The subject of altitude and the athlete is gaining greater relevance because of the increasing number of both competitive and recreational athletes participating in the wide range of sport within this particular environment. Additionally, it is not uncommon for athletes to utilize altitude/hypoxia training for the purpose of improving fitness and performance. Altitude does, however, pose serious health risks to the athlete, significantly so in the form of high-altitude illness (HAI).
HAI includes three specific syndromes that occur in the setting of acute exposure to altitude: acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) (4,7). The incidence and severity of HAI generally increases as the altitudes reached and ascent rates increase (4,20).
THE EFFECTS OF HIGH ALTITUDE
Any elevation greater than 1500 m (4921 ft) is considered to be high altitude; ``very high altitude'' is defined as 3500-5500 m (11,483-18,045 ft), and ``extreme altitude'' is 5500-8850 m (18,045-29,035 ft)(3). The exponential drop of barometric pressure with increasing altitude accordingly causes a steep drop in the partial pressure of oxygen (PO2), thus creating a hypobaric hypoxic environment. The effect of hypobaric hypoxia at altitude is illustrated by considering a skier at a resort in Colorado at 3500 m where the approximate barometric pressure of 506 mm Hg and a PO2 of 106 mm; the skier's partial pressure of arterial oxygen (PaO2) at this altitude would range between 50 and 60 mm Hg (2).
The body works to protect itself when exposed to this hypoxic environment through a process of complex physiological adjustments collectively termed acclimatization. The first adjustments, which occur within minutes of hypoxia exposure, include an increase in ventilation (the hypoxic ventilatory response [HVR]) and catecholamine-mediated increases in heart rate and cardiac output. These immediate changes can partially compensate for decreased PaO2 and suboptimal tissue oxygenation. Referring back to the previous example, as the skier's HVR response increases respiration from 14 breaths per minute to 20 per minute, the PaO2 would increase from 48 mm Hg to 61 mm Hg (2). Increased ventilation and expired additional CO2 spurred by the HVR also will cause a respiratory alkalosis, which by itself, should inhibit respiratory drive. However, ventilatory response at altitude is maintained, perhaps because of the circulation pH stabilizing effect of increased bicarbonate excretion through the kidneys (4,20).
Further acclimatization involves pulmonary, hematologic, and possible tissue adaptations. A hypoxic pulmonary vasoconstrictor response (HPVR) occurs that may function to improve ventilation-perfusion matching at the alveolar level but also may cause pulmonary hypertension, which is a primary contributing factor behind the development of HAPE. Over a period of days to weeks, however, pulmonary arterioles exposed to elevated pressure will respond with intimal smooth muscle remodeling that serves to protect capillaries from damage and ensuing alveolar edema (4,14,16). The kidneys respond to hypoxia by increasing secretion of erythropoietin, which accounts for a gain in red blood cell mass over a period of weeks given continued exposure to the hypoxic environment (4,7). Further adaptations of acclimatization that also may occur at the tissue level to facilitate the utilization and/or delivery of O2 to muscle include increases in mitochondrial density, capillary-to-fiber ratio, fiber crosssectional area, and myoglobin concentration (4,30,32). Cerebral circulation exhibits increased flow due to hypoxia-induced cerebral vasodilation, although the overall effect of this is tempered by hypocapnia caused by hyperventilation (4,35).
The time needed for adequate acclimatization to a high-altitude environment varies significantly among individuals but usually happens over several days, with more time needed for additional gains in elevation. Over time, the body is capable of acclimatizing to altitudes reaching 5500 m (4). Rapid exposure or ascent to the hypobaric, hypoxic, high-altitude environment without allowing for acclimatization greatly increases risk for HAI syndromes.
Although this article focuses primarily on HAI, several other hazards are relevant to the athlete at high altitude. Lower temperatures at high altitude increase chances for cold injuries, including both frostbite and hypothermia. Several eye conditions may develop at high altitude, such as ultraviolet photokeratitis, retinopathy, ocular palsy, cortical blindness, and refractive changes (7). Eye symptoms range from mild to severe depending on the ophthalmologic condition. Dehydration occurs easily at altitude because of increased insensible losses from the dry air and from increased metabolic/respiratory demands. Disordered sleep and depressed immune function (cell mediated) are potential problems from altitude exposure that may depress constitutional status and elevate the chance for infection (7,31). Finally, the risk of a thrombotic event (venous thrombosis, embolus) may be elevated because of the combined effects of dehydration, cold, polycythemia, and peripheral edema (7,24).
The diagnostic criteria for the HAI syndromes along with treatment and preventive strategies are detailed here and summarized in the Table.
Altitude and ascent rate are the predominant extrinsic risk factors associated with HAI. Up to 25% of tourist visitors may report symptoms of AMS at elevations of 2500 m (8202 ft); for climbers, trekkers, and military personnel at very high altitude (3500-5500 m), incidence may range from 25% to 67% (4). Although HACE and HAPE have lower incidence compared with AMS, they will occur more frequently as elevations increase (4,14,17,32). Numerous reports detail that incidence of all HAI syndromes increases dramatically when ascent to altitude occurs on a rapid basis (several hours to fewer than 3 d) (4,10,14,29). It is important to remember that weather and temperature can affect barometric pressure and thereby alter the relative altitude and PO2.
HAI does not affect individuals uniformly. Although the exact cause for this has not been conclusively identified, a genetic role affecting HAI susceptibility is very likely (4,17,22). A personal history of HAI is an important intrinsic risk highlighting a persons susceptibility and is the best predictor for future recurrence. There is no established risk for HAI based on gender alone (4,9). Those over the age of 50 yr appear to develop AMS less frequently compared with younger adults and children; additionally, children show higher susceptibility for and severity of HAPE (4,9,18). Even though a higher physical fitness level elevates the ability to perform exercise/activity at altitude, it is not protective against HAI. In fact, exertion or vigorous activity at altitude actually increases risk for HAI (4,8,19). Limited evidence points to obesity as a possible risk factor for developing AMS (5,6). Medications and ingested substances (such as opiates, sedatives, and alcohol) that cause ventilatory depression also increase risk (4). Finally, chronic medical conditions that result in pulmonary hypertension or injury/destruction of carotid bodies response predispose individuals to higher risk for HAI (4).
The pathophysiologic basis for HAI syndromes has not yet been definitively established; however, current evidence and understanding points to a process involving increased capillary leak/permeability at the blood-brain barrier (for AMS/HACE) and/or the alveolar-capillary barrier (for HAPE) as a probable mechanism. These changes in capillary permeability are thought to be caused by hypoxia-induced effects to vascular flow and subsequent elevations in hydrostatic pressure, along with the activation of biochemical factors that affect endothelial cell function (4,7,8,14). The symptoms of HAI syndromes presumably start to occur when the body fails to compensate for the edema that occurs in the brain or lungs as a result of the changes (4,7).
By far, AMS is the most common presenting HAI syndrome, with previously noted incidence ranging from 25% to 67%; fortunately, it is the most benign of the syndromes as well (4,7). Defining features of AMS include headache in the setting of recent arrival to high altitude with one or more of the following symptoms: anorexia, nausea, vomiting; fatigue or weakness; dizziness or lightheadedness; and difficulty sleeping (28). Validated clinical tools based on symptom scoring can be used to assist with diagnosis and determine the severity of AMS (i.e., Lake Louise Score) (1). Symptoms of AMS start very soon (typically within 6-10 h) after ascent to altitude (generally higher than 2500 m); incidence and severity correlate highly with rate of ascent and altitude achieved (4,7,8). For most individuals experiencing AMS, symptoms will abate within 3 d at a given altitude (8,17). Continued ascent and exertion can prolong or worsen AMS (7).
Symptoms of AMS overlap significantly with a variety of other conditions that should be considered in the differential diagnosis. High-altitude headache occurs with the absence of the other features associated with AMS, usually in persons who rapidly ascend above 3000 m. Viral illness, dehydration, exhaustion, hypothermia, carbon monoxide exposure, migraine, alcohol hangover, and medication effects are other conditions that may mimic AMS (4,7). Importantly, AMS is not characterized or diagnosed by physical findings. An individual with AMS who begins to exhibit changes in neurologic function (ataxia and/or altered mental status) should be considered as progressing to the more severe neurologic syndrome of HACE.
Treatment for mild AMS consists of stopping ascent and allowing for acclimatization. Rest and hydration also should be encouraged as initial treatments. Immediate descent of 500 m or more accomplishes a more rapid resolution of symptoms. Acetazolamide (125-250 mg PO bid) is a treatment option for AMS; its action as a carbonic anhydrase inhibitor causes a bicarbonate diuresis and metabolic acidosis, thus stimulating a compensatory hyperventilation, which improves oxygenation and aids acclimatization (4,7,13,20,32). Moderate, protracted, or worsening AMS makes a compelling argument for descent and use of supplemental oxygen therapy (1-2 L·min−1) if available (4,32). Portable hyperbaric chambers with a pressure of 2 psi simulate a descent of approximately 2000 m and can be used for a few hours as a treatment modality when descent is delayed or protracted (4,7,8). Additionally, dexamethasone (4 mg q 6 h PO/IM/IV) offers benefit in relieving symptoms, but it is accompanied with risks of hyperglycemia and rebound sickness once stopped (4,7,13,20,32).
Treatment of AMS must take into account the setting, logistics, and overall event/activity plans. Managing AMS in an environment with limited medical resources/facilities during an event (trek, hike, climb) that will require further ascent over a number of days may differ significantly from a single-day event that has ready availability of medical resources. Close monitoring of individuals with AMS in any setting is warranted as progression to HACE is possible.
HACE represents a serious, possibly fatal HAI syndrome. HACE occurs on a more infrequent basis, with generally fewer than 1% of visitors to altitude affected, but it is highly associated with and occurs more commonly in those affected by AMS (3.4%) and/or HAPE (13%-20%) (4,7,20). Pathophysiologically, it is considered to be the severe form or endstage of AMS. The hallmark features of HACE are ataxia and altered consciousness (confusion, irrational behavior, lethargy, impaired cognition, stupor, and coma) (4,7,20). Additional symptoms and physical signs may include those associated with AMS (e.g., headache, gastrointestinal disturbance, and fatigue), papilledema, retinal hemorrhage, and focal neurologic deficits (4,7,35). Usually, HACE occurs at very high or extreme altitudes, but it has been identified at lower elevations (<3000 m), as well, so it should be considered a possibility in anyone experiencing AMS symptoms, no matter the altitude (7). The onset of HACE diagnostic features generally occurs several days after arriving to altitude but may be accelerated to a period of hours in certain individuals (4,20). In fatal cases, the cause of death is brain herniation from unchecked cerebral edema (4,7,35).
Other neurologic conditions unrelated to cerebral edema or AMS that also occur at high altitude should be considered. These include, but are not limited to, migraine, transient ischemic attack, stroke, cerebral venous thrombosis, cranial nerve palsies, ophthalmological disturbances (cortical blindness, retinal hemorrhage), cognitive slowing, and emotional liability (35). Given the potentially deadly consequences, it is prudent to preferentially consider HACE as a primary diagnosis in any individual experiencing neurological abnormalities after ascending to altitude.
Proper treatment of HACE is immediate descent and use of supplemental oxygen at the highest flow rate to maintain SaO2 ≥ 90% (4,7). Administration of dexamethasone (4-8 mg IV/IM/PO initially, followed by 4 mg every 6 h) also is indicated and particularly important to have available if rapid descent is not logistically possible (4,13,20). Hyperbaric therapy with portable chambers should be used if descent/evacuation is delayed. Early intervention (before serious neurologic sequelae/unconsciousness) with descent, oxygen, and steroids is the best way to ensure full recovery from the effects of HACE (7,20). Full recovery takes several weeks for most, and some individuals may suffer permanent damage or impairment (4,7,36).
Although significantly less common than AMS (<1% of general visitors to altitude), HAPE causes the most deaths of the HAI syndromes (4,7,14). By Lake Louise criteria, the diagnosis of HAPE can be made when an individual, in the setting of recent altitude gain, has at least two symptoms and two physical signs related to respiratory status (Table) (28). Early clues of cough and decreased exercise performance often are minimized by affected individuals but should heighten suspicion for HAPE. This syndrome rarely occurs below 2400 m, but the incidence increases significantly, with reports from 4% to 15%, at very high and extreme altitudes, along with rapidity of ascent (>600 m·d−1) (4,14,20). Individual susceptibility, cold, and continued vigorous exertion are additional important factors that speed the progression of HAPE (4,7,14,17). Similar to HACE, presentation usually takes several days (1-3) after arriving at altitude; it is not uncommon for symptoms to initially present or become more apparent at night because of worsening hypoxia associated with periodic breathing during sleep (4,7,20). Nearly half of those who develop HAPE also will have AMS, which highlights the considerable overlap in individual susceptibility between the neurologic and pulmonary HAI syndromes (8,20).
The pathophysiology of the pulmonary edema in HAPE is noncardiogenic resulting from pulmonary hypertension, elevated alveolar capillary pressure, and ultimately capillary leak and alveolar edema (14,17,20). Chest radiographs reveal patchy infiltrates, more often right-sided, normal cardiac size but prominent pulmonary arteries. Severe hypoxemia may be present on arterial blood gas analysis (20,24). Increasing dyspnea, weakness, congested/wet cough, rales, cyanotic nail beds, tachycardia, ataxia, and altered consciousness are all signs and symptoms of worsening condition. Pneumonia, bronchitis, pulmonary embolism/infarct, myocardial infarct, or heart failure with pulmonary edema should be considered in the differential diagnosis (7).
Individuals with underlying cardiorespiratory disease to include pulmonary hypertension, coronary artery disease, congestive heart failure, and chronic obstructive pulmonary disease may be at higher risk for HAPE and other HAI syndromes (7,21). Optimal medical control of the cardiorespiratory disease and limiting altitude exposure both in duration and severity are the best recommendations to avoid exacerbation of said condition or occurrence of HAI. Interestingly, current evidence does not show any increased risk of developing HAI (specifically HAPE) for those individuals with asthma; again, the best recommendation to avoid asthma exacerbation at altitude is close monitoring and control of the condition (7,21).
The definitive treatment for HAPE is to improve oxygenation with descent to lower altitude and/or use of supplemental oxygen to maintain SaO2 ≥ 90% (4,17,20). Mild cases may be managed with oxygen supplementation alone and rest (4,7,20). Minimizing any exertion and maintaining warmth are important in treatment; physical exertion and cold exacerbate pulmonary hypertension and can worsen the process (4,7,20). In circumstances where descent is delayed or impractical, portable hyperbaric treatment (2-4 PSI continuously) can be an effective treatment and help with conservation of oxygen supplies (4). Other therapies that may help while waiting for definitive treatment are nifedipine (by blunting pulmonary vasoconstriction at 20-30 mg extended release q 12 h), inhaled salmeterol, and expiratory positive airway pressure masks (4,13,20). With early recognition and appropriate treatment clinical recovery can be fairly rapid (within 2 to 3 days), but return to full activity should be gradual and not start until symptoms are completely resolved and the patient demonstrates room air SaO2 ≥ 90% (2,20). Dexamethasone is not useful as a treatment for HAPE, although it is being studied for potential benefit as a preventive agent in HAPE-susceptible individuals (4,13,14,15).
PREVENTION AND RETURN-TO-PLAY STRATEGIES
Prevention concepts for AMS, HACE, and HAPE primarily focus on mitigating modifiable risk factors and use of prophylactic medications. An additional area of interest regarding prevention deals with identification of individual susceptibility to HAI.
Allowing for acclimatization to occur with graded ascent to altitude (rest day every 600-1200 m) along with gradual ascent rate (600 m·d−1 maximum) is the most widely advocated method for preventing HAI (4,7,8,21). Preacclimatization can be accomplished by living above 900 m and is associated with lowering the incidence and severity of HAI (4). Overexertion upon arrival to altitude or during acclimatization increases risk of HAI and thus should be avoided (8,21). The adage of ``climb high, sleep low'' emphasizes another preventive practice to reduce hypoxia exposure that can worsen during sleep at altitude due to nocturnal periodic breathing (17,21). Alcohol and other sedative medications may decrease ventilation and should be avoided as a standard prevention measure as well (4).
Medication prophylaxis is indicated for rapid ascent (1 d or less) to altitudes greater than 3000 m, rapid increases in sleep altitude, and for those with a history of previous HAI (7,8,21). Acetazolamide (125-250 mg bid) 12-24 h before ascent and 2-4 d after arrival to maximum altitude is effective for prevention of AMS and HACE (7,13,21). Dexamethasone (2 mg q 6 h or 4 mg q 12 h) can be used in combination or as an alternative for those intolerant of acetazolamide as prophylaxis for AMS and HACE, but its mechanism of action does not aid acclimatization, so stopping the medication after ascent can lead to rebound symptoms (13,21). The use of Ginkgo biloba has been studied as a possible preventive agent for AMS with inconsistent results; this is likely from the lack of standardization between preparations and dosing strategies (7). For those susceptible to HAPE (prior history), nifedipine (20-30 mg extended release q 12 h) has been found useful. Salmeterol (125 mcg bid inhaler) and phosphodiesterase inhibitor tadalafil (10 mg bid) also have been shown to be effective preventive agents in HAPE-susceptible persons and can be used as adjuvant to nifedipine (13,15,23). Preliminary studies indicate that acetazolamide and dexamethasone (in similar doses as used for AMS/HACE) also may be prophylactic for HAPE (13,15,20).
The variable nature in which HAI affects individuals brings to light the importance of identifying those with an inherent susceptibility or predisposition, preferably before they would ever experience an HAI syndrome. An adequate screening test or tool, aside from exposure to altitude, has yet to be discovered, but research is ongoing. An interesting study by Tannheimer and associates revealed that a measure of the lowest SaO2 during a run test at high altitude combined with the time needed to complete the run predicted risk for development of AMS in a group of acclimatized male soldiers (27). A simple performance test and physiologic measure such as this would be an ideal tool for risk stratification and tailoring of acclimatization protocols.
If return to play at altitude immediately after an HAI is deemed necessary, it should be done cautiously and, if possible, with the use of the previously outlined preventive measures. Little evidence is present to guide team physicians; clinical judgment is paramount. In general, an athlete should be completely recovered from the HAI before further participation at altitude is allowed. This is absolutely necessary in HAPE and HACE, given the potential for death in these conditions if not properly treated. Full recovery from moderate AMS also is advised because further participation before full recovery risks progression to HACE. There is anecdotal evidence of continued participation in athletes with mild untreated AMS, but reduced performance has been reported (26).
After recovery from HAI, if the activity involves continued ascent, then further acclimatization and adherence to conservative ascent guidelines (less than 600 m·d−1 and rest every 2 d) are strongly recommended. This was effective in one case series to prevent recurrent HAPE in three mountaineers (12). If further acclimatization or graded ascent are not possible, then the athlete should be counseled about the risk of recurrence, and use of prophylactic medication should be strongly considered (acetazolamide or dexamethasone for AMS; nifedipine, salmeterol, or tadalafil for HAPE). Recovery from HACE is highly variable, ranging from a few days to 12 wk, so immediate return usually is not possible nor advisable (36).
Altitude for Athletic Training
It is reasonable to conclude that the unacclimatized athlete will be physiologically disadvantaged when competing against the acclimatized athlete at a given high-altitude venue. The adaptive process of acclimatization provides for improved aerobic capacity at altitude, which is critical for optimal athletic performance. Increase in serum erythropoietin and corresponding red blood cell mass has been theorized to be the key acclimatization response that enhances both V˙O2max and performance (33,34). However, study results to support this are variable and inconclusive. In fact, several nonhematologic mechanisms/physiologic responses to hypoxia may play equal or more significant roles, including improved mitochondrial function and efficiency, augmented skeletal muscle capillary-to-fiber ratio, muscle pH regulation, and central factors (cerebral hypoxia) regulating exertion (25,33,34).
Making use of the physiologic effects of acclimatization to the hypoxic environment on performance for both altitude and sea-level competition is the driving reason behind the utilization of altitude training among athletes. Three altitude training models that have been described, studied, and commonly practiced among elite athletes include live high + train high (LH+TH), live high + train low (LH+TL), and live low + train high (LL+TH) (33).
Interestingly, investigation of the LH+TH training model has been mixed, some showing improved V˙O2max and performance but others showing the inability of endurance athletes to achieve an equivalent training intensity at altitude as they would at sea-level and actually exhibiting declines in performance evidenced by time trial measures (1,33). Limitations on the intensity of training with the LH+TH method may result from both tissue hypoxia and a centrally induced reduction in exercise effort (3,25,34). The structure of the LH+TL model addresses the training intensity limitation seen with LH+TH while still achieving beneficial effects of acclimatization (11). As with LH+TH, there is conflicting evidence for this method, with some studies showing benefit across various outcomes (athletic performance, serum erythropoietin levels, V˙O2max), while other studies show no significant difference compared with control subjects (33). As an alternative to actually living in a terrestrial high altitude, artificially created hypoxic environments accomplished via nitrogen dilution apartments, oxygen filtration apartments/tents, or training at altitude with the use of supplemental oxygen also have been used as methods within the LH+TL training model (33). Although overall analysis of the evidence for LH+TL strategies show variable results, the trend toward small improvements in athletic performance have led to this model being adopted by numerous athletes/team training programs (33).
The LL+TH approach of altitude/hypoxic training differs considerably from the other two models in that the altitude/hypoxia exposure are in smaller, more discrete time periods. For this method, the altitude/hypoxia exposure may be used either during a resting state (intermittent hypoxic exposure [IHE]) or with exercise training (intermittent hypoxic training [IHT]). IHE and IHT are limited to fairly short time intervals (<180 min), and the hypoxic environment can be either terrestrial or artificial (through nitrogen dilution or oxygen filtration). Current evidence showing this method as a means to enhance overall performance or erythropoesis also is limited, but it does seem to be effective for preacclimatization purposes prior to competition/participation in events at altitude (33).
The optimal altitude/training strategy as a means to improve athletic performance at sea level and at altitude has yet to be fully determined. Of note, the World Anti-Doping Agency has brought the ethical issues surrounding the use of simulated altitude techniques by athletes for training purposes under closer scrutiny but as of yet has not prohibited their use (33). Given the lack of conclusive evidence for altitude training and the individual variability of effect, the best recommendation for competing/participating in the high-altitude environment is to allow for adequate acclimatization over a period of weeks (25). In acclimatizing to the altitude environment, the athlete also should take prudent preventative actions against the risk of HAI as described previously.
As athletic and recreational events taking place in high-altitude environments increase in both number and participation, increasing attention should be given to the potential hazards posed to athletes within this environment. AMS, HACE, and HAPE comprise the key HAI syndromes of particular importance because of both their common occurrence (in the case of AMS) and their potential for serious harm (in the cases of HACE and HAPE). Physicians managing the care of athletes in high-altitude venues need to be aware of and use the effective treatment and preventive strategies for the HAI syndromes described in this article. Allowing for the physiologic adaptations of acclimatization to occur through graded and gradual ascent to high altitude is the best strategy for safe participation at altitude. The cornerstone of treatment for all HAI is improvement in oxygenation, through rest and acclimatization in mild AMS, and through rapid descent and oxygen administration in more severe circumstances of HACE and HAPE.
Several athletic training models incorporating altitude or artificially induced hypoxic environments are being used by contemporary athletes as a means to improve performance because of the presumed advantageous physiologic changes that occur with acclimatization. Evidence supporting performance benefit from any of these models (LH+TH, LH+TL, or LL+TH) is limited and inconclusive at this time. Prudent training advice for the athlete competing at altitude is to plan and allow for full acclimatization before the event through both exposure and practice within the altitude setting.
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