Continuing Education Activity

This activity describes the development of pulmonary hypertension due to high altitude. We describe a phenomenon known as HAPH (high altitude pulmonary hypertension), which is classically defined as a mean pulmonary arterial pressure greater than or equal to 25 mmHg on a right heart catheterization and results in pulmonary vascular remodeling. This condition can present in individuals who typically reside at altitudes greater than 2500 meters. The hypoxic stimulus of high altitude and individual genetic factors play a role in the pathophysiology of pulmonary vasoconstriction and, eventually, vascular remodeling that occurs with HAPH. This activity reviews the etiology, pathophysiology, clinical evaluation, and treatment of HAPH and highlights the interprofessional team's role in providing well-coordinated care to enhance patient outcomes.

Objectives:

• Identify the etiology of high altitude pulmonary hypertension.
• Describe the clinical evaluation of high altitude pulmonary hypertension.
• Outline the management options available for high altitude pulmonary hypertension.
• Summarize the interprofessional team strategies for improving care coordination and understanding of high altitude pulmonary hypertension to improve clinical outcomes.

Introduction

Mountainous regions are a destination for adventure travel, seasonal work, and permanent residence for many people. More than 40 million people visit high altitude areas (greater than 2500 meters) every year, and a reported 140 million people have a permanent residence at these elevations.[1] The decreased barometric and partial pressures of oxygen at high altitudes can reduce inspired oxygen levels compared to sea level. The body's exaggerated physiological response to rapid ascent, a lower level of inspired oxygen, or the persistent hypoxic stimulus experienced at high altitude can cause significant morbidity and mortality.  High altitude associated disease processes can vary from mild to life-threatening. The body's response can present in the form of acute mountain sickness (AMS), high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE), and ultimately high-altitude pulmonary hypertension (HAPH). AMS develops secondary to rapid ascent and can be described as a "hangover" and include nonspecific symptoms such as headache, nausea, dizziness, fatigue, and insomnia.[2] 

HAPE is a progression of acute mountain sickness and presents with acute pulmonary, a complication of the body's poor acclimatization. HACE, the most feared complication of altitude sickness, involves cerebral edema and associated neurological symptoms and sequela. Chronic hypoxic stimuli of high altitude living can result in permanent pulmonary vascular remodeling due to increased pulmonary vascular resistance and define a subgroup of pulmonary hypertension known as HAPH.[1] This article will focus primarily on the pathophysiology, clinical presentation, and management of HAPH.

Etiology

At altitudes above 2500 meters, the barometric pressure is lower, which results in a decrease in the partial pressure of oxygen in the air. Even though the FiO2 remains 21% at high altitudes, the actual amount of oxygen that reaches the alveoli is much less than at sea level, resulting in hypoxia and hypoxemia.[3] Hypoxia triggers pulmonary vasoconstriction and, ultimately, an increase in pulmonary artery pressures throughout the lung. The belief is that vascular remodeling secondary to abnormal smooth muscle production, a decrease in the intrinsic availability of nitric oxide, and poorly understood genetic predisposition all contribute to the development of high altitude pulmonary hypertension.

Epidemiology

While some individuals experience the spectrum of acute mountain sickness, high altitude pulmonary hypertension develops mainly in those who reside at high altitudes for extended periods. Those with preexisting pulmonary hypertension are at an even greater risk of developing acute mountain sickness because of worsening ambient hypoxia associated hemodynamics exacerbating previously elevated high pulmonary artery pressures.[4] Only a limited amount of epidemiologic data is available regarding at risk-populations for high altitude pulmonary hypertension.  Some studies of South American populations report a prevalence of 18 to 55%, and the condition tends to be more common in men.[1][5]  Lower rates of HAPH have been reported in premenopausal women compared to men living at high altitudes. The difference in reported incidence may be secondary to female sex hormones and an associated increase in ventilatory rate and drive.[6]

Pathophysiology

Hypoxic stress at high altitude induces a variety of physiological changes. Many organ systems utilize vasodilation to enhance oxygen delivery in the setting of hypoxia.  In contrast, the lung responds to hypoxia with increased pulmonary vasoconstriction.  Blood is shunted away from poorly oxygenated lung zones towards healthy alveoli in an effort to minimize V/Q mismatch.[7] This intuitively makes sense in the setting of lobar pneumonia or other focal disease processes involving the lung.  In high altitude pulmonary hypertension, all lung fields experience the same degree of hypoxia. Significant vasoconstriction in all parts of the lung and elevated pulmonary artery pressures lead to pulmonary hypertension.[8] The resultant increase in pulmonary pressure forces fluid into the lungs, causing acute pulmonary edema. 

Vascular remodeling plays a major role in the pathophysiology of HAPH. Hypoxia ultimately leads to vascular remodeling by triggering pulmonary vasoconstriction and increased vascular resistance in the small pulmonary veins and arteries. At the cellular level, chronic hypoxia causes channelopathy of both potassium and calcium channels, increasing intracellular calcium.  The proliferation of smooth muscle within the pulmonary vasculature occurs, a structure normally devoid of smooth muscle cells ( fibroblasts).[1] Vascular remodeling can be a long term and irreversible sequela of chronic hypoxia and persist despite removal of the hypoxic stimulus.[9]

Endothelial nitrous oxide (NO) is theorized to play a role in the development of HAPH. Longstanding hypoxia is known to decrease NO synthesis, contributing to the development of pulmonary hypertension.[10][1] Research and comparison of different subpopulations have demonstrated that increased concentrations of NO in pulmonary endothelium decrease the prevalence of HAPH. Studies have shown that individuals from Tibet have high NO concentrations, which correlates with a lower prevalence of HAPH than the South American Andean population.[1]

History and Physical

High altitude pulmonary hypertension presents with similar symptoms to other causes of pulmonary hypertension. The patient may present with one or more of the following symptoms: exertional dyspnea, cough, hemoptysis, chest tightness, fatigue, lower extremity swelling, or syncope. On examination, there will be signs of right-sided heart failure. Specifically, a loud P2, a right ventricular heave, tricuspid regurgitation, jugular venous distension (JVD), peripheral edema, and ascites.[1] All these findings are sequelae of right ventricular hypertrophy and right-sided heart failure. A thorough history and examination looking for signs and symptoms of other additional causes of pulmonary hypertension (autoimmune pathology, valvular heart disease, drug-induced PH, and infectious disease) are necessary when evaluating patients for suspected HAPH.

Evaluation

Patients who present with signs and symptoms of shortness of breath, dyspnea, fatigue, or peripheral edema should be evaluated for heart failure and pulmonary hypertension. To diagnose high altitude pulmonary hypertension, the patient must reside at an elevation greater than 2,500 meters.[1] Other diagnoses besides pulmonary hypertension should always be considered. Diagnostic tests that can be utilized are an EKG, echocardiogram, chest X-ray, pulmonary function tests, or a right-sided heart catheterization with pulmonary angiography. 

• An EKG can be consistent with chronic right heart strain and have findings of right ventricular hypertrophy (RVH), right bundle branch block (RBBB), and tall p-waves in inferior leads. 
• An echocardiogram can show a dilated right ventricle and right atrium, as well as increased pulmonary artery pressure. It is also essential to assess left ventricular function and ejection fraction to rule out left-sided heart failure. 
• The chest X-ray may be normal or shows signs of cardiomegaly or pulmonary vascular congestion.
• Pulmonary function tests are useful in excluding other diagnoses such as chronic obstructive pulmonary disease (COPD), asthma, or other interstitial lung diseases. 

Right-sided heart catheterization and pulmonary angiography are the most important diagnostic tools for establishing a definitive diagnosis. A mean pulmonary artery pressure (mPAP) greater than 30 mmHg or systolic PAP of greater than 50 mmHg is diagnostic for pulmonary hypertension.[1] If possible, it is important to attempt catheterization and angiography at the altitude of residence. 

Treatment / Management

Limited data is currently available to guide the long-term management of high altitude pulmonary hypertension. Several studies have shown that some treatments recommended for managing other causes of pulmonary hypertension have improved symptoms and mPAPs.

Patients suffering from high altitude pulmonary hypertension should be advised to move to lower altitudes. Some studies have shown that mPAPs for patients have normalized within two years of returning to lower altitudes.[11]  Pharmacological treatments for HAPH can include phosphodiesterase and carbonic anhydrase inhibitors. 

• Phosphodiesterase inhibitors (i.e., Sildenafil) block the breakdown of NO, promoting pulmonary artery vasodilation and decreased mPAP.[12]
• Carbonic Anhydrase Inhibitors (i.e., Acetazolamide) are useful in the prevention of AMS. Studies have also shown a decrease in pulmonary vascular resistance.[1] However, Acetazolamide has not been studied specifically for the treatment of HAPH, and the benefits may be minimal. Due to Acetazolamide's low side effect profile, it is safe to incorporate as a treatment option. 
• Endothelin receptor blockers (i.e., Bosentan) have also been used to treat pulmonary hypertension.

Some studies have shown that venovenous extracorporeal membrane oxygenation (ECMO) can be beneficial for severe cases in the acute setting. Despite all efforts and recommendations, if an individual develops irreversible pulmonary hypertension, the mainstay of treatment is pulmonary transplantation.[13]

Differential Diagnosis

Patients with high altitude pulmonary hypertension can present with dyspnea on exertion, fatigue, chest pain, and peripheral edema. Other causes of heart failure and pulmonary hypertension to consider are:

• Asthma
• Congenital heart disease
• Connective tissue disease
• COPD
• Diastolic dysfunction
• Interstitial lung disease
• Systolic dysfunction

Prognosis

Early recognition and treatment are critical for the successful management and outcomes of any form of pulmonary hypertension. Treatments that decrease pulmonary artery pressures and maximize the right ventricle, such as pulmonary vasodilators, are the mainstay of chronic management. Despite optimal medical management, many patients will still experience some degree of exercise intolerance, and others will develop irreversible pulmonary hypertension and require pulmonary transplantation.[13] After transplantation, patients have a median survival of 10.7 years.[13] If unsuccessful, there are various palliative procedures that can aid in maximizing right ventricular cardiac output. 

Few long-term studies have assessed the prognosis of high altitude pulmonary hypertension. Some research suggests that mean pulmonary artery pressures can normalize in as little as two years after descent to lower altitudes but can increase with a return to high elevation.[1] 

Complications

The most common complication of the condition is exercise intolerance, which most patients will experience to some degree, regardless of optimized treatment and therapy. More severe complications of the condition include the advancement of the disease, right ventricular failure, and death.[13]

Deterrence and Patient Education

Patient education is essential for the successful management of pulmonary hypertension. Treatment with the appropriate medications and patient understanding of the importance of adherence to the regimen provides the greatest likelihood for the best clinical outcome. Healthcare providers should work with patients to help them manage their expectations for treatment outcomes.  Some patients will still experience significant exercise intolerance and may ultimately require pulmonary transplantation. 

Patients afflicted with high altitude pulmonary hypertension should understand that pulmonary artery pressures can improve with a return to lower altitudes. If the disease's progression and severity are understood, urging the patient to return to lower altitudes can significantly improve the prognosis and quality of life.

Enhancing Healthcare Team Outcomes

High altitude pulmonary hypertension is a life-threatening condition. Optimal patient outcomes are through early recognition and treatment. During the initial acute presentation of symptoms, members of the health care team need to recognize the signs of pulmonary hypertension, treat symptomatically, and investigate with the proper modalities to determine the diagnosis of HAPH.  Primary care providers who serve communities at high altitudes also serve an important role in providing information on the condition and patient education. It is vital to have a high index of suspicion for altitude-related illness and HAPH since early detection and treatment can significantly improve the prognosis. Patients suffering from HAPH should be strongly urged to descend to lower elevations to lower their pulmonary artery pressures.