High-Altitude Pulmonary Edema (HAPE) Guidelines

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.