Altitude Illness - Pulmonary Syndromes

Acclimatization

Hypoxia is the primary physiological insult on ascent to high altitude. The fraction of oxygen in the atmosphere remains constant (0.21), but the partial pressure of oxygen decreases along with barometric pressure on ascent to altitude. The inspired partial pressure of oxygen (PiO2) is lower still because of water vapor pressure in the airways. At the altitude of La Paz, Bolivia (4000 m; 13,200 ft), PiO2 is 86.4 mm Hg, which is equivalent to breathing 12% oxygen at sea level.

The response to hypoxia depends on both the magnitude and the rate of onset of hypoxia. The process of adjusting to hypoxia, termed acclimatization, is a series of compensatory changes in multiple organ systems over differing time courses from minutes to weeks. While the fundamental process occurs in the metabolic machinery of the cell, acute physiologic responses are essential in allowing the cells time to adjust.

The most important immediate response of the body to hypoxia is an increase in minute ventilation, triggered by oxygen-sensing cells in the carotid body. Increased ventilation produces a higher alveolar PO2. Concurrently, a lowered alveolar PCO2 results in a respiratory alkalosis and so acts as to limit the increase in ventilation. Renal compensation, through excretion of bicarbonate ion, gradually brings the blood pH back toward normal and allows further increase in ventilation. This process, termed ventilatory acclimatization, requires approximately 4 days at a given altitude and is greatly enhanced by acetazolamide. Patients with inadequate carotid body response (genetic or acquired, eg, after surgery or radiation) or pulmonary or renal disease may have an insufficient ventilatory response and thus not adapt well to high altitude.

In addition to ventilatory changes, circulatory changes occur that increase the delivery of oxygen to the tissues. Ascent to high altitude initially results in increased sympathetic activity, leading to increased resting heart rate and cardiac output and mildly increased blood pressure. The pulmonary circulation reacts to hypoxia with vasoconstriction. This may improve ventilation/perfusion matching and gas exchange, but the resulting pulmonary hypertension can lead to a number of pathological syndromes at high altitude, including HAPE and altitude-related right heart failure. Cerebral blood flow increases immediately on ascent to high altitude, returning to normal over about a week. The magnitude of the increase varies but averages 24% at 3810 m and more at higher altitude. Whether the headache of AMS is related to this flow increase is not known.[5]

Hemoglobin concentration increases after ascent to high altitude, increasing the oxygen-carrying capacity of the blood. Initially, it increases due to hemoconcentration from a reduction in plasma volume secondary to altitude diuresis and fluid shifts. Subsequently, over days to months, erythropoietin stimulates increased red cell production. In addition, the marked alkalosis of extreme altitude causes a leftward shift of the oxyhemoglobin dissociation curve, facilitating loading of the hemoglobin with oxygen in the pulmonary capillary.

Sleep architecture is altered at high altitude, with frequent arousals and nearly universal subjective reports of disturbed sleep.[6] This generally improves after several nights at a constant altitude, though periodic breathing (Cheyne-Stokes) is normal above 2700 m.

Pathophysiology of HAPE[7, 8, 9, 10]

HAPE is a noncardiogenic, hydrostatic pulmonary edema, characterized by pulmonary hypertension and increased pulmonary capillary pressure. Left ventricular function is normal in HAPE. Patchy hypoxic pulmonary vasoconstriction and consequent localized overperfusion, combined with hypoxic permeability of pulmonary capillary walls, results in a high-pressure, high-permeability leak. In addition, alveolar fluid clearance may be altered in those susceptible to HAPE.

Hypoxic pulmonary vasoconstriction results in increased pulmonary artery pressures in all who ascend to high altitude, but it is exaggerated in those susceptible to HAPE, primarily due to genetically determined factors.[11] In a case-control study of a Chinese Han population, He et al found that 2 single-nucleotide polymorphisms (SNPs) of the IL6 gene, specifically rs1800796 and rs1524107, had a significant association with HAPE.[12]  IL6 encodes a cytokine with inflammatory function. This genetically based individual susceptibility is perhaps the greatest risk factor, although preexisting medical conditions associated with pulmonary hypertension or a restricted pulmonary vascular bed will greatly increase susceptibility to HAPE. Exercise increases the risk of HAPE because it increases cardiac output, severity of hypoxemia, and pulmonary artery pressure at altitude.

While it has long been held that HAPE and AMS/HACE do not share pathophysiologic basis, studies have noted increases in optic nerve sheath diameter (ONSD)—a measure of increased intracranial pressure—in patients with acute HAPE, which decreased as HAPE resolved.[13]  In a study of 429 patients with HAPE at an altitude of 4500 m, HACE occurred concomitantly in 9.32% of cases.[14]

Causes are as follows:

• Rapid ascent

• Higher altitudes are more risky.

• Low hypoxic ventilatory response

• Congenital absence of a pulmonary artery or other vascular abnormalities that create a restricted pulmonary circulatory bed

• Pulmonary hypertension

Physical exertion may precipitate or exacerbate HAPE (by raising pulmonary artery pressures).

Frequency

United States

The true incidence is unknown, although HAPE is known to occur at high-altitude ski areas in Colorado at a rate of approximately 1 case per 10,000 skier-days.

Current research with the International HAPE Registry is working to better define the incidence and factors surrounding HAPE occurrence.[15]

International

The reported incidence of HAPE varies from 0.01-15%, depending on the altitude, the ascent rate, and the population at risk. Studies have assessed high altitude illness in Denali,[16] Nepal,[17] , Tibet,[14] and the South Pole.[18]

Race-, sex-, and age-related information

Prior reports of "genetic protection" from HAPE afforded to Tibetan and Sherpa peoples must be taken as limited in scope and may well not be true. Case series of patients with HAPE from indigenous groups previously reported as "protected" from HAPE exist.

Some studies have suggested that males are affected more frequently than females; however, these studies were retrospective and did not study the population at risk.[14]

Occurrence of primary HAPE has no clear association with age, although reascent HAPE is more common in children who reside in high altitude who return to high altitudes after a lowland sojourn than in adults in the same circumstances.

The prognosis is excellent for survivors, with rapid clearing of the edema fluid and no long-term sequelae. Patients may need from 3 days to 2 weeks to recover completely; after all symptoms have resolved, cautious reascent is acceptable.

Mortality/morbidity

HAPE can be rapidly fatal within a few hours unless treated by descent or oxygen. HAPE is the most common cause of death related to high altitude.

Given appropriate treatment, recovery from HAPE is usually complete and can occur rapidly (1-2 d). This noted, even with proper treatment, a small percentage of patients will die. Patients who recover have rapid clearing of edema fluid and do not develop fibrosis or other long-term sequelae.

One report describes a case series of HAPE treated successfully at more than 14,000 ft when emergent descend was not a viable option.[19] Important to note, while these cases had good outcomes, they were being treated by physicians with expertise in treating HAPE who had full access to advanced treatment modalities. Rapid descent remains a critical treatment for most cases of HAPE.

Patients should be educated on staged ascents (see Deterrence/Prevention).

The golden rules of altitude illness are as follows:

• If a person feels sick at altitude, his or her condition is altitude illness unless proven otherwise.

• If symptoms of acute mountain sickness (AMS) are present, go no higher.

• If symptoms are worsening, fail to improve with treatment, or if HACE or HAPE is present, descend immediately.

HAPE generally occurs 2-4 days after ascent to high altitude, often worsening at night. Decreased exercise performance is the earliest symptom, usually associated with a dry cough. The early course is subtle; as the illness progresses, the cough worsens and becomes productive; dyspnea can be severe, tachypnea and tachycardia develop, and drowsiness or other CNS symptoms may develop. Chest radiographs characteristically show patchy unilateral or bilateral fluffy infiltrates and a normal cardiac silhouette. The presence of a low-grade fever has led to misdiagnosis as pneumonia and to subsequent deaths.

HAPE varies in severity from mild to immediately life-threatening. It can be fatal within a few hours, and it is the most common cause of death related to high altitude. Left untreated, HAPE has a mortality rate near 50%.[20] Differential diagnosis is sometimes problematic, but HAPE improves dramatically with descent or oxygen, whereas other diagnoses do not; these should be pursued in patients who do not fit this pattern.

Chest radiography

The chest radiograph is usually irrelevant to field diagnosis and management but is useful in the context of a high-altitude clinic or hospital. Patchy, asymmetric, unilateral or bilateral fluffy infiltrates and a normal cardiac silhouette are characteristic of HAPE.

Thoracic ultrasonography (comet tail sign)

Recent reports reveal thoracic ultrasonographic assessment for comet tail signs to be sensitive in making the diagnosis of HAPE and grading clinical severity (see images below).[21]

Thoracic ultrasonography: comet tail sign. Patient with acute high-altitude pulmonary edema (HAPE). Note wedge-shaped forms extending from pleural lining. In contrast, normal thoracic sonogram (below) reveals only diffuse, "snow storm" appearance. Courtesy of Dr Peter Fagenholz, et al.

Thoracic ultrasonography. Normal thoracic sonogram reveals only diffuse, "snow storm" appearance without comet tail sign. Courtesy of Dr Peter Fagenholz, et al.

Standard thoracic ultrasonography uses 28 standard views across the anterior chest and can be completed in minutes. Comet tail signs are artifacts resulting from increased pulmonary edema. Advantages of ultrasonography include portability of equipment, use of nonionizing radiation, rapidity of assessment, and ease of reassessment. Current studies are ongoing to define sensitivity and rate of response of ultrasonography versus standard radiography.

The mainstay of treatment is descent for anything other than mild HAPE. Descent to an altitude below that where symptoms started is always effective treatment, but it may not be practical or possible given the topography, weather, the patient's ultimate trekking or climbing goals, or group resources. Accordingly, a descent of 500-1000 m is usually sufficient. As noted above, while case series of treatment of even severe HAPE under expert care in well-equipped settings have been reported, descent for other than mild HAPE cases remains clearly indicated. Selected cases of reascent HAPE and mild HAPE at moderate altitude may be treated with oxygen and strict bedrest. If patients worsen, they must descend.

All of the following treatments are used as an adjunct to descent. Oxygen, if available, is lifesaving and should be administered at 4 L/min by mask or nasal cannula. Nifedipine should be used if descent or oxygen is not available. Nifedipine may help prevent exertional worsening in patients being evacuated on foot. Portable hyperbaric chambers (see image below) can effect a physiologic (simulated) descent when actual descent is not possible or practical.[22] End-positive pressure masks are useful in treating HAPE but are poorly tolerated. 

Hyperbaric treatment at 4250 m in a Gamow bag.

The role of acetazolamide in the treatment of HAPE remains ill-defined but may prove beneficial. Additionally, recent reports give evidence that dexamethasone might have beneficial effect in HAPE as well. While not clearly established, there is little apparent downside risk to using either acetazolamide and dexamethasone in severe HAPE.[23]

Inhaled salmeterol (a beta-agonist) has been demonstrated to help prevent acute HAPE in HAPE-susceptible populations. Salmeterol is thought to act by increasing alveolar fluid clearance through pulmonary sodium channels. Although its use in HAPE treatment has not been proven, it is often used in this indication.

Phosphodiesterase inhibitors have also been demonstrated to help prevent acute HAPE in HAPE-susceptible populations. These agents are thought to act by increasing availability of nitric oxide in pulmonary arterial vessels and so result in decreased pulmonary arterial tone and reduced pulmonary hypertension. Although its use in HAPE treatment has not been proven, it is often used in this indication.

Only limited studies provide any evidence that furosemide may be useful with acute HAPE, and it is not without downside risk. Furosemide should be used with substantial caution, if at all, as many patients are intravascularly depleted. Most authors discourage use of furosemide in treating HAPE.

Portable hyperbaric chambers (eg, Gamow, CERTEC, PAC) are widely used among adventure travel/trekking groups and climbing expeditions. These chambers are lightweight, coated fabric bags about 2 m in length and 0.7 m in diameter. The patient is placed inside the bag, which is sealed shut and inflated with a manually operated pump, pressurizing the inside to 105-220 mm Hg above ambient atmospheric pressure. This pressure gradient is regulated by pop-off valves set to the target pressure, and it is fixed depending on the brand of bag in use.

Depending on the elevation, a physiologic (simulated) descent of about 2000 m (7000 ft) may be achieved within minutes. Intermittent pumping is necessary to flush carbon dioxide from the system, unless a chemical scrubber system is used. Patients with severe HAPE may need to have their head elevated to tolerate lying down. Elevation can be accomplished by placing the bag on a rigid surface, such as boards or a wooden bed, and propping up the head end by 0.3-0.5 m (12-20 inches).

In practice, most patients with moderate HAPE tolerate lying flat after reaching the physiologic lower elevation of the pressurized bag. Patients typically are treated in 1-hour increments and then are reevaluated, with additional treatments as indicated. Closely monitor patients for rebound signs and symptoms, which may occur soon after removal from the hyperbaric environment, or they may develop over a period of hours.

For cases of persistent desaturation or dyspnea, administer oxygen to keep oxygen saturation (SaO2) above 90%.

Consider continuing nifedipine in symptomatic patients. Furthermore, consider dexamethasone, phosphodiesterase inhibitors, and inhaled beta-agonist as conditions indicate.

Emergency departments at altitude must assess the elevation at which the patient's illness occurred and determine whether further descent is necessary.

Admission criteria are as follows:

• Significant arterial oxygen desaturation at rest

• Dyspnea at rest

• Inability to descend

Treatment of moderate-to-severe HAPE after descent consists of bedrest and oxygen[24] ; continuation of nifedipine, tadalafil, dexamethasone, inhaled beta-agonist also may be helpful.

Discharge criteria are as follows:

• Normal SaO2 on room air

• No dyspnea at rest (mild dyspnea with exertion may persist for several days)

Children living at altitude who develop HAPE should undergo screening for diagnosis of underlying cardiopulmonary abnormalities, including pulmonary hypertension.

Recommendations on staged ascents are by and large adequate for the average person, but some persons will still become ill despite a slow, staged ascent. Persons traveling to high altitude should allow adequate time for acclimatization and pay careful attention to symptoms. Helpful guidelines to avoid altitude illness include the following:

• Avoid abrupt ascent to sleeping elevations over 3000 m (10,000 ft).

• Spend 1-2 nights at an intermediate elevation (2500-3000 m) before further ascent.

• Above 3000 m, sleeping elevations should not increase by more than 300-400 m per night.

• When topography or village locations dictate more rapid ascent, or after every 1000 m gained, spend a second night at the same elevation.

• Day hikes to higher elevations, with return to lower sleeping elevations help to improve acclimatization.

• Avoid overexertion.

• Avoid alcohol consumption in the first 2 days at a new, higher elevation; in addition to concerns about respiratory depression and exaggerated sleep hypoxemia, an AMS headache the next morning is all too easily dismissed as a hangover.

Significant abnormalities of pulmonary vasculature (eg, absence of the left pulmonary artery[25] ) or pulmonary hypertension are contraindications for going to high altitude.

There is limited evidence to suggest that a low hypoxic ventilatory response (HVR) at low altitudes is a predictor for HAPE at high altitudes.[26]

The indication for chemoprophylaxis of HAPE is repeated episodes. Whether one prior episode should encourage prophylaxis is arguable, but demonstrated susceptibility certainly requires caution. Oftentimes, a slower ascent is the only preventive method required. Effective agents for prevention of HAPE include nifedipine and salmeterol.[27, 28, 29] Those with a history of HAPE should carry nifedipine to use either prophylactically or with the first signs of HAPE. Salmeterol reduced HAPE by 50% in susceptible persons, appears safe, and should be considered for treatment as well, though it has not yet been studied for this indication. Other studies have shown evidence for a prophylactic role in HAPE for dexamethasone, but detailed study of optimal dosing protocol has not been reported.[30, 31] Oral phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil) have been found effective for prophylaxis of HAPE,[30, 31, 32, 33] but they have not yet been studied for treatment.

Outpatient treatment of mild HAPE after descent consists of bedrest. Follow up in 24 hours to check on clearance of HAPE edema.

Treatment of HAPE is indicated upon diagnosis. High-altitude cough may be treated when the symptoms become severe enough to interfere with the individual's activities.

A literature review conducted in 2015 concluded that current evidence does not support the efficacy of either phosphodiesterase-5 inhibitors or dexamethasone in HAPE treatment. However, the review was limited by inclusion of only 3 studies representing a total of 66 patients.[34]

Class Summary

Nifedipine is used for its pulmonary vasodilative effects. It inhibits calcium ions from entering the slow channels or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation.

Nifedipine (Adalat, Procardia)

Nifedipine is used in HAPE for pulmonary vasodilation. It often improves SaO2 modestly within a few minutes. Despite theoretical concerns about the sublingual route, it has been used in hundreds of cases without causing clinically significant hypotension. Nifedipine does not improve pulmonary hemodynamics as much as oxygen and does not have an additive effect when administered with oxygen. It is most useful when oxygen is unavailable and to help prevent exertional exacerbation of HAPE when evacuating a patient. The cap may be punctured, and the drug solution may be administered sublingually to reduce blood pressure.

Class Summary

This agent acts to increase available nitric oxide in pulmonary arterial vessels, resulting in vessel relaxation and decreased pulmonary hypertension. It has been found effective for HAPE prophylaxis in HAPE-susceptible patients.

Tadalafil (Cialis)

Tadalafil is a phosphodiesterase type 5 (PDE5) selective inhibitor. Inhibition of PDE5 increases cGMP activity, which increases the vasodilatory effects of nitric oxide. Sexual stimulation is necessary to activate the response. Increased sensitivity for erections may last 36 hours with intermittent dosing. Low-dose daily dosing may be recommended for more frequent sexual activity (ie, twice weekly); men can attempt sexual activity at anytime between daily doses. Tadalafil is available as 2.5-mg, 5-mg, 10-mg, and 20-mg tablets.

Class Summary

The exact mechanism has not yet been well defined but these agents have been found effective for HAPE prophylaxis in HAPE-susceptible patients.

Dexamethasone (AK-Dex, Alba-Dex, Baldex, Decadron, Dexone)

The mechanism in preventing HAPE is not well defined.

Class Summary

Sodium-dependent absorption of liquid from the airways may be defective in persons who are susceptible to HAPE; beta-adrenergic agents up-regulate the clearance of alveolar fluid.

Salmeterol (Serevent)

Salmeterol has been shown to be effective at preventing HAPE in susceptible persons, possibly by up-regulating the clearance of alveolar fluid.

Class Summary

These agents are possibly beneficial in the prophylaxis of HAPE.

Acetazolamide (Diamox)

Acetazolamide is a carbonic anhydrase inhibitor diuretic used for its respiratory-stimulant effects. It may be administered for prophylactic use in patients with a prior history of HAPE. It is not used as treatment for HAPE. For prophylactic use, begin using the day before ascent. Therapy should begin 24-48 hours before the ascent and continue during the ascent to at least 48 hours after arrival at the highest altitude.

Class Summary

These agents are used for the symptomatic treatment of high-altitude cough.

Hydrocodone and acetaminophen (Lortab, Vicodin)

This drug combination is for symptomatic relief of a cough and is helpful for pain relief of intercostal muscle strain associated with cough. It is often more effective than codeine.

Codeine

Codeine is for symptomatic relief of a cough. It is helpful for the pain of intercostal muscle strain associated with a cough. Codeine binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways and altering the perception and response to pain.

Benzonatate (Tessalon Perles)

Benzonatate may help patients with cough refractory to opiates. It suppresses cough by topical anesthetic action on respiratory stretch receptors.

Class Summary

These agents are indicated for the treatment of mild to moderate pain and headache.

Ibuprofen (Motrin, Advil, Nuprin)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Acetaminophen (Tylenol)

Acetaminophen is the drug of choice for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

Aspirin (Aspirin, Ascriptin, Bayer Aspirin, Bufferin)

Aspirin is used for the treatment of mild to moderate pain and headache.