Altitude illness is a broad category of disease encompassing acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) that can affect susceptible persons who travel to elevations greater than 8,200 ft (2,500 m) without adequate acclimatization. Despite extensive research for more than half a century, a thorough understanding of the mechanisms of these diseases and efforts to identify “susceptible persons” before exposure to altitude have remained elusive. Recent improvements in imaging technology and our understanding of genetic contributions have advanced our understanding of the molecular mechanisms underlying these complex disease processes. These advances have challenged long-held theories regarding the underlying pathology of altitude illness and have opened new avenues of research into treatment and prevention. We aim to review current guidelines as well as to provide updates to the understanding of the genetic predisposition, pathophysiology, prevention, and treatment based on recent research.
A consensus definition (22) for altitude illness, commonly referred to as the Lake Louise Criteria (Table 1), and various diagnostic tools exist to aid clinicians and travelers in the diagnosis of altitude illness because early recognition is essential to prevent further injury (30) and begin treatment. The early signs and symptoms can be subtle and nonspecific and are often confused with or attributed to flu-like illness, alcohol hangover, dehydration, fatigue, or hypothermia. Clinicians must keep altitude illness at the forefront of diagnostic possibilities and educate patients before travel on the signs and symptoms when discussing effective preventive strategies.
Incidence and Risk
AMS is the most common form of high-altitude illness, affecting approximately 25% of travelers at moderate altitude and 50% to 85% of travelers >4,000 m (17,20,28,32,40). HACE and HAPE are much less common (0.1% to 4%), albeit more severe, and are typically not observed below 4,000 m elevation (28).
The major risk factors (17,28,40) for the development of altitude illness include rapid ascent, poor acclimatization (e.g., no recent exposure to elevation >1,200 m), physical exertion at altitude, young age, and history of prior altitude illness (Table 2). An individual’s level of aerobic fitness does not confer a protective benefit for developing altitude illness, although obesity and existing lung disease both increase risk. It is clear that individuals who experience altitude illness are at greater risk than the general population of developing altitude illness on subsequent exposure. This predilection suggests an innate or genetic predisposition; however, despite extensive research into more than 50 proposed genes, no clear link has been identified. The data point toward multiple genes, but the degree of association remains small and outweighed by the effect of environmental exposures. The interested reader is directed to an excellent review (31) for a comprehensive analysis of the subject.
Acclimatization is a process of physiologic adaptations that offset hypoxemia and maintain consistent oxygen delivery to tissue. Recent research (49) has demonstrated that there is rapid and extensive expression of hypoxia-inducible factor 1α in multiple different tissues and that this cytokine may play a vital role in initiating and coordinating the overall response to hypoxemia. The first and most immediate clinical response to decreasing SpO2 is an increase in minute ventilation through central mechanisms triggered via carotid body chemoreceptors. Second, an increase in sympathetic nervous system activity (23) results in myriad circulatory responses that adjust peripheral blood flow to optimize oxygen delivery. These circulatory responses involve direct neural stimulation, increased catecholamine and nitric oxide (NO) production (2), and increased expression of vascular endothelial growth factor (34) among others. Third, the plasma volume contracts via a fluid diuresis (19) within 12 to 24 h of exposure to raise the oxygen-carrying capacity of the blood by increasing the hematocrit level. After several weeks, the plasma volume returns to preascent levels, and in fact, one ultimately experiences a net increase in circulating blood volume from increased erythropoiesis in response to hypoxemia. Acclimatization is complex and highly variable among individuals, but in simple terms, altitude illness results when the degree of altitude exposure exceeds an individual’s ability to acclimatize through these mechanisms.
AMS/HACE Theory and Current Research
AMS and HACE have long been considered as a continuum of disease severity whereby HACE is “end-stage” AMS (17). The validity of this construct is controversial (4), however, because cases of mild to moderate AMS do not demonstrate the edematous swelling of the brain and intracerebral hemorrhage seen in cases of severe AMS and HACE (18). Nevertheless, AMS and HACE share many common clinical features regarding identification, treatment, and prevention, and it therefore remains useful to consider them as a continuum for purposes of discussion.
Traditional theory (17,40) contends that AMS and HACE are the end result of intracranial hypertension caused by vasogenic (extracellular) edema of cerebral tissue subsequent to mechanical disruption of the blood-brain barrier. In the setting of hypobaric hypoxia, the cerebral blood vessels are adapting to maintain vital cerebral oxygen delivery, and studies have shown disordered cerebral autoregulation and increased cerebral blood flow in response to hypobaric hypoxia (2,20). It was hypothesized that susceptibility to AMS could be explained by a diminished intracranial buffering capacity to accommodate the physical swelling and has been supported by studies. The so-called “tight-fit” hypothesis (37) provides a reasonable explanation for altitude headache via trigeminovascular system (TVS) activation and predicts responses to treatment with acetazolamide (which decreases cerebrospinal fluid (CSF) production, among other actions) and triptan medications (which modulate output of the TVS).
However, a recent review (1) summarizes three important concepts that emerge from studies during the last decade, which cast doubt on this traditional model: experimental subjects with clinical AMS do not exhibit incremental brain swelling, alteration in blood-brain barrier permeability, or increased lumbar CSF pressure. The authors suggest that the mild vasogenic edema that has been proven to exist may represent the adaptive physiologic response to altitude rather than the underlying cause and propose a novel mechanism for AMS based on oxidative damage. The so-called “redox activation” hypothesis contends that hypoxemia results in oxidative stress from excess free radical formation, which initiates a cascade of events that ultimately activates the TVS, which is the common final pathway between the two theories. This hypothesis is predicated on the fact that, because of the disproportionately high oxygen demand of the CNS, it is very susceptible to hypoxic injury and is, paradoxically, ill equipped to handle oxidative stress.
Despite our incomplete understanding of the mechanism of AMS/HACE, the clinical and physiologic hallmarks of mild to moderate AMS have been consistently demonstrated in human and animal models and represent maladaptive or dysfunctional responses to the hypobaric hypoxic environment. They include fluid retention and relative hypoventilation with impaired gas exchange (7) and exaggerated sympathetic activity (23), and these remain our targets of pharmacologic prophylaxis and treatment. Treatment regimens and dosages are found in Table 3 (29).
The three proven mainstays for AMS/HACE prevention include controlled ascent, acetazolamide, and, in certain cases, dexamethasone.
The single most important factor for the prevention of AMS/HACE has been and remains to be controlled exposure to hypobaric hypoxia via controlled ascent (17,20,28). Although the optimal ascent profile has not been rigorously determined (28), a suggested ascent profile applies to travel >3,000 m and recommends a maximum of 500 m elevation change per day with a rest day every third to fourth day. It is also recommended that, for low-risk (Table 2) cases, prophylactic medications are not necessary, but moderate- and high-risk cases do warrant their use as outlined in the next paragraphs.
Acetazolamide is a carbonic anhydrase inhibitor that creates a pharmacologic substitute for altitude exposure and provides a protective benefit by stimulating acclimatization before ascent (26). The net effect is a fluid diuresis from decreased reabsorption of bicarbonate in the proximal renal tubule and an increase in ventilation in response to elevated PCO2. The benefit of acetazolamide for the prevention of AMS/HACE has been demonstrated in multiple trials (8,47), and it remains the primary pharmacologic agent of choice. Prophylaxis should be continued until either one remains at maximum altitude for 2 to 3 d or upon initiation of descent. The most commonly reported adverse effects are paresthesias, decreased exercise tolerance, and a taste aversion to carbonated beverages. Patients with a sulfonamide allergy will exhibit cross-reactivity with acetazolamide owing to its homologous structure, and the use of acetazolamide is contraindicated in patients with a history of anaphylaxis from sulfonamides. An observed trial of acetazolamide before ascent can be tried for patients with milder sulfonamide allergies (e.g., rash); however, this decision should be one that takes into account individual patient factors and sound clinical judgment.
Dexamethasone is a potent, long-acting corticosteroid that has multiple systemic effects, but its most likely protective benefit for AMS/HACE comes from modulation of sympathetic activation, decreased capillary permeability, and suppression of various proinflammatory cytokines. Several prospective controlled trials have demonstrated a benefit (13,27) with dexamethasone for the prevention of AMS/HACE; however, owing to the possibility for significant adverse effects it has a limited practical role as a prophylactic medicine.
The problems with prophylactic dexamethasone are twofold: 1) prolonged use can suppress adrenal function and lead to glucocorticoid toxicity that will create serious medical emergencies apart from altitude illness as illustrated in a recent case report (45) and 2) once initiated, dexamethasone must be taken until descent because cessation of therapy while remaining at altitude results in loss of any protective effect and a “rebound” of altitude illness signs and symptoms. Therefore, the use of dexamethasone is limited to specific circumstances such as: military/rescue personnel whose mission does not allow for controlled ascent, prevention of AMS/HACE in high-risk traveler (e.g., prior history of altitude illness) when the duration of travel is limited to <5 to 10 d, or when acetazolamide is contraindicated (e.g., history of anaphylaxis to sulfonamide therapy).
Recently, new measures for prevention have been studied, and these include intermittent hypoxic exposure, phosphodiesterase inhibitors, intravenous iron, 5-hydroxytryptamine antagonists (triptans), antioxidants, medroxyprogesterone, magnesium, and theophylline. While these agents lack the rigorous evidence and acceptance in practice as those measures are above future study may validate their effectiveness for the prevention of AMS/HACE.
Altitude Preconditioning with Intermittent Hypoxia Exposure
It has been observed for >30 years that persons who live at high altitude or who have had recent travel to elevation seemed less susceptible to altitude illness but was only recently studied (36). In this small prospective trial, the authors found that preexposure significantly decreased AMS in adults but not in children. The use of preascent altitude exposure (hypobaric hypoxia) has demonstrated efficacy in reducing AMS (35), although more research is needed. Intermittent normobaric hypoxic exposure was studied (Clinical Trial NCT00559832) in 2007, but the results were not published, and a more recent evaluation (42) using training with normobaric hypoxia before rapid ascent did not protect against AMS.
Phosphodiesterase 5 Inhibitors
Sildenafil and tadalafil are phosphodiesterase 5 (PDE-5) inhibitors that relax smooth muscle via potentiation of cyclic guanosine monophosphate activity. Specific vascular tissues, including those in the lung, demonstrate selective expression of PDE-5, and there has been research into their utility for the prevention and treatment of altitude illness, particularly HAPE. Sildenafil has demonstrated an effect on improving cerebral oxygenation and has been proposed for treatment or prevention of AMS (16). There have been two randomized controlled trials evaluating the role of PDE-5 inhibitors for the prevention or treatment of altitude illness (10,33), and in both studies, both the incidence and the severity of AMS were significantly increased among treatment subjects despite modest benefit seen for HAPE with tadalafil (33).
Two recent studies (44,46) have demonstrated a potential benefit for iron therapy in the prevention of altitude illness, but additional research is needed before a recommendation can be made.
Sumatriptan, a selective 5-hydroxytryptamine1B/1D antagonist that modulates the activity of the trigeminovascular system, has been studied for the prevention of AMS/HACE; in one randomized trial (21), it was effective in reducing AMS by >50%. No study comparing sumatriptan to acetazolamide has been performed.
Gingko biloba extract is, among many things, a free radical scavenger that has been used since antiquity as a remedy for the panoply of human affliction. It has been proposed and studied for the prevention of AMS/HACE, and the data are inconclusive (11,15,25). Additional studies with other antioxidants also have failed to demonstrate a clear benefit (3), and currently, there is not enough evidence to support the use of G. biloba for the prevention of AMS/HACE.
Progesterone is a steroid hormone that, among many actions, stimulates central respiratory drive. One trial examined the role for medroxyprogesterone in the prevention of AMS/HACE (50) and found that, although oxygenation did improve when combined with acetazolamide, the development of AMS was not affected.
Diuretic Therapy Other Than Acetazolamide
Loop diuretics such as furosemide and aldosterone antagonists such as spironolactone have been examined for a role in the prevention of AMS/HACE by augmenting the natural diuresis that occurs in response to altitude. The data for the efficacy of loop diuretics (43) have not been reproduced, and because of the increased risk for dehydration from excessive diuresis coupled with increased insensible losses from respiratory tract at altitude, its use is not recommended at this time. Spironolactone has theoretical promise because, like acetazolamide, it is a gentle diuretic that produces a mild acidosis and decreases CSF production, but it was found to be inferior to acetazolamide in a recent trial (9).
Magnesium acts as a central N-methyl-D-aspartate receptor antagonist and raises seizure threshold in the setting of hypoxia. Theoretically, magnesium could provide a protective benefit for hypoxic cerebral injury; however, studies have not demonstrated a physiologic link between the N-methyl-D-aspartate receptor and the pathology of AMS/HACE, and in one study (12), oral magnesium had no effect on prevention of AMS.
Theophylline, or dimethylxanthine, has multiple systemic effects mediated via nonselective phosphodiesterase inhibition and nonselective adenosine receptor agonist activity and, theoretically, could be useful in the prevention and treatment of altitude illness. The overall physiologic effects are to stimulate central respiratory drive, reduce capillary permeability, and reduce pulmonary arterial pressure via vasodilation. Theophylline has demonstrated an effect on reducing symptoms of AMS (14,24), and when combined with acetazolamide, it did improve sleep-disordered breathing (14); however, it did not improve oxygenation over acetazolamide alone. Also, theophylline has a very narrow therapeutic index and the toxicities can be life-threatening (arrhythmias, seizures) and therefore has a very limited practical role for the prevention of AMS/HACE in the majority of patients.
The most important aspect in the treatment of worsening AMS or development of HACE is early identification and descent (17,20,28), if feasible, until symptoms resolve. There is considerable variability among individuals, but generally, at least 300 m but no more than 1,000 m descent is required. If safe descent is not feasible, a number of interventions can be made to treat AMS/HACE.
Supplementary oxygen that is sufficient to elevate SpO2 > 90% will, by definition, counteract the hypoxemia and is considered a safe alternative to descent, but given the physical limitations of transporting oxygen, this is often not available in sufficient quantities to sustain a traveler for extended periods.
Dexamethasone when started at onset is effective in reducing symptoms of AMS and HACE and should be administered if descent is delayed or not feasible.
Portable Hyperbaric Chambers
These devices have demonstrated their effectiveness in the treatment of severe altitude illness (6), but they are labor-intensive and provide unique challenges in cases where patients who are claustrophobic or vomiting and should not be used if their use delays descent (28).
Acetazolamide has a demonstrated role for treatment at higher doses; however, the effect is delayed and, in general, is less effective as a treatment than a preventive therapy.
HAPE is a rare, life-threatening condition that typically presents within 2 to 5 d after arrival at altitude, and while incidence has been reported as high as 4% among travelers >4,000 m (48), it is rarely observed below 2,500 m. The initial clinical manifestations of HAPE are subtle, and it is essential to consider a HAPE in the differential as a patient’s clinical status can deteriorate rapidly. The normal adaptive physiologic response to decreased partial pressure of oxygen at altitude will induce a relative increase in respiratory rate and subjective shortness of breath for many travelers who are not experiencing HAPE. Clinical manifestations of HAPE begin as exertional dyspnea, cough, and reduced exercise tolerance that, untreated, will progress to worsening cough, orthopnea, dyspnea at rest, and, ultimately, pink, frothy sputum production with gurgling in the chest consistent with frank pulmonary edema.
HAPE Theory and Current Research
The pathologic hallmark of HAPE is acute, excessive hypoxic pulmonary hypertension that directly increases pulmonary capillary hydrostatic pressure and forces extravasation of fluid across the permeable vascular endothelium into the alveolar space. It has been demonstrated that the early stages of HAPE are the result of mechanical forces and not systemic inflammation; however, in later stages, an exaggerated inflammatory response occurs, which exacerbates endothelial permeability and increases fluid leak into the alveolar space (39). In addition, recent evidence suggests that impaired reabsorption of alveolar fluid may be a significant contributor to HAPE as discussed below.
The mechanism by which patients who are susceptible to HAPE develop this excessive vasoconstriction has been the subject of much research during the last few decades (17,32,39). Although not completely elucidated, several factors seem to be involved, notably 1) impaired relaxation of pulmonary vasculature via defective NO synthesis by NO synthase (expressed on both capillary endothelium and respiratory epithelium), 2) excessive endothelin 1 (vasoconstrictor) production by capillary endothelium (may be direct result of decreased NO production), 3) exaggerated sympathetic activation, and 4) right-to-left intracardiac shunt (e.g., through patent foramen ovale). Although excessive pulmonary capillary pressure is the sine qua non of HAPE, it has been shown that it is not, of itself, sufficient to trigger HAPE (39).
Controlled ascent and nifedipine are the mainstays for the prevention of HAPE (28,32). Salmeterol (38), dexamethasone, and PDE-5 inhibitors (10,33) (discussed earlier) have been studied for the prevention of HAPE but are not recommended as first-line preventative agents at present time.
Like AMS/HACE, the most effective preventive strategy in the prevention of HAPE is by gradual acclimatization via a controlled ascent (17,32). This will optimize the adaptation of the pulmonary vasculature and respiratory epithelium to the hypobaric hypoxic environment.
Nifedipine is a dihydropyridine Ca2+ channel blocker that acts as a peripheral and pulmonary vasodilator via relaxation of vascular smooth muscle cells. Sustained-release nifedipine has been known for several decades (5) to be effective for the prevention of HAPE in susceptible individuals.
Treatment of HAPE
The most important treatment goal is rapid restoration of normal gas exchange by improving availability of alveolar oxygen, reducing pulmonary capillary pressure to decrease edema formation, and improving alveolar fluid reabsorption (28,32). Descent, supplementary oxygen, and portable hyperbaric chambers are well-established treatments for HAPE.
The best initial treatment for HAPE remains descent of at least 1,000 m if feasible (28,32); however, if adequate medical services (e.g., supplementary oxygen and hyperbaric treatment) are available at altitude, descent is not always necessary. Physical exertion should be minimized if HAPE is suspected because continued exertion will only exacerbate the condition and hasten the deterioration of pulmonary gas exchange.
Maximizing alveolar oxygen concentrations can help with pulmonary gas exchange, and providing sufficient supplementary oxygen to maintain SpO2 > 90% should be a goal of initial therapy (32).
Portable Hyperbaric Chambers
Portable hyperbaric chambers have not been rigorously studied as they have for AMS/HACE; however, theoretically, their role in reversing the physiologic problem associated with HAPE suggests a role in treatment that has been supported in various reports. The use of portable hyperbaric chamber should not delay descent where feasible (28).
Other possible treatments that have been studied include nifedipine, dexamethasone, and supplementary positive airway pressure. There is a well-established role for nifedipine for the prevention of HAPE (5,17); however, once disease develops, the role of nifedipine is inferior to descent, supplementary oxygen, or hyperbaric therapy. Therefore, nifedipine should only be used as an adjunct treatment and is only recommended for primary treatment if none of these are available. Dexamethasone has a clear role for treatment in HACE, but its role in the treatment of HAPE is less clear (33) and further study is required. The use of expiratory positive airway pressure has been shown (41) to improve pulmonary gas exchange and oxygenation in patients with HAPE, and by extension, continuous positive airway pressure has been proposed as a treatment modality; however, adequate studies to determine optimal pressure settings or to demonstrate an improvement in patient outcomes have not been performed. While the risks of continuous positive airway pressure are small, the potential for increased intrathoracic and central venous pressure can complicate cardiovascular problems and may increase susceptibility for HACE (32).
Altitude illness can occur to those that perform activity above 2,500 m and can significantly affect recreational travel, high-altitude rescue, and military personnel. The most important aspects of prevention and treatment remain controlled ascent, rapid recognition of symptoms, and initiation of treatment by descent, if feasible. Despite extensive research, the identification of susceptible persons remains a challenge, and pharmacologic prophylaxis is indicated for moderate- and high-risk cases. New research into new prophylactic and treatments continues to be performed, and as technology and our understanding of disease continue to improve, we are likely to see more and more effective treatment options to allow safer alpine activity for more individuals.
The authors declare no conflicts of interest and do not have any financial disclosures.
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