INTRODUCTION — Anyone who travels to high altitude, whether a recreational hiker, skier, mountain climber, soldier, or worker, is at risk of developing high-altitude illness. High-altitude pulmonary edema (HAPE) is a life-threatening non-cardiogenic pulmonary edema and the most common fatal manifestation of severe high-altitude illness .
The pathophysiology, clinical presentation, treatment, and prevention of HAPE are reviewed here. Other forms of high-altitude illness are discussed separately. (See "Acute mountain sickness and high-altitude cerebral edema" and "High-altitude illness: Physiology, risk factors, and general prevention" and "High-altitude disease: Unique pediatric considerations".)
PATHOPHYSIOLOGY — HAPE is the abnormal accumulation of plasma and some red blood cells in the lung air sacs due to a breakdown in the pulmonary blood-gas barrier, triggered by hypobaric hypoxia. This breakdown develops from a number of maladaptive responses to the hypoxia encountered at higher altitudes, including poor ventilatory response, increased sympathetic tone, exaggerated and uneven pulmonary vasoconstriction (pulmonary hypertension), inadequate production of endothelial nitric oxide, overproduction of endothelin, and inadequate alveolar fluid clearance, many of which are genetically determined [2,3]. The end result is a patchy accumulation of extravascular fluid in the alveolar spaces that impairs gas exchange and can, in severe cases, prove fatal.
Genetics clearly play an important role in the risk of HAPE, as suggested by the marked variability in individual susceptibility, the higher rates of recurrence among some individuals, familial groupings, and the pathophysiologic factors mentioned above. However, HAPE genetic studies are conflicting, and clear conclusions are elusive. Genes associated with HAPE have included those in the pathways for nitric oxide, renin-angiotensin-aldosterone, hypoxia-inducible factor (HIF), heat shock protein (HSP 70), pulmonary surfactant proteins A1 and A2, aquaporin-5, and the BMPR2 gene that is associated with pulmonary arterial hypertension [2,4,5].
High mean pulmonary artery pressure, in excess of 35 to 40 mmHg, appears to be the initiating event. However, while elevated pulmonary artery pressure is essential for HAPE, this by itself is insufficient. The other essential factor is uneven vasoconstriction. Specific segmental and subsegmental capillary beds with relatively less vasoconstriction are disproportionately exposed to elevated microvascular pressures (>20 mmHg) that arise from the elevated mean pulmonary artery pressure. This uneven vasoconstriction and regional overperfusion result in failure of the alveolar-capillary barrier and patchy pulmonary edema .
As disruption of the alveolar-capillary barrier progresses, high molecular weight proteins, cells, and fluid leak into the alveolar space. Eventually, basement endothelial and epithelial cell membranes are disrupted, leading to alveolar hemorrhage.
A striking feature of HAPE is the rapid reversibility of this process with descent or simply the administration of oxygen. Pulmonary vascular resistance and pulmonary artery pressure drop immediately and return to normal within days after treatment or descent to low altitude.
EPIDEMIOLOGY AND RISK FACTORS — HAPE is divided into two types:
●Classic HAPE, involving acute ascent of those normally residing at low altitude
●Re-entry HAPE, involving re-ascent of those normally residing at high altitude after a stay at low altitude
Another category has been suggested for children living at high altitude who develop pulmonary edema with respiratory infection but without a change in altitude .
HAPE generally occurs above 2500 meters (8000 feet) and is uncommon below 3000 meters (10,000 feet) (table 1 and table 2) [8,9]. The risk depends upon individual susceptibility, altitude attained, rate of ascent, and time spent at high altitude. In those without a history of HAPE, the incidence is 0.2 percent with ascent to 4500 meters (14,800 feet) over four days but 6 percent when ascent occurs over one to two days. In those with a history of HAPE, recurrence is 60 percent with an ascent to 4500 meters over two days. At 5500 meters (18,000 feet), the incidence ranges between 2 and 15 percent, again depending upon rate of ascent.
Symptoms of acute mountain sickness develop in a high percentage of those with HAPE [10,11]. HAPE and high-altitude cerebral edema (HACE) may also occur concomitantly due to the severe hypoxemia of HAPE. (See "Acute mountain sickness and high-altitude cerebral edema".)
Factors associated with an increased incidence of HAPE include male sex, cold ambient temperatures, pre-existing respiratory infection, and vigorous exertion . Pre-existing conditions or anatomic abnormalities that lead to increased pulmonary blood flow, pulmonary hypertension, or increased pulmonary vascular reactivity may predispose to HAPE, even at altitudes below 2500 meters. These include pulmonary hypertension of any etiology, congenital absence of one pulmonary artery, and intracardiac shunts, such as atrial septal defects and ventricular septal defects.
A patent foramen ovale (PFO), in the setting of rising pulmonary vascular resistance during hypoxic pulmonary vasoconstriction, may reverse the direction of blood flow, shunting blood from right to left and further exacerbating hypoxemia. PFO is four times more common among HAPE-susceptible individuals. Larger PFOs correlate directly with increased arterial hypoxemia and a trend toward an increased risk of developing HAPE. However, PFO does not cause a greater rise in pulmonary artery pressure . Whether PFO contributes to HAPE or is merely a marker of increased vascular reactivity and susceptibility remains unknown. There is currently no indication for closing PFO in susceptible persons in hopes of preventing HAPE.
Presentation in adults
Symptoms and signs — HAPE generally begins with a subtle, nonproductive cough, and shortness of breath with exertion, often when walking uphill [9,13]. Such nonspecific symptoms are easily mistaken for a benign upper respiratory tract infection or attributed to normal breathlessness at high altitude or exhaustion. Initial symptoms typically appear two to four days after arrival at a new altitude. Occasionally, HAPE develops precipitously. This occurs more often at night or after severe exertion. HAPE almost never develops after a week at the same altitude.
As HAPE progresses, dyspnea becomes noticeable at rest and severe with any attempt at exertion. Even walking on a level surface becomes an effort. A cardinal clinical feature of HAPE is the early progression from dyspnea with exertion to dyspnea at rest. In about 50 percent of cases, HAPE is accompanied by acute mountain sickness . (See "Acute mountain sickness and high-altitude cerebral edema".)
As symptoms progress, the cough can become productive of pink, frothy sputum and may produce frank blood. Severely restricted exercise tolerance becomes debilitating, and severe hypoxemia may become life threatening without prompt descent or supplemental oxygen. Severe hypoxemia may cause drowsiness or concomitant high-altitude cerebral edema (HACE).
On physical examination, tachycardia, tachypnea, and low-grade fever (up to 38°C) are common. Inspiratory crackles may be more prominent in the right middle lobe initially but become bilateral and diffuse as HAPE progresses. Auscultation of the right middle lobe is best performed at the mid-lateral chest wall. Persons with blunted carotid body function, genetic or acquired (eg, carotid endarterectomy, neck radiation), may present without respiratory symptoms and instead with drowsiness, confusion, and other central nervous system symptoms and findings that might more commonly be associated with HACE.
Oxygen saturation — Pulse oximetry reveals saturation values (SpO2) at least 10 points lower than expected for the altitude, and absolute values may be as low as 40 to 50 percent. Typically, the patient appears better than expected given the severity of hypoxemia, and the oxygen saturation improves promptly (usually within 10 to 15 minutes) in response to supplemental oxygen. This rapid correction of the SpO2 and clinical status with supplemental oxygen in the setting of a severe infiltrative lung process seen on radiograph are virtually pathognomonic for HAPE, as this does not occur with other pulmonary processes (eg, pneumonia, acute decompensated heart failure) capable of causing such severe hypoxemia and associated with diffuse crackles or rhonchi.
Thus, pulse oximetry is often a useful tool for distinguishing HAPE from other conditions. However, expected SpO2 values vary with a number of factors, including the altitude, degree and rate of acclimatization, patient's hypoxic ventilatory drive, and method of measurement (eg, variation among pulse oximeters); and therefore should be interpreted carefully. SpO2 is lowest on the first day at high altitude and rises over four days to a near-maximum value, usually 3 to 5 points higher than day one. Although expected values can vary widely in normal individuals at any given altitude, comparing SpO2 measurements with others in the same travel group who arrived at high altitude together can help to establish a relative "normal" range. The following figures provide approximate average values for SpO2 and other parameters at a range of altitudes (figure 1 and table 3).
Presentation in children — In children, HAPE typically presents as increasing respiratory distress over one to two days but may develop more precipitously. Young children may manifest only pallor or cyanosis and depressed consciousness, though most will have tachypnea, hypoxemia, and crackles . In infants, increased pulmonary artery pressure and fetal shunting, without HAPE, can cause severe hypoxemia. (See 'Pathophysiology' above and "High-altitude disease: Unique pediatric considerations".)
HAPE alone does not cause an elevation in body temperature over 38.3°C (101°F), and young children with a higher temperature should be assessed for other causes of fever. Respiratory infection and HAPE can coexist. (See "Fever without a source in children 3 to 36 months of age: Evaluation and management".)
The differential diagnosis in children includes pneumonia, undetected intracardiac shunts, and (in infants) opening of fetal shunts in response to high-altitude pulmonary hypertension. Some authors suggest that children who develop HAPE should be evaluated for structural heart problems [14,15]. (See "Pathophysiology of left-to-right shunts" and "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis" and "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation'.)
Plain radiograph, computed tomography, and echocardiography — As with acute mountain sickness and high-altitude cerebral edema (HACE), the diagnosis of HAPE is based upon the history and physical examination. However, chest radiography is useful and reveals characteristic patchy alveolar infiltrates, predominantly in the right central hemithorax, which become more confluent and bilateral as the illness progresses (image 1). However, in some cases, the infiltrates may start in the left lung . Rarely, the edema is entirely unilateral even when severe, which suggests a pulmonary artery agenesis or obstruction .
Although the radiographic appearance of HAPE may mimic that of infectious infiltrates, we often find a significant discrepancy between the extensive infiltrates on radiograph and the patient's clinical status. The patient with HAPE often does not appear as severely ill as one would expect based on the radiograph findings and steadily improves with oxygen therapy. In contrast, a patient with a comparable chest radiograph due to pneumonia typically appears critically ill and often requires tracheal intubation and mechanical ventilation.
Computed tomography (CT) of the chest, while rarely indicated, reveals a patchy lobular ground-glass appearance and consolidative opacities, reflecting heterogeneous alveolar filling (image 2). Echocardiography reveals increased pulmonary artery pressure and sometimes right heart dysfunction and paradoxical septal motion [1,2].
Ultrasound — Observational studies suggest that ultrasonography is a highly sensitive and semi-quantitative means of detecting increased extravascular lung water [18-20]. If traditional chest radiography is unavailable (eg, at a remote clinic or in the field), chest sonography is a practical and useful tool for identifying HAPE.
In the appropriate clinical setting, namely ascent to high altitude by an unacclimatized person who develops typical signs and symptoms and an abnormally low oxygen saturation (SpO2), HAPE can be confirmed by the presence of ultrasound lung comets (ULCs) (image 3 and movie 1). ULCs are sonographic artifacts originating from water-thickened interlobular septa fanning out from the lung surface. They are caused by the air-fluid interface in the presence of increased extravascular lung water. ULCs may be referred to as B-lines or "comet tails" and are the sonographic equivalent of radiographic Kerley B-lines, which are described separately. (See "Evaluation of diffuse lung disease by conventional chest radiography", section on 'Linear'.)
While the quantity of ULCs corresponds closely to clinical and oximetry findings, it is not yet known what number of ULCs is an appropriate diagnostic threshold for HAPE, as opposed to subclinical pulmonary edema. Nevertheless, the technique for identifying ULCs is easily performed and may be useful in the proper clinical setting, such as when the cause of dyspnea is unclear despite a careful history and physical examination [21,22].
Drawbacks to using ultrasound to diagnose HAPE include a lack of specificity and questions about its utility. Ultrasound cannot differentiate HAPE from cardiogenic pulmonary edema and other causes of increased extravascular lung water. In addition, ultrasound findings may not be clinically relevant at high altitude, as clinically insignificant ULCs are commonly seen in recreational climbers who are asymptomatic and do not develop HAPE [22-24]. Finally, ultrasound findings may not add to what is already known from examination findings and oximetry.
LABORATORY TESTS — No laboratory test demonstrates adequate specificity to aid in the diagnosis of HAPE. In patients with HAPE, the white blood cell count may be modestly elevated. Brain natriuretic peptide (BNP) and related tests (eg, pro-BNP) may be slightly elevated at high altitudes, and troponin may be elevated in the setting of HAPE associated with right heart strain. However, such results are not helpful in distinguishing among potential diagnoses (eg, acute coronary syndrome, acute decompensated heart failure) and may not be elevated in the patient with HAPE. The results of other readily available tests are also nonspecific and unhelpful in diagnosing HAPE. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Natriuretic peptide'.)
DIAGNOSIS — HAPE is typically diagnosed clinically on the basis of the history and examination findings. The initial symptoms typically begin two to four days after arrival at high altitude and include a subtle nonproductive cough, shortness of breath on exertion, and difficulty walking uphill. Symptoms can develop more precipitously in children. Over one to two days, the cough often becomes productive. Early progression from dyspnea with exertion to dyspnea at rest is a cardinal feature. Prominent examination findings include tachycardia, tachypnea, low-grade fever (up to 38°C), and pulmonary crackles. Oxygen saturation is lower than expected for a given altitude. Treatment with supplemental oxygen and rest can lead to rapid improvement. Characteristic findings on imaging studies, when available and indicated, help to confirm the diagnosis.
Diagnoses confused with HAPE — Pneumonia heads the list of differential diagnoses that can be confused with HAPE, but others to consider include pulmonary embolism, acute decompensated heart failure, acute coronary syndrome, bronchitis, reactive airway disease, and exercise-associated hyponatremia [25,26]. Of note, HAPE and infection can coexist. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Approach to diagnosis and evaluation of acute decompensated heart failure in adults" and "Diagnosis of acute myocardial infarction" and "Exercise-associated hyponatremia".)
Differentiating HAPE from such ailments as pneumonia or acute decompensated heart failure can be difficult, particularly in older patients with comorbid conditions. In such patients, HAPE is a diagnosis of exclusion, and alternative diagnoses should be worked up in standard fashion. HAPE is associated with marked weakness and often severe hypoxemia (oxygen saturation [SpO2] of 50 to 75 percent; partial pressure of oxygen [PaO2] of 25 to 40 mmHg). While ill appearing, such patients with HAPE generally look better than would be expected given their extreme hypoxemia and improve rapidly with supplemental oxygen therapy.
More commonly, the diagnosis of HAPE is entertained in otherwise healthy patients with a characteristic history and examination findings. Rapid response over one to two hours of oxygen therapy strongly suggests the diagnosis of HAPE in this setting. Rapid improvement with descent is another important clue to the diagnosis of HAPE.
There is no pathophysiologic or clinical relationship between HAPE and severe acute respiratory syndrome coronavirus 2, as has been suggested by some [27-29].
Distinguishing HAPE and pneumonia — The non-specific symptoms and signs associated with pneumonia, including cough, dyspnea, low-grade fever, pulmonary infiltrates, and hypoxemia; and laboratory abnormalities such as a modestly elevated white blood cell count are also common features of HAPE.
HAPE may be precipitated by or co-exist with pneumonia, and distinguishing between these diagnoses can be challenging. The presence of marked hypoxemia (common with HAPE), extensive infiltrates on chest radiograph, and modest elevations of the white blood cell count (10,000 to 15,000/microL) frequently influence clinicians treating HAPE to administer empiric antibiotics for the possibility of concomitant bacterial pneumonia. While the decision to treat HAPE with empiric antibiotics based on such concerns remains clinical and subjective, many cases of pneumonia (when in fact present) in this setting are of viral etiology and do not warrant antibiotic administration.
There is little published, high-quality evidence that can help to distinguish reliably between isolated HAPE and HAPE with concomitant pneumonia, but a number of clinical findings can provide some insight. Purulent sputum (particularly if a properly performed gram stain is positive for bacteria), temperature >38°C (100.5°F), elevated white blood cell count (>15,000/microL with a left shift, ie, predominately bands), elevated procalcitonin (>0.25 mcg/L) or highly elevated C-reactive protein, positive polymerase chain reaction respiratory panel, and a history of respiratory tract infection in the two to three days preceding the development of HAPE are consistent with an infectious process, and the authors believe that treatment with empiric antibiotics is appropriate in this setting.
Conversely, in otherwise healthy patients with a characteristic history of HAPE and examination findings consistent with the diagnosis, antibiotics are typically not necessary. In such cases, a rapid response over several hours to oxygen therapy strongly suggests the diagnosis of HAPE. In contrast, symptoms and signs of pneumonia require several days before clinical improvement. Rapid improvement with descent to lower altitude is another important diagnostic clue suggesting the diagnosis of HAPE without pneumonia.
General approach to treatment — Early recognition of HAPE and prompt intervention are critical to assuring a favorable outcome . Unlike high-altitude cerebral edema (HACE), immediate descent is not mandatory in all treatment settings. Instead, treatment of HAPE varies depending upon a number of factors, including severity of illness, available treatments, setting, clinician experience, and patient preference. As examples, management of a resort skier at 2500 meters may consist solely of supplemental oxygen and rest, while management of a mountaineer camping in a remote location at 5500 meters and without access to supplemental oxygen requires immediate descent.
The key principle in successful treatment of HAPE, regardless of the setting or patient age, is prompt reduction of pulmonary artery pressure. Means to achieve this end include limiting physical exertion and cold exposure, providing supplemental oxygen via tank or concentrator, and, when indicated, evacuation to a lower altitude or simulating descent using hyperbaric therapy. Descent (simulated or actual), supplemental oxygen, or the two combined are effective and appear to be superior to any pharmacologic therapy.
Because of ethical considerations, no trials have been performed in patients with HAPE that directly compare treatment with oxygen and descent versus pharmacologic therapy alone. In the one uncontrolled study in which nifedipine alone was used for treatment, clinical outcomes were poor relative to those reported in studies where treatment consisted of oxygen and descent without medications . Nevertheless, if supplemental oxygen is unavailable and descent difficult or impossible, medication could be lifesaving [2,30].
When oxygen and/or descent are employed, the addition of medication may not be necessary. In a trial with 113 HAPE patients, adding nifedipine to descent and oxygen provided no additional benefit . In a trial performed with the Indian military, 153 HAPE patients showed no additional benefit from either dexamethasone or nifedipine given with oxygen compared with those treated with oxygen alone .
Oxygen — Supplemental oxygen is first-line therapy for HAPE and should be provided in all treatment settings when available [34-37]. It can be lifesaving. Relieving hypoxemia is the most effective method of reducing pulmonary artery pressure, reversing capillary leak, and protecting the brain and other organs. Supplemental oxygen immediately increases partial pressure of oxygen (PaO2) and reduces both the heart and respiratory rates.
Based on the authors' field experience, when supplies are limited, low-flow oxygen given for a longer duration is preferable to high flow and short duration. Supplemental oxygen combined with descent (or hyperbaric therapy) is the ideal treatment.
In the hospital setting, supplemental oxygen and rest are generally sufficient therapy [34,37]. A common regimen in North American hospitals near ski resorts (elevation approximately 2500 to 3000 meters) is to treat with high-flow supplemental oxygen by nasal cannula or face mask for several hours until the patient's oxygen requirement is ≤3 L/min, with the oxygen saturation (SpO2) maintained at 90 percent or higher. If the patient is clinically improved and appropriate for outpatient therapy, they may be sent home with an oxygen concentrator to be used continuously and strict instructions to rest. The patient's condition and SpO2 are rechecked daily until an ambulatory SpO2, measured while the patient breathes room air, is ≥90 percent. The usual duration of oxygen therapy is two to three days. At this point, supplemental oxygen can be discontinued. The patient is advised to return to activity gradually over the following one to three days. Descent is not mandatory but is always an option in this setting.
Rest and warmth — Strenuous physical exertion and cold stress both elevate pulmonary artery pressure and can exacerbate HAPE. Thus, limiting exertion and avoiding exposure to cold are fundamental aspects of treatment. A patient with HAPE, for example, should not carry a pack while descending. The role of bedrest is unclear. A study with 36 patients with mild to moderate re-entry HAPE at 3750 meters in Peru showed that while bedrest alone resulted in complete recovery, bedrest with oxygen was more effective . Most subsequent studies have used the combination of bedrest and oxygen [32,33,36]. In the Colorado ski resorts, we generally do not recommend strict bedrest during oxygen therapy in the patient's domicile.
Descent — In remote high-altitude settings where supplemental oxygen is unavailable, descent should begin as soon as HAPE is suspected [2,30]. HAPE can progress rapidly, and the opportunity for evacuation may be lost if there is delay. At higher elevations (>4000 meters), descent is mandatory, in part because of the risk of developing HACE. Ideally, immediate evacuation is undertaken to a hospital below 3000 meters that is capable of providing high-flow oxygen.
Nevertheless, in practice, scores of HAPE patients are treated successfully in remote clinics or base camps with modest descent and rest, sometimes in combination with portable hyperbaric therapy, low-flow supplemental oxygen, and medication. Many remote clinics are located only 500 to 1000 meters below the elevation of HAPE onset. When HAPE is diagnosed early and treated in the manner described, many climbers go on to reascend slowly after three days or more of recovery . Recurrence of HAPE in such circumstances has not been reported. Severe cases require evacuation to a medical facility at lower elevation.
Hyperbaric therapy — In remote settings, lightweight portable hyperbaric chambers may be lifesaving, particularly when supplemental oxygen is unavailable or in short supply . These devices, although costly, are well-suited to mountaineering and trekking expeditions at high altitude, where compressed oxygen cylinders are too heavy and bulky to transport and are difficult to maintain.
In isolated mountain settings, hyperbaric therapy is commonly combined with pharmacotherapy and supplemental oxygen, if available. In the hospital setting, elevation is generally lower, and high-flow oxygen is readily available. Hyperbaric therapy is not practical or necessary in such hospitals or clinics. (See "Acute mountain sickness and high-altitude cerebral edema", section on 'AMS treatment' and "Acute mountain sickness and high-altitude cerebral edema", section on 'HACE treatment'.)
Positive airway pressure and other therapies — The use of a breathing mask providing pressure on expiration (EPAP) has been shown to improve gas exchange in HAPE and may be useful as a temporizing measure . A similar effect may be achievable by having the patient breathe through pursed lips.
Continuous positive airway pressure (CPAP) is used in some ski resort clinics with anecdotal success. Nevertheless, no controlled study has established that CPAP improves clinical outcome in patients with HAPE, and in published case reports, CPAP has only been used in combination with other therapies . A CPAP helmet has been used in the field .
High-flow nasal canula for the management of HAPE has not been studied, although theoretically, this intervention would be useful for all forms of type 1 (hypoxemic) respiratory failure.
Pharmacologic interventions — A summary of medications used to treat HAPE is provided (table 4). More thorough discussions of these treatments are found below.
Nifedipine — In the field setting, oxygen and descent remain the most important treatments for HAPE. Nifedipine may be considered adjunctive therapy when oxygen is unavailable and descent is difficult or impossible, although little clinical evidence supports the practice. (See 'General approach to treatment' above.)
Nifedipine is a nonspecific calcium channel blocker that acts by reducing pulmonary vascular resistance and pulmonary artery pressure, as well as systemic resistance and blood pressure. It also slightly improves PaO2.
Recommended doses vary, but a common regimen is to give 30 mg of a slow-release formulation every 12 hours. Nifedipine is well tolerated by most patients and is unlikely to cause significant hypotension in previously healthy persons. Clinicians should give or be prepared to give isotonic intravenous fluid (eg, normal saline) to any critically ill HAPE patient who may be intravascularly depleted and is receiving nifedipine.
One unblinded, uncontrolled study of six patients with HAPE found that nifedipine treatment led to clinical improvement. However, another observational study involving 133 patients with HAPE reported that nifedipine offered no advantage when used as an adjunct to oxygen and descent .
Tadalafil and sildenafil — Tadalafil and sildenafil are phosphodiesterase-5 (PDE-5) inhibitors that augment the pulmonary vasodilatory effects of nitric oxide by blocking the degradation of cyclic guanosine monophosphate (cGMP), the intracellular mediator of nitric oxide. Nitric oxide is a potent pulmonary vasodilator and reduces hypoxic pulmonary vasoconstriction and pulmonary hypertension in HAPE . Both tadalafil and sildenafil have been shown to be effective as prophylaxis for HAPE, but neither has been studied as treatment [43-45]. (See 'Prophylactic medications' below.)
Nevertheless, based upon their mechanism of action, both tadalafil and sildenafil may be effective adjunct treatments for established HAPE when neither oxygen nor descent is an available option. These drugs may have advantages over nifedipine because they lower pulmonary artery pressure with less risk of lowering systemic blood pressure. However, tadalafil caused a marked headache in 2 of 10 subjects in one small randomized trial, a well-known side effect of this class of medications . The appropriate dose for treatment is unknown but might be similar to that used for prophylaxis (tadalafil 10 mg by mouth every 12 hours; sildenafil 50 mg by mouth every eight hours).
Dexamethasone — Although glucocorticoids may have a role in prophylaxis, they have not been studied as treatment for HAPE. Nonetheless, some experts have recommended their use based on the mechanism of action , while others disagree . We reserve glucocorticoids for treatment of HACE or severe acute mountain sickness, which may co-exist with HAPE. (See 'Prophylactic medications' below.)
Ineffective or contraindicated therapies — Diuretic therapy, nitrates, and morphine are no longer recommended in the treatment of HAPE and could be harmful.
Suggested approach to prophylaxis — Gradual ascent remains the primary method for preventing all forms of high-altitude illness, including HAPE. For those with a history of HAPE, we recommend an ascent rate of no more than 400 meters per day in sleeping altitude. For patients with no history of medical problems at high altitude or of pulmonary hypertension, the risk of HAPE is low, and routine pharmacologic prophylaxis is not warranted.
In individuals at high risk, particularly those with a history of HAPE, pharmacologic prophylaxis may be prudent, especially when time does not allow for adequate acclimatization. Nifedipine is the drug of choice for prophylaxis against HAPE. It should be started the day prior to ascent if possible and continued for five days at a fixed altitude, or continued with progressive altitude gain (up to seven days after reaching the destination altitude in individuals who ascend faster than recommended) until the start of descent.
While the results of initial small studies are promising, further research is needed to determine whether dexamethasone or phosphodiesterase 5 (PDE-5) inhibitors such as tadalafil are effective prophylactic medications. Based upon mechanism and clinical experience, acetazolamide is a reasonable medication for HAPE prophylaxis, but formal studies are lacking. Salmeterol should be considered only an adjunct prophylactic medication to nifedipine in high-risk individuals with a clear history of recurrent HAPE.
Prophylactic medications — A summary of medications used for the prophylaxis and treatment of HAPE is provided (table 4). More thorough discussions of the drugs used for prophylaxis are found below.
Nifedipine — Nifedipine is the preferred drug for the prevention of HAPE but is used only in high-risk individuals and only when acclimatization is not possible. Ideally, treatment is started 24 hours prior to ascent and continued for five days at the destination altitude. In higher-risk scenarios, treatment may be continued for up to seven days at the destination altitude or until the start of descent. We give 30 mg of the extended-release formulation every 12 hours.
In a small randomized trial, 20 mg of a slow-release formulation taken by mouth every eight hours while the participants performed a steep ascent prevented HAPE in 9 of 10 subjects with a history of repeated episodes documented by chest radiograph . Seven of the 11 subjects given placebo developed radiographically proven HAPE. Note that 20 mg extended-release formulations are not available in the United States.
Dexamethasone — Further study is needed to determine whether dexamethasone is an appropriate medication for prophylaxis against HAPE. In one randomized trial of 29 individuals with a history of HAPE, none of the 10 participants given dexamethasone prophylaxis (8 mg every 12 hours) developed HAPE during a rapid ascent from 490 to 4559 meters with an overnight stay . Prophylaxis with dexamethasone has the added advantage of preventing acute mountain sickness/high-altitude cerebral edema (HACE), whereas nifedipine and the PDE-5 inhibitors have no such effect.
Dexamethasone's mechanism of action remains unclear. It may involve upregulation of nitric oxide production and upregulation of alveolar epithelial membrane sodium channels and sodium-potassium ATPase.
Tadalafil and sildenafil — In small studies, the PDE-5 inhibitors sildenafil and tadalafil prevented hypoxic pulmonary hypertension and the development of HAPE [49-51]. Optimal doses have not been established. Regimens for sildenafil have varied from a single dose of 50 or 100 mg just prior to exposure for acute ascent, to 40 mg three times per day for individuals who spend two to six days at high altitude; we give 50 mg every eight hours. For tadalafil, 10 mg every 12 hours is the usual dose. These drugs are potentially safer than nifedipine because there is less risk of hypotension, but they are more expensive and carry the risk of severe headaches. Sildenafil has shorter dosing intervals because its half-life is four to five hours; tadalafil's half-life is 17 hours. These drugs can be started the day of ascent and continued for three to five days after reaching maximal altitude; they can be extended for up to seven days or until start of descent in individuals who ascend faster than recommended.
Beta agonist — Salmeterol prevented HAPE in 50 percent of subjects in one small study and thus appears less effective than other agents . However, it is safe and can be used in combination with acetazolamide or other medications. Salmeterol was chosen for prophylactic studies because of its relatively longer duration of action. Albuterol is less expensive and may be effective prophylaxis, but this has not been studied.
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SUMMARY AND RECOMMENDATIONS
●Epidemiology and risk factors – High-altitude pulmonary edema (HAPE) generally occurs above 2500 meters (8000 feet). The incidence depends upon individual susceptibility, altitude attained, rate of ascent, and time spent at high altitude. Symptoms of acute mountain sickness develop in approximately 50 percent of those with HAPE. High-altitude cerebral edema (HACE) may occur concomitantly. (See 'Pathophysiology' above and 'Epidemiology and risk factors' above and "Acute mountain sickness and high-altitude cerebral edema".)
Pre-existing conditions or anatomic abnormalities that lead to increased pulmonary blood flow, pulmonary hypertension, or increased pulmonary vascular reactivity may predispose to HAPE, even at altitudes below 2500 meters. Such conditions include pulmonary hypertension of any etiology and intracardiac shunts, such as atrial septal defects and ventricular septal defects. Additional risk factors are described in the text. (See 'Epidemiology and risk factors' above.)
●Clinical presentation in adults – HAPE generally begins with a subtle, nonproductive cough, shortness of breath with exercise, and difficulty walking uphill. Symptoms typically appear two to four days after arrival at higher altitude. As HAPE progresses, dyspnea becomes noticeable at rest and severe with any attempt at exertion. Tachycardia, tachypnea, and low-grade fever are common. A cardinal clinical feature of HAPE is the progression from dyspnea with exertion to dyspnea at rest over a relatively brief period. Oxygen saturation values are at least 10 points below normal for altitude and usually range from 50 to 75 percent. (See 'Clinical presentation' above.)
●Clinical presentation in children – In children, HAPE presents as increasing respiratory distress over one to two days but may develop more precipitously. Young children may manifest only pallor and depressed consciousness or other nonspecific symptoms. It can be difficult to differentiate between HAPE and viral respiratory infection, and the two may coexist. (See 'Presentation in children' above.)
●Diagnostic imaging – Chest radiography usually reveals characteristic patchy alveolar infiltrates, predominantly in the right central hemithorax, which become more confluent and bilateral as the illness progresses. A significant discrepancy often exists between the extensive infiltrates on radiograph and the clinical status of the patient, who often does not appear severely ill and steadily improves with oxygen therapy. Ultrasound can detect increased extravascular lung water, which can help to confirm the diagnosis of HAPE. Other commonly available tests are nonspecific. (See 'Imaging studies' above.)
●Distinguishing HAPE from heart failure or pneumonia – Differentiating HAPE from such ailments as acute decompensated heart failure or pneumonia can be difficult, particularly in older patients with comorbid conditions. In such patients, HAPE is a diagnosis of exclusion. In general, HAPE is associated with marked weakness and hypoxemia that is more severe than that associated with most cases of pneumonia. Rapid improvement over hours in response to oxygen therapy or descent strongly suggests the diagnosis of HAPE. In otherwise healthy patients with a characteristic history of HAPE and examination findings consistent with the diagnosis, antibiotics are typically not necessary. (See 'Diagnoses confused with HAPE' above and 'Distinguishing HAPE and pneumonia' above.)
●Management – Early recognition of HAPE and prompt intervention are critical to assuring a favorable outcome. Immediate descent is not mandatory in all cases, if oxygen is available; treatment varies depending upon the severity of illness, available treatments, setting, and clinician experience. (See 'Treatment' above.)
We recommend that supplemental oxygen be given as first-line treatment, rather than any pharmacologic therapy, to all patients with HAPE whenever it is available (Grade 1B). Descent to lower altitude may be needed in addition to supplemental oxygen depending on the circumstances. At higher elevations (>4000 meters), descent is mandatory.
Oxygen and descent (actual or simulated using a hyperbaric enclosure) are often effective alone and appear to be superior to any pharmacologic therapy. In the hospital setting, supplemental oxygen and rest are generally sufficient treatment. In remote high-altitude settings, descent should begin as soon as HAPE is suspected. Adjunctive medical therapies may be helpful and are discussed in the text. (See 'Pharmacologic interventions' above.)
●Prophylaxis – For patients with no history of medical problems at high altitude, the risk of HAPE is low, and routine prophylaxis is not warranted. We suggest prophylaxis with nifedipine, rather than other pharmacologic therapy (eg, dexamethasone), for individuals with a history of HAPE or with known predisposing factors who must ascend to altitudes above 2500 meters without adequate time for acclimatization (Grade 2C). In such circumstances, we give nifedipine (30 mg of a slow-release formulation every 12 hours). Additional adjunct medications for prophylaxis are discussed in the text. (See 'Prevention' above.)
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