodiesterase inhibitor (may not be necessary if supplemental oxygen available). Avoid concurrent use of nifedipine and phosphodiesterase inhibitor No further ascent until asymptomatic while off treatment medications

HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema.

Table 4.

Medications Used for Prevention and Treatment of Acute Altitude Illness

Medication	Use	Dosage	Dose adjustment with renal insufficiency
Acetazolamide	AMS prevention	125 or 250 mg every 12 h	Avoid in patients with GFR <10 mL/min
	AMS treatment	250 mg every 12 h
Dexamethasone	AMS prevention	2 mg every 6 h or 4 mg every 12 h	No dose adjustments necessary
	AMS treatment	4 mg every 6 h
	HACE treatment	8 mg once then 4 mg every 6 h
Nifedipine	HAPE prevention and treatment	30 mg sustained release version every 12 h	No dose adjustments necessary
Salmeterol	HAPE prevention	125 μg every 12 h	No dose adjustments necessary
Sildenafil	HAPE prevention and treatment^a	50 mg every 8 h	No dose adjustments necessary
Tadalafil	HAPE prevention and treatment^b	10 mg every 12 h	If GFR 30–50 mL/min, use 5 mg dose, maximum 10 mg in 48 h; If GFR <30 mL/min, no more than 5 mg in 72 h

Clinical studies have not documented a benefit for prevention or treatment of HAPE.

Clinical studies have only shown benefit in prevention of HAPE.

One of the challenges associated with evaluating the ill transplant recipient at high altitude is that some posttransplant complications or issues can mimic the signs of acute altitude illness. For example, headache is the cardinal symptom of AMS, but is also a prominent feature in patients with symptomatic tacrolimus toxicity. Similarly, the onset of dyspnea in a traveler at high altitude always raises suspicion for HAPE, but this symptom may also occur in heart or lung transplant patients manifesting signs of acute rejection or pneumonia. As a result, it is important to maintain a broader differential in ill transplant patients and consider entities besides acute altitude illness.

Providers should stress the role of slow ascent in altitude illness prevention. Once above 3000 m in elevation, travelers should not increase their sleeping elevation by more than 300–500 m/night and should include a rest day every 3–4 days of ascent to aid acclimatization (Luks, 2012, 2014). Given the lack of evidence that organ transplant recipients are at increased risk for acute altitude illness, pharmacologic prophylaxis against these entities should not be routinely used in all cases and, instead, should be used only in moderate to high-risk ascents (Table 5), as is the case for nontransplant recipients (Luks et al., 2014). The selection of particular medications for the prevention or treatment of altitude illness must be made in light of the medications transplant recipients are taking as part of their routine posttransplant care, a topic discussed further below.

Table 5.

Risk Categories for AMS

Risk category	Description
Low	Individuals with no prior history of altitude illness and ascending to ≤2800 m
	Individuals taking ≥2 days to arrive at 2500–3000 m with subsequent increases in sleeping elevation <500 m/day and an extra day for acclimatization every 1000 m
Moderate	Individuals with prior history of AMS and ascending to 2500–2800 m in 1 day
	No history of AMS and ascending to >2800 m in 1 day
	All individuals ascending >500 m/day (increase in sleeping elevation) at altitudes above 3000 m, but with an extra day for acclimatization every 1000 m
High	Individuals with a history of AMS and ascending to >2800 m in 1 day
	All individuals with a prior history of HACE or HAPE
	All individuals ascending to >3500 m in 1 day
	All individuals ascending >500 m/day (increase in sleeping elevation) above >3000 m without extra days for acclimatization
	Very rapid ascents (e.g., <7 day ascents of Mt. Kilimanjaro)

Altitudes listed in the table refer to the altitude at which the person sleeps. Ascent is assumed to start from elevations <1200 m. The risk categories described above pertain to unacclimatized individuals.

Originally published in Luks et al. (2014).

While descent is the best treatment for all forms of acute altitude illness, most cases of mild-moderate AMS can be treated without descent. Because of the high risk of infection in transplant recipients and the risk of other transplant-related complications, the threshold for descending to lower elevation and/or accessing formal medical care should be lower in the transplant recipient than in the nontransplant traveler.

Infection prevention

While much of the attention with high-altitude travel focuses on avoiding and treating acute altitude illness, it is important to remember that infection is another highly common problem when traveling in this environment, particularly in low-income countries; Murdoch (1995), for example, studied 283 trekkers in Nepal and found that 87% reported at least one symptom of infection such as coryza, sore throat, and diarrhea, while others studies have documented incidence rates for traveler's diarrhea between 10% and 100% in various low-income regions of the world (Steffen, 2005). Given that SOT recipients are, as a rule, taking immunosuppressive medications to prevent organ rejection, the risk of infection may be particularly high in their case. It should also be noted that the risk of infection is not limited to travel in low-income areas, as itineraries on high-altitude trips in any region of the world often being in close proximity to other individuals who may be ill through, for example, travel on airplanes, buses, or trains and dining and lodging arrangements on the trip itself.

For this reason, all SOT recipients traveling to high altitude should be counseled regarding infection prevention and treatment. They should receive instructions regarding hand and food hygiene (Table 6) and be vaccinated according to published guidelines (wwwnc.cdc.gov/travel) and, where appropriate, use malaria prophylaxis. They should also travel with medications for traveler's diarrhea and other common infections and clear instructions on how to respond to such contingencies. Due to the broader differential diagnosis for infectious symptoms and signs and consequences of infection in this patient population, the threshold for descending and accessing further medical care should be low. Further information on managing infectious risks can be found in several reviews of this topic, Askling and Dalm (2014); Kotton et al. (2005); and McCarthy and Mileno (2006), as well as on the traveler's health website for the Centers for Disease Control and Prevention (CDC; wwwnc.cdc.gov/travel/), which includes information specific for immune-suppressed travelers.

Table 6.

Hygiene Measures

Use boiled or bottled water and other beverages

Avoid ice in beverages

Do not share drinks with travel partners

Liberal use of hand sanitizer, particularly before meals

Avoid uncooked meats and vegetables

Avoid food sold by street vendors

Avoid fruits that cannot be peeled

Sun exposure

As noted above, UV light exposure increases significantly at high altitude particularly when traveling on snow-covered terrain, which reflects far more UV radiation than grass-covered terrain (Buettner, 1969; West et al., 2013). Because the risk of squamous cell carcinoma and basal cell carcinoma are increased 65- and 10-fold, respectively, in SOT recipients (Ingvar et al., 2010; Zwald and Brown, 2011) and risk is a function of UV exposure (Mudigonda et al., 2013), all transplant recipients traveling to high altitude must take appropriate precautions against the sun. This includes covering as much skin as possible while outside, wearing wide-brimmed hats, liberal and frequent application of sunscreen on exposed skin, and use of eye protection with side shields.

Exercise and other training

Because of the difficulties with physical exertion at high altitude, individuals not already engaged in a vigorous exercise program should participate in a 3–6 month training program focused on endurance activities before their sojourn. There is no particular regimen that has been proven superior to others for this purpose.

SOT recipients who have never been to high altitude before may benefit from other trips to the mountains before the planned excursion that are of shorter duration and have rapid descent options. This will give them a sense of how they feel and perform in this environment and the ability to descend and access care quickly if they have problems. Interest has been raised in using various preacclimatization strategies to decrease the risk of altitude illness following ascent (Muza et al., 2010), but the optimal strategy for such approaches is not clear (Luks et al., 2014).

Other Aspects of Trip Preparation

If they become ill while traveling, one challenge SOT recipients may face is that medical providers they encounter may not be familiar with transplant-related issues or have access to certain medications or laboratory tests such as tacrolimus level assays. For these reasons, transplant recipients should travel with an adequate supply of medications and strongly consider traveling with a back-up supply that they keep apart from their main supply in the event of baggage loss. They should also travel with contact information for their transplant physician, a thorough list of their medications, and, in the case of heart transplant patients, a copy of their most recent electrocardiogram. Travelers should identify the closest medical facilities to their planned destination that might be able to address transplant-related issues. Finally, all travelers should purchase traveler's insurance, as this will greatly facilitate evacuation to definitive care in the event of severe illness or injury.

Medication Issues During High-Altitude Travel

As indicated above, slowing the rate of ascent is the most appropriate strategy to prevent acute altitude illness, while conservative measures, including rest, rehydration, and symptomatic treatment, may be all that is needed to treat mild AMS (Luks et al., 2014). In some circumstances, however, pharmacologic prophylaxis may be indicated or individuals may require treatment for severe AMS, HACE, or HAPE. When considering the appropriate medications for these purposes, it is important to remember that organ transplant recipients are generally taking multiple medications to prevent graft rejection and opportunistic infections. As a result, it is necessary to consider the risk of drug interactions that may affect the pharmacokinetics and pharmacodynamics of either the altitude illness medications or the transplant medications. The reported interactions between the medications used for altitude illness prophylaxis on the one hand and standard immunosuppressive medications and medications used for opportunistic infection prophylaxis on the other are listed in Tables 7 and 8, respectively. Even though ginkgo biloba is not part of standard protocols for AMS prophylaxis or treatment (Luks et al., 2014), it has been included in these tables due to anecdotal reports of its use among travelers at high altitude. The fact that there are no apparent interactions between this herbal supplement and medications used for immunosuppression and opportunistic infection prophylaxis should in no way be viewed as an indication to use this medication for altitude illness prophylaxis in SOT recipients traveling at high altitude.

Table 7.

Interactions Between Medications Used For Immunosuppression and Altitude Illness Prevention or Treatment

	Immunosuppressive medication
Altitude illness medication	Cyclosporine	Tacrolimus	Mycophenolate mofetil	Azathioprine
Acetazolamide	Increased cyclosporine concentration¹	None	None	None
Dexamethasone	None^a	Decreased tacrolimus concentration²	None	None
Nifedipine	None^b	Increased tacrolimus concentration³	None	None
Sildenafil	None	None	None	None
Tadalafil	None	None	None	None
Salmeterol	None	None	None	None
Gingko Biloba⁴	None	None	None	None

Sources:

University of Maryland Medical Center Drug Interaction Tool: http://umm.edu/health/medical/drug-interaction-tool

Micromedex Solutions Interaction Tool:

www.micromedexsolutions.com/micromedex2/librarian

Citations:

Tabbara et al. (1998).

Anglicheau et al. (2003).

Seifeldin et al. (1997).

Izzo and Ernst (2009).

Despite reported interactions with other corticosteroids, there is no reported interaction between dexamethasone and cyclosporine.

Despite reported interactions with other calcium channel blockers, there is no reported interaction between nifedipine and cyclosporine.

Table 8.

Interactions Between Medications Used For Opportunistic Infection Prophylaxis and Altitude Illness Prevention or Treatment

	Opportunistic infection prophylaxis medication
Altitude illness medication	Trimethoprim sulfamethoxazole	Acyclovir	Ganciclovir	Valacyclovir	Fluconazole	Itraconazole	Voriconazole	Caspofungin
Acetazolamide	None	None	None	None	None	None	None	None
Dexamethasone	None	None	None	None	Increased concentration of dexamethasone¹	None	None	Decreased concentration of caspofungin²
Nifedipine	None	None	None	None	None	None	None	None
Sildenafil	None	None	None	None	Increased concentration of sildenafil	Increased concentration of sildenafil³	Increased concentration of sildenafil	None
Tadalafil	None	None	None	None	None	Increased concentration of tadalafil	None	None
Salmeterol	None	None	None	None	Increased risk of QT prolongation	Increased concentration of salmeterol	Increased concentration of salmeterol	None
Ginkgo biloba⁴	None	None	None	None	None	None	None	None

Sources:

University of Maryland Medical Center Drug Interaction Tool: http://umm.edu/health/medical/drug-interaction-tool

Micromedex Solutions Interaction Tool:

www.micromedexsolutions.com/micromedex2/librarian

Citations:

Varis et al. (2000).

Chen et al. (2011).

Dresser et al. (2000).

Izzo and Ernst (2009).

In considering the information in Tables 7 and 8, it should be noted that while cyclosporine has reported interactions with the calcium channel blockers amlodipine, diltiazem, nicardipine, and verapamil, there are no reported interactions in adults with nifedipine (McNally et al., 1989). Similarly, there are no interactions between dexamethasone and cyclosporine despite reported interactions between the latter and other corticosteroids.

Because the specific medication regimen will vary from individual to individual depending on the type of transplant, the time elapsed since transplant, and other factors, a detailed review of the medication list should be undertaken before any high-altitude travel to identify a safe regimen of altitude illness medications to use if either pharmacologic prophylaxis or treatment is indicated.

Another important consideration beyond the potential for drug interactions is the state of the patient's renal function (Luks and Swenson, 2008). Many renal transplant recipients have reduced glomerular filtration rate more than 12 months out following their transplant (Gill et al., 2003; Marcen et al., 2010), while other SOT patients may have had impaired renal function before transplant that has not normalized in the posttransplant period. Dose adjustments for the altitude illness medications in renal insufficiency are described in Table 4.

A final issue to consider in SOT recipients is whether the metabolism of immunosuppressive medications is altered by acute hypoxia. Among the commonly used medications, cyclosporine and tacrolimus are metabolized in the liver through the CYP3A pathway, which does not appear to be affected by hypoxia (Jurgens et al., 2002; Streit et al., 2005), while mycophenolate and azathioprine are conjugated to glucuronides through a hepatic pathway that also does not appear to be affected at altitudes as high as 4550 m (Berendsohn, 1962). When viewed in conjunction with the data noted above by Suh et al. (2015) that drug concentrations were unchanged in transplant recipients climbing Island Peak, this information suggests dose adjustments are not necessary around the time of ascent. Given the limited nature of the data on this issue, however, medication toxicity should always remain on the differential of SOT patients who become ill at a high altitude.

Summary

While there is limited information in the literature about the risks of high-altitude travel in SOT recipients, the available evidence suggests that these individuals have physiologic responses to hypobaric hypoxia comparable to those seen in nontransplanted individuals and well selected transplant recipients can tolerate ascents to as high as 5500–6200 m. All transplant recipients planning high-altitude travel should undergo careful pretravel assessment and counseling with the latter emphasizing not only the recognition, prevention, and treatment of altitude illness but also the importance of preventing and recognizing infection and limiting sun exposure. Travel should be deferred in any patients manifesting symptoms, signs, or other evidence suggestive of acute rejection until further evaluation is completed. Medication can be used for altitude illness prophylaxis and treatment, but the choice and dose of medication should take into account the patient's preexisting medication regimen and current renal function. Patients should travel with a full supply of medications and useful medical information, including their medication list and contact information for their transplant physician.

Footnotes

Disclosure and Funding

No competing financial interests exist to report regarding the material presented in this article. There was no funding from outside sources or foundations for this work.

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