High-altitude syndromes are those attributed directly to the hypoxia: acute hypoxia, AMS, pulmonary edema, cerebral edema, retinopathy, peripheral edema, sleeping problems, and a group of neurologic syndromes. Other syndromes occurring at high altitude, which are not necessarily related to hypoxia, include thromboembolic events (which may be attribuTable to dehydration, prolonged incapacitation, polycythemia, and cold), high-altitude pharyngitis and bronchitis, and ultraviolet keratitis. Although the different hypoxic clinical syndromes overlap, all share a fundamental mechanism, all are seen in the same setting of rapid ascent in unacclimatized persons, and all respond to the same essential therapy: descent and oxygen.
The syndrome of acute hypoxia occurs in the setting of sudden and severe hypoxic insult, such as accidental decompression of a pressurized aircraft cabin or failure of the oxygen system used by a pilot or high-altitude mountaineer. Sudden overexertion precipitating arterial desaturation, acute onset of pulmonary edema, carbon monoxide poisoning, and sleep apnea may result in relatively acute hypoxia as well. Unacclimatized persons become unconscious at an SaO2 of 50% to 60%, a PaO2 of less than approximately 30 mm Hg, or a jugular venous PO2 of <15 mm Hg. Acute hypoxia reverses with immediate administration of oxygen, rapid descent, and correction of the underlying cause. Symptoms of acute hypoxia reflect the sensitivity of the CNS to this insult: dizziness, light-headedness, and dimmed vision progressing to loss of consciousness. Hyperventilation increases the time of useful consciousness during acute alveolar hypoxia.
AMS is a syndrome characterized by headache along with some combination of GI disturbance, dizziness, fatigue, or sleep disturbance (Table 221-2). It occurs in the setting of more gradual and less severe hypoxic insult than in acute hypoxia syndrome. Its incidence varies by location, ease of access to the high-altitude environment, rate of ascent, and sleeping altitude. One study found a 25% incidence of AMS in physicians attending a continuing-education meeting held at 2100 m (6900 ft) in Colorado. Other studies at resorts at altitudes between 2220 and 2700 m (7280 and 8860 ft) claim an incidence between 17% and 40%, and a sleeping altitude of 2740 m (9000 ft) seems to be a threshold for an increase in attack rate.2 Approximately 40% of trekkers in Nepal on the path to Mount Everest experience AMS, and climbers on Mount Rainier have a very high incidence of 70% because of the rapidity of ascent.
TABLE 221-2Lake Louise Acute Mountain Sickness (AMS) Self-Questionnaire* ||Download (.pdf) TABLE 221-2 Lake Louise Acute Mountain Sickness (AMS) Self-Questionnaire*
Severe headache, incapacitating—3
2. GI symptoms
Poor appetite or nausea—1
Moderate nausea or vomiting—2
Severe nausea and vomiting, incapacitating—3
Not tired or weak at all—0
Mild fatigue or weakness—1
Moderate fatigue or weakness—2
Severe fatigue or weakness, incapacitating—3
Severely light-headed, fainting/passing out—3
5. Difficulty sleeping
Did not sleep as well as usual—1
Woke many times, poor night's sleep—2
Could not sleep at all—3
Total symptom score
In addition to rate of ascent and sleeping altitude, inherent factors determine individual susceptibility to AMS. Blunted carotid body response and low vital capacity are examples. Age has little influence on incidence, with children being as susceptible as adults, although those >50 years of age tend to have less AMS. Women are just as likely to develop mountain sickness but appear to have less pulmonary edema. Obesity has recently been linked to the development of AMS, possibly due to greater nocturnal oxygen desaturation.3 Susceptibility to AMS generally is reproducible in an individual on repeated exposures. Persons living at intermediate altitudes of 1000 to 2000 m (3300 to 6600 ft) already are partially acclimatized and do much better than lowlanders on ascent to higher altitudes. There is no relationship between susceptibility to AMS and physical fitness.
AMS is due to hypobaric hypoxia, but the exact sequence of events leading to illness is unclear. Cerebral vasodilation appears to be the initiating event. Vasodilation occurs in the brain in all persons ascending to high altitude, thus increasing cerebral blood flow and blood volume. Whether this is solely sufficient to cause the symptoms of mild AMS is unclear. However, in persons who progress to high-altitude cerebral edema, vasogenic edema is evident as increased T2 signal on MRI.4 The leaky blood–brain barrier in high-altitude cerebral edema is due either to loss of autoregulation leading to overperfusion, or to increased permeability caused by mediators such as vascular endothelial growth factor or bradykinin. A combination of these two processes is also possible. The fact that dexamethasone so effectively treats AMS also supports the notion of vasogenic edema. An alternative notion is that the trigeminal-vascular system is triggered by hypoxic vasodilation or by noxious agents such as nitric oxide or free oxygen radicals.
The diagnosis of AMS is based on an appropriate setting paired with characteristic symptoms. The setting is rapid ascent of an unacclimatized person to 2000 m (6560 ft) or higher. On arrival the person typically feels light-headed and slightly breathless, especially with exercise. Symptoms develop between 1 and 6 hours later, but sometimes are delayed for 1 or 2 days (especially after a night's sleep). Symptoms of mild AMS are remarkably similar to those of an alcohol hangover. Headaches are usually bifrontal and worsen with exertion, bending over, or performing a Valsalva maneuver. GI symptoms include anorexia, nausea, and sometimes vomiting, especially in children. The chief constitutional symptoms are lassitude and weakness. The person with AMS can be irriTable and often wants to be left alone. Sleepiness and a deep inner chill also are common. The Lake Louise AMS self-report questionnaire can be helpful in following the severity of the illness (Table 221-2).
As the illness progresses, headache becomes more severe while vomiting and oliguria develop. Lassitude may progress so that the victim requires assistance in eating and dressing. The onset of ataxia and altered level of consciousness heralds high-altitude cerebral edema. Coma may ensue within 12 hours if treatment is delayed. The diagnosis of AMS can be difficult in preverbal children and should be a diagnosis of exclusion.5
Physical findings in mild AMS are nonspecific. Heart rate and blood pressure are variable and usually in the normal range, although postural hypotension may be present. Presenting percent SaO2 is typically normal or slightly low for a given altitude, and percent SaO2 overall correlates poorly with the diagnosis of AMS. Localized rales are detecTable in up to 20% of persons with AMS. Fundoscopy reveals venous tortuosity and dilatation, and retinal hemorrhages are common at altitudes >5000 m (>16,400 ft) and in those with pulmonary and cerebral edema. Facial and peripheral edema sometimes accompanies AMS.
The differential diagnosis in this setting includes hypothermia, carbon monoxide poisoning, pulmonary or CNS infection, dehydration, migraine, and exhaustion. Carbon monoxide poisoning may have a presentation very similar to that of AMS and is not uncommon in mountain towns in the winter. Reduced oxyhemoglobin levels complicate hypoxia from high altitude, and the effects are additive. Hypoxia may trigger a migraine headache in patients with a personal or family history of migraine.6 Headache from AMS often dissipates within 10 to 15 minutes with supplemental oxygen administration, unlike headaches from other causes. Providers may find this to be a useful diagnostic maneuver.
The average duration of AMS at a Colorado resort (3000 m or 9840 ft) was 15 hours, with a range of up to 94 hours. Half of those affected with AMS chose to self-medicate.2 At higher sleeping altitudes the illness may last much longer, up to weeks if untreated, and is more likely to progress to pulmonary or cerebral edema. Eight percent of those with AMS at 4270 m (14,000 ft) in Nepal developed cerebral or pulmonary edema or both.7
The goals of treatment (Table 221-3) are to prevent progression, treat symptoms, and improve acclimatization. Early diagnosis is essential. Initial clinical presentation does not predict eventual severity, and all persons with AMS must be observed carefully for progression. The three principles of treatment are (1) do not proceed to a higher sleeping altitude in the presence of symptoms, (2) descend if symptoms do not abate or become worse despite treatment, and (3) descend and treat immediately in the presence of a change in consciousness, ataxia, or pulmonary edema. Descent is the definitive treatment for all forms of altitude illness. However, descent is not always an option, nor is it always necessary.
TABLE 221-3Suggested Treatment Options for High-Altitude Illness ||Download (.pdf) TABLE 221-3 Suggested Treatment Options for High-Altitude Illness
|Mild AMS ||No further ascent |
| ||Descent to lower altitude or acclimatization at same altitude |
| ||Acetazolamide, 125–250 milligrams PO twice a day, to speed acclimatization |
| ||Symptomatic treatment as necessary with analgesics and antiemetics |
|Moderate/severe AMS ||Immediate descent for worsening symptoms |
| ||Low-flow oxygen if available |
| ||Acetazolamide, 250 milligrams PO twice a day, and/or dexamethasone, 4 milligrams PO every 6 h |
| ||Hyperbaric therapy |
|High-altitude cerebral edema ||Immediate descent or evacuation |
| ||Oxygen 2–4 L/min or titrated to SaO2>90% |
| ||Dexamethasone, 8 milligrams PO, IM, or IV, then 4 milligrams every 6 h |
| ||Hyperbaric therapy if patient cannot descend |
|High-altitude pulmonary edema ||Immediate descent or evacuation |
| ||Oxygen 4 L/min or titrated to SaO2>90% |
| ||Nifedipine, 30 milligrams PO extended release every 12 h if no oxygen or descent* |
| ||Hyperbaric therapy if patient cannot descend |
| ||Measures to minimize patient exertion and keep patient warm |
| ||Dexamethasone if cerebral signs present, 4 milligrams PO every 6 h |
|Periodic breathing/insomnia ||Acetazolamide, 62.5–125.0 milligrams PO at bedtime as needed |
Descent and Oxygen Mild AMS is self-limited and generally improves with an extra 12 to 36 hours of acclimatization if ascent is halted. Remarkably, a drop in altitude of only 300 to 1000 m (980 to 3280 ft) usually is effective. Evacuation to a hospital or to sea level is unnecessary except in the most severe cases. To simulate descent, porTable hyperbaric bags are being used in various locations to treat high-altitude illness. The patient is inserted into the fabric chamber, and a pressure of 0.9 kg/2.5 cm2 (2 lb/in.2) is achieved by means of a manual or automated pump, equivalent to a drop in altitude of 1500 m (4920 ft). A valve system creates sufficient ventilation to avoid carbon dioxide accumulation or oxygen depletion.
Oxygen effectively relieves symptoms, but it is generally unavailable in the field or reserved for those with moderate to severe AMS in order to conserve supplies. Oxygen supplementation quickly relieves headache and dizziness. Nocturnal administration of low-flow oxygen (0.5 to 1 L/min) is particularly helpful and efficient. The combination of oxygen and descent provides optimal therapy, especially in more severe illness.
Medical Therapy Pharmacologic treatment offers an alternative to descent or oxygen administration in patients with mild to moderate AMS. Acetazolamide acts by inhibiting the enzyme carbonic anhydrase. In the kidney, acetazolamide reduces reabsorption of bicarbonate, causing a bicarbonate diuresis and metabolic acidosis that stimulates ventilation. As a result, PaO2 is higher. Acetazolamide thus reverses the deleterious effects of hypobaric hypoxia. The drug also maintains cerebral blood flow despite greater hypocapnia.
The treatment regimen for AMS varies: 125 milligrams PO twice daily is effective for some individuals, whereas others may require 250 mg PO twice daily. Side effects are more common with higher doses and include peripheral paresthesias and sometimes nausea or drowsiness. Although acetazolamide contains a sulfhydryl moiety, cross-reactivity in those with sulfa antibiotic allergy is uncommon. Nevertheless, individuals with a history of anaphylaxis to sulfa antibiotics should avoid acetazolamide. Treatment should be continued until symptoms of AMS resolve. It can always be restarted if symptoms return. Because the drug inhibits carbonic anhydrase on the tongue, carbonated beverages such as soda or beer may have an altered flavor.
Symptomatic treatment of AMS is often sufficient. Aspirin, 650 milligrams, acetaminophen, 650 to 1000 milligrams (with or without codeine), or ibuprofen, 600 to 800 milligrams, is effective for headache. Aspirin is effective for prophylaxis of headache in persons who are not exercising.8 Ondansetron orally disintegrating tablets, 4 to 8 milligrams every 4 to 6 hours, effectively treat nausea and vomiting associated with AMS and should be the first-line antiemetic in this setting.
Dexamethasone, 4 milligrams PO, IM, or IV every 6 hours, is quite effective for mountain sickness, but is best reserved for cases of moderate to severe AMS because of potential side effects. Also dexamethasone does not aid acclimatization and may result in some rebound symptoms when discontinued. A short taper period may prevent rebound. The administration of acetazolamide to speed acclimatization and a brief course of dexamethasone to treat illness is a useful combination. Another useful treatment regimen but one that is not yet validated is a one-time dose of dexamethasone followed by a course of acetazolamide.
Frequent nighttime awakening is a common nuisance at high altitude. Before bedtime, acetazolamide, 62.5 to 125 milligrams, improves sleep oxygenation and reduces apneic periods, thereby improving sleep quality. The newer nonbenzodiazepine sleep agents can also be used. These include zolpidem, 5 to 10 milligrams, zolpidem controlled-release, 6.25 to 12.5 milligrams, or eszopiclone, 1 to 2 milligrams. These drugs are safe at altitude and do not depress ventilation. Diphenhydramine, 25 to 50 milligrams before bedtime, is a safe over-the-counter alternative (Table 221-4).
TABLE 221-4Medications for High-Altitude Illnesses ||Download (.pdf) TABLE 221-4 Medications for High-Altitude Illnesses
|Agent ||Indication ||Dosage ||Adverse Effects ||Comments |
|Acetazolamide ||Prevention of AMS ||125–250 milligrams PO twice a day beginning 24 h before ascent and continuing during ascent and for at least 48 h after arrival at highest altitude || |
Common: paresthesias, polyuria, altered taste of carbonated beverages
Less common: drowsiness, nausea
|Can be taken episodically for symptoms (speeds acclimatization); no rebound effect; pregnancy category C, avoid in breastfeeding |
| ||Treatment of AMS ||250 milligrams PO every 8–12 h || || |
| ||Pediatric AMS ||5 milligrams/kg/d PO in divided doses every 8–12 h || || |
| ||Periodic breathing ||125 milligrams PO 4 h before bedtime || || |
|Dexamethasone ||Treatment of AMS ||4 milligrams every 6 h PO, IM, or IV ||Mood changes, hyperglycemia, dyspepsia ||Rapidly improves AMS symptoms; can be lifesaving in HACE, may improve HACE enough to facilitate descent; no value in HAPE; pregnancy category C but preferably avoided in pregnancy or breastfeeding |
| ||HACE ||8 milligrams initially, then 4 milligrams every 6 h PO, IM, or IV || || |
| ||Pediatric HACE ||0.15 milligram/kg every 6 h PO, IM, or IV, not to exceed 16 milligrams/d || || |
|Tadalafil ||Prevention of HAPE ||10 milligrams PO twice a day starting 1 d prior to ascent and continuing for 2–4 d at maximum sleeping altitude ||Headache, hypotension (less than with nifedipine), priapism (rare), visual/hearing change or loss (extremely rare) ||More effectively blunts hypoxic pulmonary vasoconstriction than sildenafil; better tolerated than nifedipine; pregnancy category B |
|Nifedipine ||Prevention of HAPE ||20–30 milligrams extended-release PO every 12 h ||Reflex tachycardia, hypotension (uncommon) || |
| ||Treatment of HAPE ||30 milligrams extended-release formulation PO every 12 h || ||No value in AMS or HACE; not necessary if supplemental oxygen available; pregnancy category C |
Graded ascent with adequate time for acclimatization is the best prevention. A recommendation for those visiting moderate-altitude resorts in the western United States is to spend a night at an intermediate altitude of 1500 to 2000 m (4920 to 6560 ft) (Denver or Salt Lake City) before sleeping at altitudes >2500 m (>8200 ft). Mountaineers and trekkers should avoid abrupt ascent to sleeping altitudes over 3000 m (9840 ft) and then allow 2 nights for each 1000-m (3230-ft) gain in camp altitude starting at 3000 m (9840 ft). Other preventative measures include avoiding overexertion, alcohol, and respiratory depressants. Prophylactic acetazolamide benefits those with a history of AMS or those with forced rapid ascent to sleeping altitude above 2500 m. Because the drug prevents AMS by enhancing ventilatory acclimatization, fear of masking serious illness is unwarranted. The drug should be started 24 hours before the ascent and should be continued for the first 2 days at altitude. It can be restarted if illness develops. Acetazolamide reduces the symptoms of AMS by approximately 75% in persons ascending rapidly to sleeping altitudes of >2500 m (>8200 ft). An alternative for those with anaphylaxis to sulfa is dexamethasone, 4 milligrams PO every 12 hours, starting the day of ascent and continuing for the first 2 days at altitude. Conflicting evidence exists on the use of ginkgo biloba for AMS prevention. A few studies indicate that 100 milligrams twice a day started 3 to 5 days before ascent is effective in preventing AMS, but other studies have shown no benefit.9 Lack of standardization of gingko preparations likely explains conflicting results, and the active ingredient is still unknown. Despite the variable results, ginkgo is a safe option for those who desire a natural alternative.
Preacclimatization Although graded ascent is the most effective means of preventing altitude illness, this strategy is not always feasible. Numerous preacclimatization strategies have been proposed using intermittent exposure either to hypobaric hypoxia by use of hypobaric chambers or normobaric hypoxia through commercially available low-oxygen tents or breathing masks. The overall goal is to reduce the incidence of altitude illness and to improve exercise performance on ascent to altitude. These strategies vary considerably in their use of hypoxic "dose" (simulated altitude), duration of exposure, and overall number of exposures over a period of days. Although many of these strategies induce physiologic responses suggestive of acclimatization, only a few are able to demonstrate a significant decrease in AMS incidence.10,11,12 Short-term exposure to hypoxia of less than 6 hours per day has not been shown to be efficacious in preventing mountain sickness. The most efficient and effective preacclimatization strategy has yet to be determined.
HIGH-ALTITUDE CEREBRAL EDEMA
High-altitude cerebral edema is defined as progressive neurologic deterioration in someone with AMS or high-altitude pulmonary edema. It is characterized by altered mental status, ataxia, stupor, and progression to coma if untreated. Headache, nausea, and vomiting are not always present. Because of raised intracranial pressure, focal neurologic signs, such as third and sixth cranial nerve palsies, may result. High-altitude cerebral edema at intermediate altitudes is all but nonexistent with the rare case likely precipitated by severe hypoxia associated with high-altitude pulmonary edema and/or a preexisting space-occupying cerebral lesion.
High-altitude cerebral edema is usually associated with pulmonary edema. Pathologically, necropsies have described severe, diffuse cerebral edema with multiple small hemorrhages and sometimes thrombosis.
Treatment of high-altitude cerebral edema is oxygen supplementation, descent, and steroid therapy (Tables 221-3 and 221-4). Descent is the highest priority. Acetazolamide may be used as an adjunct, but immediate reversal of the illness is the goal. Improving acclimatization comes later. In acutely ill patients who cannot descend, a combination of steroids, supplemental oxygen, and a hyperbaric bag is optimal therapy but rarely available. Persons remaining ataxic or confused after descent should be admitted to hospital. The possibility of encephalitis or meningitis, stroke, or subarachnoid hemorrhage should be considered in patients whose condition does not improve with treatment. Comatose patients require an advanced airway. Typically the partial pressure of arterial carbon dioxide is already low and the pH high, and hyperventilation could produce cerebral ischemia. Evidence is lacking for the use of hypertonic saline, loop diuretics, or mannitol in high-altitude cerebral edema. Coma may persist for days, even for weeks, after evacuation to lower altitude, yet the patient may still recover. Persistent coma is unusual, however, and mandates exclusion of other possible causes. MRI findings of high-altitude cerebral edema include reversible white matter edema evidenced by increased T2 signal, especially in the splenium of the corpus callosum (Figure 221-1).4 In contrast, hemosiderin depositions in the corpus callosum may be detected by MRI for years after a case of high-altitude cerebral edema; this may be useful in the setting of diagnostic uncertainty.13
MRI of a 34-year-old male high-altitude mountaineer with high-altitude cerebral edema. The arrows indicate the markedly increased T2 signaling in the splenium of the corpus callosum indicating edema.
HIGH-ALTITUDE PULMONARY EDEMA
High-altitude pulmonary edema is the most lethal of the altitude illnesses. The cause of death is usually lack of early recognition, misdiagnosis, or inability to descend to a lower altitude. The condition is easily reversible with descent and oxygen administration.
The incidence of high-altitude pulmonary edema varies from less than 1 in 10,000 skiers in Colorado to 2% to 3% of climbers on Mount McKinley; an incidence of 15% was reported in some regiments of the Indian army that were airlifted to high altitude during the Indian-Chinese war. Women appear less susceptible than men. Risk factors include heavy exertion, rapid ascent, cold, excessive salt ingestion, use of a respiratory depressant, a previous history indicating inherent individual susceptibility, and pulmonary hypertension. Genetic factors include diminished lung epithelial sodium channel activity, excessive hypoxic pulmonary hypertension, and immunogenetic factors.14,15 Pulmonary hypertension from any cause greatly predisposes to high-altitude pulmonary edema. As a result, high-altitude pulmonary edema has been reported in patients with intracardiac shunts (atrial septal defect, patent ductus arteriosus, patent foramen ovale), congenital absent pulmonary artery, drug-induced pulmonary hypertension (phentermine), and chronic venous thrombotic disease.16,17 Preexisting respiratory infection may predispose children to high-altitude pulmonary edema.18
High-altitude pulmonary edema is a noncardiogenic, hydrostatic edema; left ventricular function is normal. Left ventricular end-diastolic pressure, wedge pressures, and left atrial pressures are low to normal, cardiac output is low, and pulmonary vascular resistance and pulmonary artery pressure are markedly elevated. The culprit in high-altitude pulmonary edema is high microvascular pressure. Pulmonary hypertension is an essential component, but not all persons with pulmonary hypertension develop high-altitude pulmonary edema. Other factors that play a role include pulmonary venous constriction and uneven arterial vasoconstriction, which leads to overperfusion of some areas of the lung vasculature. Inflammation is not present early in the course of high-altitude pulmonary edema, as measured by the chemical composition of bronchoalveolar lavage fluid, but appears to be a secondary finding later in the illness.19 Predisposed individuals have a low hypoxic ventilatory response and an abnormal pulmonary circulation response to hypoxia, and tend to experience high-altitude pulmonary edema on repeated exposures to high altitude.
The differential diagnosis of shortness of breath at altitude is broad. This includes pneumonia, pulmonary embolism, myocardial infarction, congestive heart failure, mucous plugging, and bronchitis. Early in the course of high-altitude pulmonary edema, the individual develops a dry cough, decreased exercise performance, dyspnea on exertion, and increased recovery time from exercise. Localized rales, usually in the right mid-lung field, are common. Resting percent SaO2 is often 10 to 20 points lower than normal for a given altitude and will drop further with exertion. Late in the course of the illness, tachycardia, tachypnea, dyspnea at rest, marked weakness, productive cough, cyanosis, and more generalized rales develop. As hypoxemia worsens, altered mental status and eventually coma develop.
Early diagnosis is critical, and decreased exercise performance and dry cough are enough to raise the suspicion of early high-altitude pulmonary edema. Progression of dyspnea with exertion to dyspnea at rest is a hallmark of high-altitude pulmonary edema. The typical victim is strong and fit and may or may not have symptoms of AMS before the onset of high-altitude pulmonary edema. The condition typically worsens at night and is most commonly noticed on or after the second night at a new altitude. Rales are not audible in 15% of persons with high-altitude pulmonary edema at rest but can be elicited immediately after a short bout of exercise. Low-grade fever is common, and tachycardia and tachypnea generally correlate with the severity of illness. On cardiac auscultation, a prominent P2 and right ventricular heave may be appreciated. ECG may reveal right-axis deviation and a right ventricular strain pattern consistent with acute pulmonary hypertension. Chest radiographic findings progress from interstitial to localized alveolar to generalized alveolar infiltrates as the illness progresses from mild to severe (Figure 221-2). The absence of infiltrates should alert the clinician to the possibility of an alternate diagnosis.
Chest radiograph of an 11-year-old girl with reentry high-altitude pulmonary edema at 2670 m (8750 ft).
The key to successful treatment of high-altitude pulmonary edema (Tables 221-3 and 221-4) is early recognition, because the condition in its early stage is easily reversible. The optimal therapy depends on the environmental setting, evacuation options, availability of oxygen or hyperbaric units, and ease of descent. Immediate descent is the treatment of choice, but this is not always possible. During descent, exertion by the patient must be minimized. Reports of patients dying during descent probably are related to overexertion that offsets the benefit of lower altitude. Oxygen supplementation produces excellent results and can completely resolve the pulmonary edema without descent to a lower altitude, but it may require 36 to 72 hours to do so. In settings such as Colorado ski resorts, for example, keeping the patient at altitude but on oxygen is a practical option. The required quantities of oxygen are rarely available to trekking, mountaineering, and back country skiing groups, however. Oxygen immediately lowers pulmonary artery pressure and improves arterial oxygenation. Its use is lifesaving when descent is not an option; in such cases, rescue groups should make delivery of oxygen to the victim the highest priority. As in the treatment of AMS and high-altitude cerebral edema, the porTable hyperbaric bag is a useful adjunct to therapy when immediate descent is not possible.
Bed rest may be adequate for very mild cases, and bed rest with supplemental oxygen may suffice for moderate illness, as long as the safety of the patient can be ensured by the presence of a medical facility, adequate oxygen, or immediate descent capability should the patient's condition deteriorate.20 Because cold stress elevates pulmonary artery pressure, the patient should be kept warm. The use of an expiratory positive airway pressure mask increases SaO2 by 10% to 20% in high-altitude pulmonary edema patients by enhancing alveolar recruitment. The mask is lightweight, is well tolerated, and may be a useful adjunct to descent. Continuous positive airway pressure or bilevel positive airway pressure ventilation would likely work as well.
Because oxygen supplementation and descent are so effective, experience with drugs has been limited. Several studies have demonstrated that nifedipine, either as a 10-milligram capsule or 30-milligram extended-release formulation, reduces pulmonary artery pressure by 30% to 50% but increases SaO2 only slightly.21 Nifedipine, 20 milligrams (slow-release preparation) every 8 hours while ascending, provides effective prophylaxis in those who have previously experienced high-altitude pulmonary edema.22 Nitric oxide lowers pulmonary artery pressure and redistributes blood away from edematous areas but is rarely available.23
The phosphodiesterase-5 inhibitors sildenafil and tadalafil blunt hypoxic pulmonary vasoconstriction.24 Tadalafil, 10 milligrams PO twice a day 24 hours prior to ascent, effectively prevents high-altitude pulmonary edema in susceptible individuals.25 These agents may also prove to be useful for treatment of high-altitude pulmonary edema when oxygen is unavailable.
Inhaled salmeterol twice a day reduces the incidence of high-altitude pulmonary edema by 50% in persons with previous repeat episodes of high-altitude pulmonary edema.26 The mechanism is presumed to be upregulation of the epithelial sodium channel and increased clearance of alveolar fluid, a known effect of β-agonists. Although these agents have not yet been studied for the treatment of high-altitude pulmonary edema, given their likely benefit and safety and ease of use, treatment of high-altitude pulmonary edema with β-agonists is reasonable. None of these agents is as effective as oxygen administration or descent, which still remain the treatments of choice.
Hospitalization is warranted for severe illness that does not respond immediately to descent, especially if cerebral edema is present. Intubation, oxygen supplementation with a high fraction of inspired oxygen (FIO2), and positive end-expiratory pressure ventilation are rarely required. Antibiotics are indicated for coexisting infection when present. Measurement of brain natriuretic peptide level or echocardiography may be needed to exclude a cardiac component of edema in persons with potential heart failure. Patients with high-altitude pulmonary edema who do not make the usual rapid improvement or who develop the condition at <2500 m (<8200 ft) should be evaluated for pulmonary emboli or other anatomic abnormalities, such as congenital absence of a pulmonary artery or intracardiac shunt. Echocardiography with bubble contrast material can assess for the presence or absence of shunting from a patent foramen ovale or other cardiac abnormality.
Adequate discharge criteria are progressive clinical and radiographic improvement and a PaO2 of 60 mm Hg or an SaO2 of >90%. Residual effects such as fibrosis or abnormal pulmonary function tests have not been reported. An episode of high-altitude pulmonary edema is not a contraindication to subsequent ascent, but patients should be counseled regarding the advisability of staged ascent; prophylaxis with acetazolamide along with tadalafil, sildenafil, or nifedipine; and the importance of recognizing early signs and symptoms.
Swelling of the face and distal extremities is common at high altitude. Peripheral edema was reported in 18% of trekkers at 4200 m (13,800 ft) in Nepal and was twice as common in women.7 It often was associated with AMS but not in all cases. The presence of peripheral edema should raise suspicion of altitude illness and prompt a thorough examination for pulmonary and cerebral edema. The problem can be treated with diuretics but will resolve spontaneously with descent. The mechanism is presumably similar to that of fluid retention altitude illness but with edema formation peripherally rather than in the brain and lung.
Retinal abnormalities described at high altitude include retinal edema, tortuosity and dilatation of retinal veins, disc hyperemia, retinal hemorrhage, and, rarely, cotton-wool exudates. Retinal hemorrhages are asymptomatic, except for rarely occurring macular hemorrhages, and are not considered an indication for descent unless vision changes are present. They resolve spontaneously in 10 to 14 days. Hemorrhages are common at sleeping altitudes of >5000 m (>16,400 ft) and occur at lower altitudes in persons with altitude illness.
Many unacclimatized persons exercising at altitudes of >2500 m (>8200 ft) develop a dry, hacking cough. Breathing high volumes of dry, cold air may induce respiratory heat loss, secretions, and bronchospasm. As in cough-variant asthma, fast-acting β-agonists, such as albuterol, delivered by metered-dose inhaler may provide relief from these coughing spasms. Prophylactic use of long-acting β-agonists and inhaled steroids may be useful for prevention of debilitating cough for those staying at altitude for long periods. Those staying at ski resorts or indoors at altitude may find humidifiers helpful. Wearing a silk balaclava or a scarf of similar material across the nose and mouth that is sufficiently porous to allow large-volume ventilation but that traps some moisture and heat may help ameliorate this bothersome high-altitude condition.
CHRONIC MOUNTAIN POLYCYTHEMIA/CHRONIC MOUNTAIN SICKNESS
Monge's disease, also called chronic mountain sickness, has been recognized in all high-altitude locations of the world. Both long-term high-altitude residents and lowlanders who relocate to high altitude may develop this condition after variable lengths of residence. Males have a much higher incidence, and incidence increases with age. The disease is characterized by excessive polycythemia for a given altitude, which causes symptoms such as headache, muddled thinking, difficulty sleeping, impaired peripheral circulation, drowsiness, and chest congestion. The diagnosis is based on presence of the characteristic symptoms and a hemoglobin value greater than expected for the altitude, generally over 20 to 22 grams/dL. Any problem causing hypoxemia at sea level causes greater hypoxemia at altitude, and the cause of chronic mountain polycythemia can be traced to problems such as chronic obstructive pulmonary disease and sleep apnea in 50% of patients. "Pure" chronic mountain polycythemia is attributed to idiopathic hypoventilation based on diminished ventilatory drive.
Therapy includes phlebotomy, relocation to a lower altitude, or home oxygen use. Respiratory stimulants such as acetazolamide (250 milligrams PO twice a day) and medroxyprogesterone acetate (20 to 60 milligrams PO per day) also have been used successfully. The response to respiratory stimulants supports the role of hypoventilation in this disorder.
ULTRAVIOLET KERATITIS (SNOW BLINDNESS)
Ultraviolet A and ultraviolet B light penetrate the atmosphere to a greater degree at high altitude because there is less cloud cover, less water vapor, and less particulate matter in the air. Radiation increases roughly 5% for every 300 m (980 ft) gained and is exacerbated by reflection back from snow. The cornea absorbs ultraviolet radiation of <300 nm (ultraviolet B), and high levels can cause corneal burns in 1 hour. Symptoms may not become apparent for 6 to 12 hours. Severe pain, a foreign-body or gritty sensation, photophobia, tearing, marked conjunctival erythema, chemosis, and eyelid swelling comprise the main symptoms of photokeratitis. Ultraviolet keratitis generally is self-limited and heals within 24 hours, but the condition is sufficiently painful to warrant administration of systemic analgesics. Application of cold compresses also may provide some relief. Prevention cannot be overemphasized, because this condition can be disabling, especially in hazardous terrain. Sunglasses should transmit <10% of ultraviolet B light. Side shields are necessary if one is traveling on snow, and polarizing lenses help by absorbing glare. Makeshift protection can be fashioned by cutting narrow horizontal slits in cardboard, foam, or any available material ("Eskimo sunglasses").
INDIVIDUALS WITH ILLNESSES AGGRAVATED BY HIGH ALTITUDE
Chronic Lung Disease Patients with chronic obstructive pulmonary disease ascending to altitude often report increased dyspnea and reduced exercise performance. Patients with hypoxemia, pulmonary hypertension, disordered control of ventilation, and sleep-disordered breathing at sea level may require supplemental oxygen at altitude because of greater alveolar hypoxia. Patients who are oxygen dependent at sea level will need to increase their FIO2. The required FIO2 can be calculated by multiplying low-altitude FIO2 by the ratio of low-altitude barometric pressure to high-altitude barometric pressure. This will ensure the delivery of the same PO2 as at low altitude. Although no data exist to suggest that persons with chronic obstructive pulmonary disease are more likely to develop AMS or high–altitude pulmonary edema, these patients may simply avoid travel to high altitude. In fact, persons with mild to moderate chronic obstructive pulmonary disease already are partially acclimatized and may do well at modest altitude. High altitude per se does not exacerbate asthma, and persons with chronic bronchospasm often report easier breathing at high altitude due to lower air density and/or cleaner air. Patients with allergic asthma do better at high altitude because of reduced allergens.
Arteriosclerotic Heart Disease A healthy heart and cardiovascular system can tolerate even extreme hypoxia remarkably well. Examinations of numerous ECGs, echocardiograms, heart catheterization findings, and exercise test results demonstrate no cardiac ischemia or cardiac dysfunction in healthy persons at high altitude, even when PaO2 is <30 mm Hg. Those with arteriosclerotic disease may not have the same adaptive capabilities and intuitively seem more likely to experience acute cardiac events. Epidemiologic data, however, do not support this supposition. Long-term residence at high altitude reduces morbidity and mortality from arteriosclerotic heart disease,27 and visitors apparently do not have increased risk of acute myocardial infarction. Ischemia may be provoked with less exercise during the first few days at 2500 m (8200 ft) among persons with coronary artery disease; however, after 5 days of acclimatization, patients perform at their sea-level exercise capacity without increased or early-onset angina.28 A cohort of individuals who underwent revascularization for acute coronary syndrome 6 months previously were able to perform symptom-limited exercise testing after rapid ascent to 3,454 m without ECG evidence of myocardial ischemia or significant arrhythmia.29
Congestive heart failure may worsen in tourists arriving at the moderate altitude of ski resorts; this is related to fluid retention rather than depressed ventricular function from hypoxia. Therefore, patients with congestive heart failure should maintain or increase their diuretic dosage during travel to high altitude, and clinicians may consider administering low-flow oxygen during sleep to patients with congestive heart failure, at least for the first few nights after arrival at altitude. Individuals who have undergone coronary artery bypass grafting have trekked to altitudes of >5000 m (>16,400 ft) without problems.
Ascent to altitude produces a mild increase in blood pressure in normotensive and hypertensive persons secondary to increased sympathetic tone. However, the magnitude of blood pressure response varies significantly and is quite unpredictable. Patients should continue hypertensive medications at altitude, and blood pressure monitoring might be prudent. Occasionally, hypertensive medication dosages may need to be temporarily adjusted. No data suggest that hypertensive patients have a higher risk for any of the altitude illnesses, and in general, hypertension is not a contraindication to altitude exposure.
Neurologic Syndromes of High Altitude Until recently, most neurologic events at high altitude were attributed to high-altitude cerebral edema or AMS. Clearly, this has been a diagnostic oversimplification. Other syndromes now recognized as related to high altitude include altitude syncope, cerebrovascular spasm (migraine equivalent), cerebral arterial or venous thrombosis (infarct), transient ischemic attack, and cerebral hemorrhage. These syndromes are characterized by more focal neurologic findings than in cerebral edema, although differentiation in the field may be difficult. Other symptoms may be due to exacerbation or unmasking of underlying disease. Cortical blindness and various focal neurologic signs, such as transient hemiparesis or hemiplegia, also occur. Focal neurologic signs should be thoroughly evaluated and not attributed to altitude illness.
Other symptoms may be due to exacerbation or unmasking of underlying disease, such as previously asymptomatic brain tumors and epilepsy. Presumably, space-occupying lesions become symptomatic because of increased brain volume at altitude. Hyperventilation (hypocapnic alkalosis), which is commonly used to induce seizure activity on electroencephalography, may explain unmasking of seizure disorder at altitude, whereas changes in cerebral blood flow may exacerbate preexisting vascular lesions such as aneurysm or arteriovenous malformation, leading to spontaneous intracerebral hemorrhage.
In the field, it is reasonable to treat neurologic events as if cerebral edema were present, with rapid descent to lower altitude, oxygen supplementation, administration of steroids, and evacuation to hospital if symptoms persist. It is prudent to avoid use of agents that may contribute to hypotension and decrease cerebral perfusion.
Sickle Cell Disease Even the modest cabin altitude of pressurized aircraft (1500 to 2000 m [5000 to 6600 ft]) may cause persons with hemoglobin SC and sickle cell–thalassemia disease to experience vaso-occlusive crisis. Exposure to high altitude thus requires oxygen supplementation for such individuals. Although sickle cell trait is not considered a risk factor for increased altitude-related problems, splenic infarction syndrome during heavy exercise at altitude has been reported in individuals with the trait. Left upper quadrant pain should alert the physician at high altitude to consider splenic infarction syndrome.
Pregnant Women Pregnant women who live at high altitude have an increased prevalence of hypertension, delivery of low-birth-weight infants, and neonatal hyperbilirubinemia in their offspring. However, an increased incidence of pregnancy complications in lowlanders who visit high altitude has not been reported. The normal PaO2 of the fetus is 29 to 33 mm Hg, and the mild maternal hypoxia induced by traveling to resort-type altitudes does not generate significantly more hypoxic stress. Few data exist regarding exercise in pregnant women at altitudes of >2500 m (>8200 ft), so a conservative approach should be used.30 Pregnant women should avoid altitudes at which SaO2 falls to <85%, such as a sleeping altitude of 3000 m (10,000 ft) or higher.30 Perhaps of more concern than mild hypoxia is the fact that high-altitude locations are often remote from medical facilities. Patients need to be aware that without access to sophisticated medical care, complications may be associated with more serious consequences. Patients with high-risk pregnancies should be managed at low altitude.