High-Altitude Pulmonary Edema (HAPE)

High-altitude pulmonary edema (HAPE) is a potentially fatal form of severe high-altitude illness, a type of noncardiogenic pulmonary edema caused by hypoxia.[1]  (See the following image.)

High-altitude illness may result from short-term exposures to altitudes in excess of 2000-2500 m (6562 -8202 ft).[1, 2, 3]  This illness comprises a spectrum of clinical entities that are probably the manifestations of the same disease process. HAPE and cerebral edema (HACE) are the most ominous of these symptoms, whereas acute mountain sickness, retinal hemorrhages, and peripheral edema are the milder forms of the disease. The rate of ascent, the altitude attained, availability of acclimatization days, the amount of physical activity at high altitude, and individual susceptibility are contributing factors to the incidence and severity of high-altitude illness.[1, 3, 4]  It's important to note that high-altitude illness should not be excluded if an individual is below 2500 m.

High-altitude pulmonary edema generally occurs 2-4 days after rapid ascent to altitudes in excess of 2500 m.[2, 3] Young people and previously acclimatized people reascending to a high altitude following a short stay at low altitude seem to be more predisposed to HAPE. Cold weather and physical exertion at high altitude are other predisposing factors.

Signs and symptoms of high-altitude pulmonary edema include:

• Dyspnea with exertion and, eventually, dyspnea at rest, associated with weakness and cough
• Decreased exercise tolerance and slow recovery from exercise
• Extreme fatigue/weakness
• Tachycardia and tachypnea at rest
• Nonproductive cough, frothy sputum
• Rales
• Cyanosis
• Symptoms worse at night

High-altitude pulmonary edema may be fatal within a few hours if left untreated. Patients who recover from HAPE have rapid clearing of edema fluid and do not develop long-term complications. 

The treatment of high-altitude pulmonary edema includes rest, administration of oxygen, and descent to a lower altitude. If diagnosed early, recovery is rapid with a descent of only 500-1000 m. A portable hyperbaric chamber or supplemental oxygen administration immediately increases oxygen saturation and reduces pulmonary artery pressure, heart rate, respiratory rate, and symptoms. In situations where descent is difficult, these treatments can be lifesaving.[5, 6]

Also see Altitude Illness - Cerebral Syndromes and Altitude Illness - Pulmonary Syndromes.

For patient education resources, visit the First Aid & Emergencies Center. Also, see the patient education article Altitude Sickness.

Although all forms high-altitude illness are caused by hypobaric hypoxia leading to hypoxemia,[7] the pathophysiology high-altitude pulmonary edema (HAPE) is not well understood.[8] HAPE is a noncardiogenic form of pulmonary edema resulting from a leak in the alveolar capillary membrane; left-ventricular function is preserved. The various mechanisms believed to be responsible are pulmonary arterial vasoconstriction and elevated pulmonary artery pressure, resulting in circulatory shear forces and a consequent permeability leak and antidiuresis possibly mediated by increased antidiuretic hormones, which contribute to fluid retention. The inciting factor appears to be excessive hypoxia.[9]

A number of compensatory mechanisms improve oxygen delivery when its inspired concentration is reduced. The first adaptation to high altitude is an increase in minute ventilation. The ventilatory response to a relatively hypoxic stimulus can be divided into four phases: (1) initial increase on ascent, (2) subsequent course over hours and weeks, (3) deacclimatization on descent, and (4) long-term response of high-altitude natives.

The barometric pressure decreases with distance above the Earth's surface in an approximately exponential manner. The pressure at 5500 m (18,000 ft) is only half the normal 760 mm Hg, so that the partial pressure of oxygen (PO2) of moist inspired gas is (380-47) × 0.2093 = 70 (47 mm Hg is the partial pressure of water vapor at body temperature [ie, 37ºC]). At the summit of Mount Everest (altitude 8848 m or 29,028 ft), the inspired PO2 is only 43. In spite of hypoxia associated with high altitude, approximately 15 million people live at elevations over 3050 m, and some permanent residents live higher than 4900 m in the Andes. A remarkable degree of acclimatization occurs when humans ascend to these altitudes. Climbers have lived for several days at altitudes that would cause unconsciousness within a few seconds in the absence of acclimatization.

Spirometric studies have shown that with increasing altitude, both forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are reduced by up to 25% (74.8% / 74.6% of baseline). In the same study, peak expiratory flow (PEF) initially increased up to 4451 m and returned to baseline values above 5000 m. After descent below 2000 m, all values normalized within one day. These findings were consistent with increasing pulmonary restriction at high altitudes (without a marked reduction of PEF). Portable spirometry may provide clinically relevant information (impending pulmonary edema) in high-altitude travelers.[10, 11, 12]

Bronchoalveolar lavage fluid (BALF) studies have shown that after heavy exercise, under all conditions, athletes develop a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. Exercise at altitude (3810 m) caused significantly greater leakage of RBCs (92,000 [SD 3.1] cells/mL) into the alveolar space than that seen with normoxic exercise (54,000 [SD 1.2] cells/mL). At altitude, the 26-hour postexercise BALF had significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.[13]

Autopsy studies performed on patients who died of HAPE have shown a proteinaceous exudate with hyaline membranes. The studies have shown areas of pneumonitis with neutrophil accumulation, although none was noted to contain bacteria. Pulmonary veins were not dilated. Most reports mention capillary and arteriolar thrombi with deposits of fibrin, hemorrhage, and infarcts. The findings suggest a protein-rich edema with a possibility that clotting abnormalities may be partially responsible for this illness.

Bronchoalveolar lavages performed on patients with HAPE have also shown the fluid to have a high protein content, higher than in patients with adult respiratory distress syndrome (ARDS). The fluid was also highly cellular. Unlike ARDS, which primarily has neutrophils in the lavage fluid, HAPE fluid contains a higher percentage of alveolar macrophages. Additionally, chemotactic (leukotriene B4) and vasoactive (thromboxane B2) mediators were present in the lavage.

High-altitude pulmonary edema (HAPE) generally occurs 2-4 days after rapid ascent to altitudes in excess of 2500 m (8202 ft). Young people and previously acclimatized people reascending to a high altitude following a short stay at low altitude seem more predisposed to HAPE. Other predisposing factors include the following[1] :

• Cold weather
• Physical exertion at high altitude
• Male sex
• Use of sleep medications
• Excessive salt ingestion

Preexisting conditions that may predispose toward the development of high-altitude pulmonary edema include the following[1] :

• Conditions that lead to increased pulmonary blood flow
• Pulmonary hypertension
• Increased pulmonary vascular reactivity
• Patent foramen ovale

United States data

The incidence of high-altitude pulmonary edema (HAPE) ranges from an estimated 0.01% to 15.5%. In Colorado, the incidence of HAPE is 1 per 10,000 skiers and up to 1 per 100 climbers at more than 4,270 m (14,010 ft).

The risk of HAPE rises with increased altitude and faster ascent. At 4500 m, the incidence is 0.6% to 6%,; at 5500 m, the incidence is 2% to 15%.[1] Climbers with a previous history of HAPE, who ascent rapidly above 4,500 m (14,764 ft) have up to a 60% chance of illness recurrence.[1, 14]

International data

In a study on Mount Everest trekkers, the incidence of high-altitude pulmonary edema (HAPE) was about 1.6%. The incidence of mountain sickness appears to be unusually high in trekkers on Mount Rainier; however, the incidence of pulmonary edema is the same as in other places. One study reported that Everest region trekkers were more likely to be evacuated for altitude illness than trekkers in other regions.[15]

Sex-related demographics

Men and women are equally susceptible to acute mountain sickness, but women may be less likely to develop high-altitude pulmonary edema. In addition to individual differences in susceptibility, other factors, such as alcohol, respiratory depressants, and respiratory infections, may enhance vulnerability to altitude illness.

Age-related demographics

The typical patient with high-altitude pulmonary edema (HAPE) is a young person who is otherwise physically fit. HAPE is rare in infants and small children.

High-altitude pulmonary edema (HAPE) may be fatal within a few hours if left untreated. Patients who recover from HAPE have rapid clearing of edema fluid and do not develop long-term complications. Although outcome varies significantly depending on altitude, management, and access to medical care, the mortality rate has been reported to be as high as 11% with treatment[16]  but up to 50% if untreated.[1] As many as 50% of patients with high-altitude pulmonary edema may have concurrent acute mountain sickness, and up to 14% have concurrent high-altitude cerebral edema.[1]

One study has shown that the estimated incidence of altitude illness–related death was 7.7 deaths in 100,000 trekkers. The mortality has been increasing over the last decade.[15]

Although reports document successful ascents of Mount Everest following episodes of high-altitude pulmonary edema, the safety of continuing ascent following treatment and resolution of high-altitude pulmonary edema remains controversial. If ascent is pursued, the individual should be symptom-free and off any medications for at least several days before initiating further ascent, and they should strongly consider pharmacologic prophylaxis for their ascent.[2, 17]

High-altitude pulmonary edema (HAPE) generally occurs 2-4 days after rapid ascent to altitudes in excess of 2500 m (8000 ft). Young people and previously acclimatized people reascending to a high altitude following a short stay at low altitude seem more predisposed to HAPE. Cold weather and physical exertion at high altitude are other predisposing factors.

The earliest indications are decreased exercise tolerance and slow recovery from exercise, and a dry cough.[7]

The person usually notices fatigue, weakness, and dyspnea on exertion.

The condition typically worsens at night, and tachycardia and tachypnea occur at rest. Periodic breathing during sleep is almost universal in sojourners at high altitude. Patients may also complain of chest tightness or congestion.[18]

Cough, frothy sputum (may be pink or contain frank blood[1] ), cyanosis, rales, and dyspnea progressing to severe respiratory distress are symptoms of the disease.[1, 4]

A low-grade fever, respiratory alkalosis, and leukocytosis are other common features.

In severe cases, an altered mental status, hypotension, and death may result.

In addition to the symptoms discussed, signs of high-altitude pulmonary edema (HAPE) may include the following signs:

• Tachycardia

• Prominent P2 and right-ventricular heave on auscultation/palpation

• Tachypnea

• Crackles on auscultation (generally first appreciated in the right mid-lung field[7] )

• Central cyanosis

• Productive cough, with pink, frothy sputum or frank blood[1]

• Disproportionately low oxygen saturation relative to altitude (eg, 10-20 points lower than asymptomatic individuals at the same altitude[7] )

The clinical diagnosis of high-altitude pulmonary edema (HAPE) generally includes at least two of the following signs/symptoms[1, 18] :

• Dyspnea at rest
• Cough
• Weakness or reduced exercise performance
• Chest tightness or congestion
• Tachycardia
• Tachypnea
• Rales/wheezes in at least one lung field
• Central cyanosis 

In patients with chest radiographic evidence of infiltrates, rapid clinical and oxygen saturation improvement with administration of supplemental oxygen is pathognomonic for high-altitude pulmonary edema.[1]  

Laboratory studies are general of limited use.[1]

Always consider the possibility of concomitant acute mountain sickness and/or high-altitude cerebral edema.[1, 2, 3, 4]

Note that the coronavirus disease 2019 (COVID-19) pandemic has raised concerns over whether affected patients with respiratory distress have presentations more like high-altitude pulmonary edema (HAPE) than that of acute respiratory distress syndrome (ARDS).[20, 21] Therefore, the Guidelines section also contains the following COVID-19-related guidance:

• FDA Policy for Face Masks, Face Shields, and Respirators in COVID-19 (2020)
• COVID-19–Related Airway Management Clinical Practice Guidelines (SIAARTI/EAMS, 2020)
• COVID-19 Ventilation Clinical Practice Guidelines (ESICM, 2020)

For more COVID-19 information, please go to Medscape's Novel Coronavirus Resource Center, COVID-19 Clinical Guidelines, and Coronavirus Disease 2019 (COVID-19).

Findings on laboratory studies from high-altitude pulmonary edema (HAPE) patients are nonspecific.

Arterial blood gas (ABG) measurement typically shows severe hypoxemia and respiratory alkalosis. The partial pressure of oxygen is usually between 30 and 40 mm Hg.[7] A mild leukocytosis also may be present.

Some studies have demonstrated increase in interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and cross-reacting protein (CRP) in response to high altitude. The systemic increase of these inflammatory markers may reflect considerable local inflammation.[22]

Radiography

Chest radiography in high-altitude pulmonary edema (HAPE) patients reveals bilateral patchy infiltrates, with a normal heart size/mediastinum.{ref29)[7] If infiltrates are absent, consider an alternative diagnosis.

Ultrasonography

B-lines consistent with pulmonary edema may be seen on sonograms[1]

In one study, stress echocardiography was used to quantitate pulmonary artery systolic pressure responses to prolonged hypoxia and normoxic exercise.[23] The data from the study indicate that individuals who are susceptible to HAPE have abnormal vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, this modality may be a useful noninvasive screening method to identify subjects susceptible to HAPE.

Chest ultrasonography was evaluated in one study and showed that the comet-tail technique, which has been shown in cardiogenic pulmonary edema, effectively recognizes and evaluates the degree of pulmonary edema in HAPE patients.[24]

Electrocardiography

Electrocardiography (ECG) in high-altitude pulmonary edema (HAPE) patients may reveal a right-sided heart strain pattern suggestive of pulmonary hypertension[7]  and/or ischemia.[1]

Educate travelers with the following three Centers for Disease Control and Prevention (CDC) principles to prevent death or serious consquences from altitude illness[4] :

• Know the early symptoms of altitude illness, and be willing to acknowledge when they are present.
• Never ascend to sleep at a higher altitude when experiencing symptoms of altitude illness, no matter how minor they seem.
• Descend if the symptoms become worse while resting at the same altitude.

Supplemental oxygen and descent are the definitive therapy for all forms of altitude illness; however, descent may not always be possible due to climate, environmental, or logistic issues.

See the Guidelines section for prevention and treatment recommendations from the Wilderness Medical Society [2, 3]  and the Centers for Disease Control and Prevention.[4]  

Note that the coronavirus disease 2019 (COVID-19) pandemic has raised concerns over whether affected patients with respiratory distress have presentations more like high-altitude pulmonary edema (HAPE) than that of acute respiratory distress syndrome (ARDS).[20, 21] Therefore, the Guidelines section also contains the following COVID-19-related guidance:

• FDA Policy for Face Masks, Face Shields, and Respirators in COVID-19 (2020)
• COVID-19–Related Airway Management Clinical Practice Guidelines (SIAARTI/EAMS, 2020)
• COVID-19 Ventilation Clinical Practice Guidelines (ESICM, 2020)

For more COVID-19 information, please go to Medscape's Novel Coronavirus Resource Center, COVID-19 Clinical Guidelines, and Coronavirus Disease 2019 (COVID-19).

See also the Guidelines section for treatment recommendations from the Wilderness Medical Society[2, 3]  and the Centers for Disease Control and Prevention.[4]

The treatment of high-altitude pulmonary edema (HAPE) includes rest, administration of oxygen (first line), and descent to a lower altitude (first line if oxygen is unavailable).[2, 3, 4, 7, 18]  If diagnosed early, recovery is rapid with a descent of only 500-1000 m. A portable hyperbaric chamber (see the following image) or supplemental oxygen administration immediately increases oxygen saturation and reduces pulmonary artery pressure, heart rate, respiratory rate, and symptoms. In situations where descent is difficult, these treatments can be lifesaving.[5, 6]

In one study, 11 patients at 4240 m altitude in Pheriche, Nepal, were treated for HAPE with bed rest, oxygen, nifedipine, and acetazolamide.[25] Sildenafil and salmeterol were used in most, but not all patients. Seven of these had serious-to-severe HAPE (Hultgren grades 3 or 4). Oxygen saturation was improved at discharge (84% ± 1.7%) compared with admission (59% ± 11%), as was the ultrasound comet-tail score (11 ± 4 at discharge vs 33 ± 8.6 at admission), a measure of pulmonary edema for which admission and discharge values were obtained in 7 patients.

A randomized, double-blinded, placebo-controlled study showed that adults with previous HAPE who received prophylactic tadalafil (10 mg) or dexamethasone (8 mg) had significantly less HAPE compared with those who received placebo twice daily. The medications were administered during ascent and at a stay at 4559 m altitude.[26]

Two participants who received tadalafil developed severe acute mountain sickness upon arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. HAPE developed in 7 of 9 participants who received placebo and in 1 of the remaining 8 participants who received tadalafil, but it did not develop in any of the 10 participants who received dexamethasone (P = .007 for tadalafil vs placebo; P< .001 for dexamethasone vs placebo). Eight of 9 participants who received placebo, 7 of 10 who received tadalafil, and 3 of 10 who received dexamethasone had acute mountain sickness (P = 1.0 for tadalafil vs placebo; P = .020 for dexamethasone vs placebo).

At high altitude, systolic pulmonary artery pressure increased less in participants who received dexamethasone (16 mm Hg [95% confidence interval, 9-23 mm Hg]) and tadalafil (13 mm Hg [95% confidence interval, 6-20 mm Hg]) than in those who received placebo (28 mm Hg [95% confidence interval, 20-36 mm Hg]) (P = .005 for tadalafil vs placebo; P = .012 for dexamethasone vs placebo).

The conclusion was that both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE.[27] Dexamethasone prophylaxis may also reduce the incidence of acute mountain sickness in these adults.

Portable hyperbaric chambers (Gamow, CERTEC) are in wide use by trekkers. A physiologic (simulated) descent of approximately 2000 m may be achieved in a few minutes. Patients are typically treated in 1-hour increments. Patients should be closely observed for rebound symptoms after hyperbaric treatments.

Finally, the use of an expiratory positive airway pressure mask improves oxygenation and may be useful as a temporizing measure.

Admission to a hospital is warranted for significant arterial desaturation and clinical deterioration despite outpatient management of HAPE.

See also the Guidelines section for prevention guidance from the Wilderness Medical Society[2, 3] and the Centers for Disease Control and Prevention.[4]

Prophylaxis for high-altitude pulmonary edema (HAPE) is indicated for persons who have been identified (from past experience) as being susceptible to developing high-altitude illness or who must ascend rapidly to a high altitude. Acetazolamide and dexamethasone have been shown to be effective agents for prophylaxis against high-altitude illness. These agents must be started 24 hours before ascent and continued for 48-72 hours at altitude. Acetazolamide, which appears to hasten acclimatization, is considered the drug of choice because of a low incidence of significant adverse effects.[28]   

Because acetazolamide hastens acclimatization, it should be effective at preventing all forms of acute altitude illness. It has been shown to blunt hypoxic pulmonary vasoconstriction but there are no data specifically supporting a role in HAPE prevention. Clinical observations suggest acetazolamide may prevent reentry HAPE, a disorder seen in individuals who reside at high altitude, travel to lower elevation, and then develop HAPE upon rapid return to their homes.[2]

Based on a single randomized, placebo-controlled study[29] and extensive clinical experience, the Wilderness Medical Society recommends nifedipine for HAPE prevention in high risk individuals.[2, 3]  

Other preventive measures include:

• Eating a high-carbohydrate diet
• Avoiding heavy exertion at high altitude
• Slow ascent
• Avoiding abrupt ascent to sleeping elevations higher than 3000 m: If possible, spend 2 nights at altitudes of 2500-3000 m before further ascent.
• Avoiding alcohol and sedatives

Guidelines for the prevention and treatment of high-altitude pulmonary edema (HAPE) have been issued by the following organizations:

• Wilderness Medical Society (WMS) ^{[2, 3]}
• Centers for Disease Control and Prevention (CDC) ^[4]

The coronavirus disease 2019 (COVID-19) pandemic has raised concerns over whether affected patients with respiratory distress have presentations more like high-altitude pulmonary edema (HAPE) than that of acute respiratory distress syndrome (ARDS).[21, 20] Therefore, this Guidelines section also contains the following COVID-19-related guidance:

• FDA Policy for Face Masks, Face Shields, and Respirators in COVID-19 (2020)
• COVID-19–Related Airway Management Clinical Practice Guidelines (SIAARTI/EAMS, 2020)
• COVID-19 Ventilation Clinical Practice Guidelines (ESICM, 2020)

For more COVID-19 information, please go to Medscape's Novel Coronavirus Resource Center, COVID-19 Clinical Guidelines, and Coronavirus Disease 2019 (COVID-19).

Guidelines for the prevention and treatment of high-altitude pulmonary edema (HAPE) have been issued by the following organizations:

• Wilderness Medical Society (WMS) ^{[2, 3]}
• Centers for Disease Control and Prevention (CDC) ^[4]

Prevention

A gradual ascent is the primary recommendation for the prevention of HAPE.[2, 3]  The risk of HAPE can be reduced by sleeping one night at an intermediate altitude. Above an altitude of 3000 m, the sleeping elevation should not be increased by more than 500 m per day and should include a rest day every 3-4 days. In the event that logistical factors prevent strict adherence to 500 m per day sleeping elevation, strongly consider additional acclimatization days in the itinerary before or after large gains in elevation and elsewhere to ensure that the overall ascent rate averaged over the entire trip falls below the 500 m per day threshold.[2, 3]

Additional prevention recommendations include the following[2, 3] :

• Drug prophylaxis should only be considered for individuals with a prior history of HAPE, especially multiple episodes.
• Nifedipine is the preferred agent; initiate the day before ascent and continue nifedipine either until descent begins or the individual has spent 4 days at the highest elevation, perhaps up to 7 days if the rate of ascent was faster than recommended. (Note: These durations are longer than use of acetazolamide for prevention of acute mountain sickness.)
• Stop prophylactic medications when beginning descent for individuals who ascend to a high point and then descend toward the trailhead.
• Further research is needed before tadalafil or dexamethasone can be recommended over nifedipine for prophylaxis.
• In general, acetazolamide facilitates acclimatization, but this agent should not be relied on as the sole preventive agent in individuals with known HAPE susceptibility.

The CDC strongly recommends acetazolamide prophylaxis in all individuals with a prior history of HAPE or HACE, as well as with the following[4] :

• History of acute mountain sickness and ascending more than 2,800 m in 1 day
• All people ascending to more than 3,500 m in 1 day
• All people ascending more than 500 m per day (increase in sleeping elevation) above 3,000 m, without extra days for acclimatization
• Very rapid ascents

The CDC recommends the following pharmacologic agents and regimens for HAPE prophylaxis[4] :

• Oral nifedipine (generally reserved for HAPE-susceptible individuals) - 30 mg sustained-release formulation every 12 hours (same regimen for HAPE treatment)
• Oral tadalafil - 10 mg twice daily
• Oral sildenafil - 50 mg every 8 hours

In addition, educate travelers with the following three principles to prevent death or serious consquences from altitude illness[4] :

• Know the early symptoms of altitude illness, and be willing to acknowledge when they are present.
• Never ascend to sleep at a higher altitude when experiencing symptoms of altitude illness, no matter how minor they seem.
• Descend if the symptoms become worse while resting at the same altitude.

For travel to remote high-altitude areas, where descent to a lower altitude could be problematic, a pressurization bag (such as the Gamow bag) can be beneficial. A foot pump produces an increased pressure of 2 lb/in2, mimicking a descent of 1,500-1,800 m, depending on the starting altitude.[4]  

Treatment

Recommendations [2, 3]

• Descent is indicated for individuals with HAPE
• When available, supplemental oxygen sufficient to achieve an S _pO ₂ of >90% or to relieve symptoms should be used while waiting to initiate descent when descent is infeasible and during descent in severely ill patients.
• When descent is infeasible or delayed or supplemental oxygen is unavailable, a portable hyperbaric chamber may be used to treat HAPE.
• Nifedipine should be used for HAPE treatment when descent is impossible or delayed and reliable access to supplemental oxygen or portable hyperbaric therapy is unavailable.
• Diuretics or acetazolamide should not be used for treatment of HAPE.
• No recommendation can be made regarding beta-agonists or dexamethasone for HAPE treatment due to insufficient/lack of data.
• Tadalafil or sildenafil can be used for HAPE treatment when descent is impossible or delayed, access to supplemental oxygen or portable hyperbaric therapy is impossible, and nifedipine is unavailable.
• CPAP or expiratory positive airway pressure (EPAP) may be considered for treatment of HAPE when supplemental oxygen or pulmonary vasodilators are not available or as adjunctive therapy in patients not responding to supplemental oxygen alone.

The WMS advises that before treatment is initiated to consider other causes of high-altitude respiratory distress, including pneumonia, pneumothorax, pulmonary embolism, viral upper respiratory tract infection, mucous plugging, asthma, bronchospasm, or myocardial infarction.[2, 3]

If HAPE is suspected or diagnosed, initiate oxygen if available, and start descent to a lower elevation. If logistics prohibit or delay descent, continue supplemental oxygen or place the individual in a portable hyperbaric chamber.

Initiate descent in the following situations:

• Supplemental oxygen and/or continuous positive airway pressure (CPAP) does not improve the patient's oxygenation.
• The patient's condition deteriorates despite reaching an oxygen saturation above 90%.
• Appropriate interventions for HAPE fail to demonstrate signs of improvement in the individual.
• Consider early descent in more remote locations.

Additional treatment recommendations include[2, 3] :

• In the field setting, nifedipine can be used as an adjunct to descent, supplemental oxygen, or portable hyperbaric therapy; only use as primary therapy if other measures are unavailable.
• A phosphodiesterase inhibitor may be used if nifedipine is not available, but concurrent use of multiple pulmonary vasodilators is not recommended.
• In the hospital setting, CPAP can be considered as an adjunct to supplemental oxygen, and nifedipine can be added if patients fail to respond to oxygen therapy alone.  
• There is no established role for acetazolamide, beta-agonists, diuretics, or dexamethasone in the treatment of HAPE, although dexamethasone should be considered where there is concern for concomitant high-altitude cerebral edema (HACE).

After treatment for HAPE, patients may further ascend or reascend under the following conditions:

• HAPE symptoms have completely resolved.
• Stable oxygenation is maintained at rest and with mild exercise while off supplemental oxygen and/or vasodilator therapy.

Consideration may be given to using nifedipine or another pulmonary vasodilator on resuming ascent.

Concurrent HAPE and HACE

Some patients with HAPE may have neurologic dysfunction caused by hypoxic encephalopathy rather than true HACE, but differentiating between the diagnoses in the field can be difficult.[2, 3]  The WMS recommends adding dexamethasone to the treatment regimen for patients with HAPE and neurologic dysfunction that does not resolve rapidly with administration of supplemental oxygen and improvement in the patient’s oxygen saturation. If supplemental oxygen is not available, initiate dexamethasone in addition to medications for HAPE in those with mental status changes and/or suspected concurrent HACE.

 Other key recommendations include the following[2, 3] :

• Dexamethasone should be administered at the doses recommended for the treatment of HACE.
• Nifedipine or other pulmonary vasodilators may be used to treat concurrent HAPE and HACE, but avoid lowering mean arterial pressure, as this may decrease cerebral perfusion pressure and thereby increase the risk for cerebral ischemia.

The guidelines on policy for face masks and respirators during the coronavirus disease 2019 (COVID-19) public health emergency were released on March 25, 2020 by the US Food and Drug Administration (FDA) and revised in April 2020.[30]

Face Masks, Face Shields, and N95 Respirators Not Intended for a Medical Purpose

Face masks, face shields, and respirators are devices when they are intended for a medical purpose, such as prevention of infectious disease transmission (including uses related to COVID-19). Face masks, face shields, and respirators are not devices when they are intended for a nonmedical purpose, such as for use in construction.

When considering whether face masks, face shields, and respirators are intended for a medical purpose, among other considerations, FDA will look at the following:

• Whether they are labeled or otherwise intended for use by a healthcare professional
• Whether they are labeled or otherwise for use in a healthcare facility or environment
• Whether they include any drugs, biologics, or antimicrobial/antiviral agents

Face Masks Intended for a Medical Purpose That Are Not Intended to Provide Liquid Barrier Protection

In general, FDA recommends that healthcare providers follow current Centers for Disease Control and Prevention (CDC) guidance regarding the use of personal protective equipment (PPE) that should be used during the COVID-19 outbreak.

For the duration of the public health emergency, FDA does not intend to object to the distribution and use of face masks, with or without a face shield (not including respirators), that are intended for a medical purpose (whether used by medical personnel or by the general public), without compliance with prior submission of a premarket notification where the face mask does not create an undue risk in light of the public health emergency.

FDA currently believes that such devices would not create an undue risk in the following cases:

• The product's labeling accurately describes the product as a face mask (as opposed to a surgical mask or filtering facepiece respirator [FFR]) and includes a list of the body-contacting materials (which does not include any drugs or biologics).

• The product's labeling makes recommendations that would sufficiently reduce the risk of use—for example, recommendations against use in any surgical setting or a setting where significant exposure to liquid, bodily fluids, or other hazardous fluids, may be expected; use in a clinical setting with a high risk of infection through inhalation exposure; and use in the presence of a high-intensity heat source or flammable gas.

• The product is not intended for any use that would create an undue risk in light of the public health emergency—for example, the labeling does not include uses for antimicrobial/antiviral protection or related uses or uses for infection prevention/reduction or related uses and does not include particulate filtration claims.

Face Shields Intended for a Medical Purpose

In general, FDA recommends that healthcare providers follow current CDC guidance regarding the use of PPE that should be used during the COVID-19 outbreak.

For the duration of the public health emergency, FDA does not intend to object to the distribution and use of face shields that are intended for a medical purpose (whether used by medical personnel or the general public), without compliance with the following regulatory requirements where the face shield does not create an undue risk in light of the public health emergency: Registration and Listing requirements in 21 CFR 807, Quality System Regulation requirements in 21 CFR Part 820, reports or corrections and removals in 21 CFR Part 806, and Unique Device Identification requirements in 21 CFR Part 830 and 21 CFR 801.20.

FDA currently believes that such devices would not create an undue risk in the following cases:

• The product's labeling accurately describes the product as a face shield and includes a list of the body-contacting materials (which does not include any drugs or biologics).

• The face shield does not contain any materials that will cause flammability, or the product meets class I or class II flammability requirement per 16 CFR 1610 (unless labeled with a recommendation against use in the presence of a high-intensity heat source or flammable gas).

• The product is not intended for any use that would create an undue risk in light of the public health emergency—for example, the labeling does not include uses for antimicrobial/antiviral protection or related uses or uses for infection prevention/reduction or related uses, or for radiation protection.

Surgical Masks Intended to Provide Liquid Barrier Protection

Surgical masks are class II devices that cover the user’s nose and mouth and provide a physical barrier to fluids and particulate materials and are tested for flammability and biocompatibility. 

For the duration of the declared public health emergency, FDA does not intend to object to the distribution and use of surgical masks without prior submission of a premarket notification in instances where the surgical masks do not create an undue risk in light of the public health emergency.

FDA currently believes that such devices would not create an undue risk in the following cases:

• The product meets fluid resistance testing (liquid barrier performance) requirements in a manner consistent with standard methods.

• The product meets standard class I or class II flammability requirements (unless labeled with a recommendation against use in the presence of high-intensity heat sources or flammable gas).

• The product's labeling accurately describes the product as a surgical mask and includes a list of the body-contacting materials (which does not include any drugs or biologics).

• The product is not intended for any use that would create an undue risk in light of the public health emergency—for example, the labeling does not include uses for antimicrobial/antiviral protection or related uses or uses for infection prevention/reduction or related uses and does not include particulate filtration claims.

Alternatives When FDA-Cleared or NIOSH-Approved N95 Respirators Are Not Available

See the CDC-published Strategies for optimizing the Supply of N95 Respirators: Crisis/Alternate Strategies, which, as part of a set of crisis management recommendations, identifies alternatives to FDA-cleared or National Institutes of Occupational Safety and Health (NIOSH)-approved N95 respirators approved under standards used in other countries, some of which were evaluated under methods that are similar to NIOSH-approved N95 respirators.

For the duration of the public health emergency, when FDA-cleared or NIOSH-approved N95 respirators are not available, FDA does not intend to object to the distribution (including importation) and use of respirators identified in the CDC recommendations without compliance with prior submission of a premarket notification.

Because FDA cannot confirm the authenticity of the respirators described above, FDA recommends that importers take appropriate steps to verify the authenticity of the products they import. 

Intended Approach for Emergency Use Authorizations (EUAs) for Face Masks and Respirators

EUAs for decontamination of face masks and filtering facepiece respirators

To facilitate safe reuse and conservation of PPE for a medical purpose for the duration of the emergency, FDA is interested in interacting with manufacturers on the decomtamination of otherwise disposable face masks and FFRs to facilitate marketing authorization through an EUA for contaminated devices. Firms should contact FDA (CDRH-COVID19-SurgicalMasks@fda.hhs.gov), and provide the following information, if available:

• Description of the process for disinfection/decontamination controls
• Validation of bioburden reduction/disinfection
• Description of chain of custody and safeguards to prevent inadvertent exposure
• Material compatibility
• Filtration performance
• Fit test data
• Copy of the decontaminated device product labeling

EUAs for face masks intended for a medical purpose, surgical face masks, and N95 respirators

FDA has already issued EUAs that authorize certain FFRs, including NIOSH-approved FFRs and imported non-NIOSH-approved disposable FFRs, for use in healthcare settings by healthcare personnel to increase availability of these devices to frontline personnel during the public health emergency.

FDA is interested in interacting with manufacturers on additional device-specific EUAs. This may include both manufacturers of masks and respirators not currently legally marketed in the US and manufacturers who have not previously manufactured masks or respirators but have the capability to increase the supply of these devices.

For current face mask and respirator manufacturers whose product(s) are not currently marketed in the US, FDA recommends providing the following information:

• General information (eg, contact information, general information about the device)
• Copy of the product labeling.
• Any current marketing authorization (if any) for the device in another regulatory jurisdiction (including certification number, if available)
• Whether the device is manufactured in compliance with an appropriate quality system and whether documentation of such is available
• Description of any testing conducted on the device, including any standards met

Face mask manufacturers who have not previously been engaged in medical device manufacturing but with capabilities to increase supply of these devices should send an email to FDA (CDRH-COVID19-SurgicalMasks@fda.hhs.gov) and describe their proposed approach.

For any face mask or FFR (including N95 respirators) issued an EUA, FDA will include appropriate conditions of authorization in accordance with section 564 of the FD&C Act on a case-by-case basis. The following conditions will likely be included:

• Appropriate conditions designed to ensure that healthcare professionals administering the device, and individuals being administered the device, are informed of FDA EUA of the device; and of the significant known potential benefits/risks of the emergency use of the device, and of the extent to which such benefit/risks are unknown.

• Appropriate conditions designed to ensure healthcare professionals administering the device are informed of the available alternatives to the device, and of their benefits/risks

• Appropriate conditions designed to ensure individuals being administered the device are informed of the option to accept/refuse administration of the device, of the consequence, if any, of refusing administration of the device, and of the available alternatives to the device and of their benefits/risks

• Appropriate conditions for the monitoring and reporting of adverse events associated with the emergency use of the device

• For device manufacturers, appropriate conditions concerning recordkeeping and reporting, including records access by FDA, with respect to emergency use of the device

In March 2020, the Società Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva (SIAARTI) Airway Research Group and the European Airway Management Society released coronavirus disease 2019 (COVID-19) recommendations that included guidance on airway management and tracheal intubation.[31]

Perform airway management procedures electively rather than as an emergency, employing any means required to maximize first-pass success.

Carry out procedures in a negative pressure chamber (if available) or an isolation area that is equipped with a replenished, complete, and checked emergency airway trolley.

Strict monitoring of entry and departure of staff from the immediate clinical area is necessary, with restriction of personnel to whoever is required.

Through thorough airway evaluation, clinicians should determine whether it is safe to employ asleep tracheal intubation, rather than awake tracheal intubation (ATI).

The use of ATI requires careful consideration owing to the fact that it is potentially a highly aerosol-generating procedure.

Tracheal Intubation

Effective pre-oxygenation is mandatory in patients with COVID-19 owing to their risk of rapid arterial oxygen desaturation.

Following preemptive optimization and correction of hemodynamic disturbances, perform pre-oxygenation with a fraction of inspired oxygen of 1.0 for at least 3 minutes at tidal volume breathing or eight vital capacity breaths.

Rapid sequence intubation, indicated for all cases to minimize the apnea time, can result in significant aerosolization with facemask ventilation. Therefore, facemask ventilation should only be performed gently should critical arterial oxygen desaturation occur.

Unless otherwise indicated, cricoid force should not be performed, so that first-pass success can be maximized and optimal ventilation (if needed) is not compromised.

Apneic oxygenation is recommended to prevent desaturation, with low-flow nasal oxygenation ideally used during tracheal intubation attempts.

Because it is an aerosol-generating technique, high-flow nasal oxygen should be avoided.

It is recommended that general anesthetic agents be administered, cautiously, to minimize hemodynamic instability, and that rocuronium 1.2 mg/kg or suxamethonium 1 mg/kg be provided to ensure rapid onset of neuromuscular blockade, maximize first-pass success, and prevent coughing and associated aerosolization.

It is advisable to perform neuromuscular monitoring.

Employment of a videolaryngoscope, ideally disposable but with a separate screen to minimize patient contact, is strongly recommended.

Should tracheal intubation fail, gentle manual ventilation may be used, with a maximum of two attempts at tracheal intubation subsequently employed (with consideration of position change, device, and technique between attempts).

Should tracheal intubation fail twice, or if a rescue airway is needed, it is strongly advised that a second-generation supraglottic device, preferably one that permits flexible bronchoscopic intubation, be used.

Consider an early emergency front-of-neck airway (surgical or percutaneous cricothyroidotomy) before a “cannot intubate, cannot oxygenate” scenario independently of critical arterial oxygen desaturation.

An experienced operator should perform an indicated ATI; employment of intravenous sedation may minimize coughing.

Minimize aerosol or vaporized local anesthesia delivery, and consider using mucosal atomizers, swabs, and tampons, as well as (if clinical expertise permits) nerve blocks.

To reduce the risk of cross-contamination, employ single-use flexible bronchoscopes; a separate screen is strongly advised.

Because it is faster than flexible bronchoscopy, ATI with videolaryngoscopy can be considered.

Despite the potential for aerosolization, tracheostomy with local anaesthesia must be considered in the event of a failed ATI.

In the event of a “cannot intubate, cannot oxygenate” scenario, carry out an emergency front-of-neck airway.

If emergency tracheal intubation is required for a COVID-19 patient, personal protective equipment (PPE) must be donned by team members prior to airway management. Gentle facemask ventilation may be required in a hypoxic patient to give more time to the patient and clinicians.

Place high-efficiency particulate air filters between the primary airway device and the breathing circuit, including the expiratory limb of the circuit once the patient is connected to the ventilator.

Unnecessary respiratory circuit disconnections should be avoided, in order to prevent viral dispersion. If disconnection is required, optimize patient sedation to prevent coughing, turn the ventilator to stand-by mode, and clamp the tracheal tube.

Ventilation clinical practice guidelines in adults with coronavirus disease 2019 (COVID-19) were released by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine.[32]

Ventilation-Related Recommendations and Suggestions for Adults With COVID-19

It is suggested to start supplemental oxygen if the peripheral oxygen saturation (SPO2) is less than 92%. It is recommended to start supplemental oxygen if the SPO2 is less than 90%.

In the event of acute hypoxemic respiratory failure on oxygen, it is recommended that the SPO2 be maintained at no higher than 96%.

In patients with acute hypoxemic respiratory failure despite conventional oxygen therapy, it is suggested that a high-flow nasal cannula be used rather than conventional oxygen therapy.

In patients with acute hypoxemic respiratory failure, it is also suggested that a high-flow nasal cannula be used over noninvasive positive-pressure ventilation.

In these patients with acute hypoxemic respiratory failure, in the event a high-flow nasal cannula is not available and the patient has no urgent indication for endotracheal intubation, it is suggested that a trial of noninvasive positive-pressure ventilation be conducted, with close monitoring and short-interval assessment for worsening of respiratory failure.

While considered an option, no recommendation was made regarding helmet noninvasive positive-pressure ventilation versus mask noninvasive positive-pressure ventilation.

In patients receiving either noninvasive positive-pressure ventilation or high-flow nasal cannula, it is recommended they be closely monitored for worsening respiratory status; early intubation in a controlled setting is recommended if worsening occurs.

In patients with acute respiratory distress syndrome (ARDS) who are on mechanical ventilation, it is recommended to use low-tidal-volume ventilation (4-8 mL/kg of predicted body weight) versus higher tidal volumes (>8 mL/kg).

In patients with ARDS who are on mechanical ventilation, it is recommended to target plateau pressures at less than 30 cm water.

In patients with moderate-to-severe ARDS who are on mechanical ventilation, it is suggested to use a higher positive end-expiratory pressure (PEEP) strategy versus a lower PEEP strategy. When using a higher PEEP strategy (ie, PEEP >10 cm water), monitor patients for barotrauma.

In patients with ARDS who are on mechanical ventilation, it is suggested to use a conservative fluid strategy versus a liberal fluid strategy.

In patients with moderate-to-severe ARDS who are on mechanical ventilation, it is suggested to use prone ventilation for 12-16 hours versus no prone ventilation.

In patients with moderate-to-severe ARDS who are on mechanical ventilation, it is suggested to use, as needed, intermittent boluses of neuromuscular blocking agents versus a continuous infusion, to facilitate protective lung ventilation.

Use of a continuous infusion of neuromuscular blocking agents is suggested in the event of persistent ventilator dyssynchrony, a need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures.

In patients with ARDS who are on mechanical ventilation, routine use of inhaled nitric oxide is not recommended.

In mechanically ventilated patients with severe ARDS and hypoxemia despite optimization of ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilator is suggested as rescue therapy; if rapid improvement in oxygenation is not observed, taper off treatment.

In mechanically ventilated patients with severe ARDS and hypoxemia despite optimization of ventilation, use of recruitment maneuvers is suggested over not using recruitment maneuvers. If recruitment maneuvers are used, staircase (incremental PEEP) recruitment maneuvers are not recommended.

In those patients on mechanical ventilation who have refractory hypoxemia despite optimization of ventilation and who have undergone rescue therapies and proning, it is suggested to use venovenous extracorporeal membrane oxygenation (EMCO) if available; alternatively, refer the patient to center that has ECMO. However, because EMCO is resource-intensive and it requires experienced centers/healthcare workers and infrastructure, it should only be considered in carefully selected patients with severe ARDS.

Drugs are not as effective as descent from altitude and oxygen in the treatment of high-altitude pulmonary edema (HAPE). Nifedipine, by reducing pulmonary arterial pressure, may be effective in treating HAPE.[29] However, in two separate studies, nifedipine did not outperform placebo or oxygen alone.[33, 34]

Prevention

In general, acetazolamide facilitates acclimatization, but this agent should not be relied on as the sole preventive agent in individuals with known HAPE susceptibility.[2, 3]

The Centers for Disease Control and Prevention (CDC) strongly recommends acetazolamide prophylaxis in all individuals with a prior history of HAPE or HACE, as well as with the following[4] :

• History of acute mountain sickness and ascending more than 2,800 m in 1 day
• All people ascending to more than 3,500 m in 1 day
• All people ascending more than 500 m per day (increase in sleeping elevation) above 3,000 m, without extra days for acclimatization
• Very rapid ascents

The CDC recommends the following pharmacologic agents and regimens for HAPE prophylaxis[4] :

• Oral nifedipine (generally reserved for HAPE-susceptible individuals) - 30 mg sustained-release formulation every 12 hours (same regimen for HAPE treatment)
• Oral tadalafil - 10 mg twice daily
• Oral sildenafil - 50 mg every 8 hours

Treatment

Further research is needed before tadalafil or dexamethasone can be recommended over nifedipine for prophylaxis. The Wilderness Medical Society (WMS) advises that diuretics or acetazolamide should not be used for treatment of HAPE, and it makes no recommendation regarding beta-agonists or dexamethasone for HAPE treatment due to insufficient/lack of data.[2, 3] Furthermore, WMS indicates there is no established role for acetazolamide, beta-agonists, diuretics, or dexamethasone in the treatment of HAPE, although dexamethasone should be considered where there is concern for concomitant high-altitude cerebral edema (HACE)

In the setting of concomitant HAPE and HACE, WMS recommends adding dexamethasone to the treatment regimen for patients with HAPE and neurologic dysfunction that does not resolve rapidly with administration of supplemental oxygen and improvement in the patient’s oxygen saturation.[2, 3] If supplemental oxygen is not available, initiate dexamethasone in addition to medications for HAPE in those with mental status changes and/or suspected concurrent HACE. Note the following:

• Dexamethasone should be administered at the doses recommended for the treatment of HACE.
• Nifedipine or other pulmonary vasodilators may be used to treat concurrent HAPE and HACE, but avoid lowering mean arterial pressure, as this may decrease cerebral perfusion pressure and thereby increase the risk for cerebral ischemia.

Class Summary

Nifedipine is used for its pulmonary vasodilating effects.

Nifedipine (Procardia, Adalat)

Nifedipine is used in HAPE for pulmonary vasodilation. It often improves SaO2 modestly within a few minutes.

Class Summary

These agents are helpful in the prevention of HAPE.

Acetazolamide (Diamox)

Acetazolamide is used in the prevention of HAPE. It is not used in the treatment of this condition. Acetazolamide promotes renal excretion of bicarbonate, which stimulates respiration. For the prophylaxis of altitude illness, start 24-48 hours before ascent and continue for 48 hours after arrival at high altitude.

Class Summary

These agents have profound and varied metabolic effects. They suppress inflammation and the immune response.

Dexamethasone (Decadron)

Dexamethasone alleviates vasogenic cerebral edema and improves endothelial integrity.