The mountains are popular and sought out destinations for adventure travel, seasonal work, and permanent residence for a growing number of the world's population. More than 40 million people visit areas of high altitude (greater than 2500 meters) every year, and a reported 140 million people have a permanent residence at these elevations. At high altitudes, the concentration of oxygen in inspired air is much lower when compared to sea level due to a decrease in barometric pressure and a decrease in the partial pressure of oxygen. The body's physiological response and adaptation to a hypoxic stimulus such as high altitude can cause significant morbidity and mortality and presents 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). The disease processes can vary from mild to life-threatening. AMS develops due to rapid ascent and can be described as a "hangover" and includes nonspecific symptoms such as headache, nausea, dizziness, fatigue, and insomnia. HAPE is a progression of the disease process and presents with acute pulmonary complications due to poor acclimatization. HACE, the most feared complication of altitude sickness, involves the development of neurological symptoms and sequela due to cerebral edema. These conditions are essentially a range of severity based on similar pathophysiology resulting from hypoxic stimuli during rapid ascent to high altitudes. 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. This activity will focus primarily on the pathophysiology, clinical presentation, and management of HAPH.
At altitudes above 2500 meters, the barometric pressure is lower, which results in a decrease in the partial pressure of oxygen in the air. If the FiO2 is 2%, at high altitudes, the actual amount of oxygen that reaches the alveoli is much less than at sea level, and this results in hypoxia and hypoxemia. Ambient air hypoxia triggers pulmonary vasoconstriction and, ultimately, an increase in pulmonary artery pressures. The pathogenesis and etiology of high altitude pulmonary hypertension are complex and multifactorial. The belief is that vascular remodeling owing 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.
While there are individuals who experience the spectrum of acute mountain sickness acutely, high altitude pulmonary hypertension develops mainly in persons who reside at high altitudes for an extended period. Those with preexisting pulmonary hypertension are at an even greater risk of worsening hemodynamics related to high pulmonary artery pressures associated with ambient hypoxia at high altitudes and are more likely to develop acute mountain sickness. There is a minimal amount of epidemiological research regarding at risk-populations for high altitude pulmonary hypertension, but some studies done in South America report a prevalence of 55 to 18%, which tends to be more common in men. The lower prevalence of HAPH in premenopausal women living at high altitudes compared to men may be related to protective female sex hormones, which increase the ventilatory rate and drive.
Hypoxic stress at high altitude induces a variety of physiological changes. While many organ systems utilize vasodilation to maximize oxygen transport, the pulmonary system employs vasoconstriction at the level of the small pulmonary artery and veins. This intuitively makes sense in the case of lobar pneumonia or other focal disease processes. Pulmonary vasoconstriction leads to shunting of blood away from poorly oxygenated lung zones towards healthy alveoli to minimize V/Q mismatch. In high altitude pulmonary hypertension, given that all lung fields are experiencing the same hypoxia, there is massive vasoconstriction and elevation in the pulmonary artery pressures, which ultimately leads to pulmonary hypertension. This increase in pulmonary pressure forces fluid into the lungs, causing pulmonary edema acutely.
Vascular remodeling plays a major role in the pathophysiology of HAPH. Hypoxia triggers pulmonary vasoconstriction, and this increases the vascular resistance in the small pulmonary veins and arteries, ultimately leading to vascular remodeling. At the cellular level, chronic hypoxia leads to channelopathy of both potassium and calcium channels resulting in an increase in intracellular calcium and proliferation of smooth muscle within the pulmonary vasculature, an area normally devoid of smooth muscle cells ( fibroblasts). For people who reside in high altitudes, vascular remodeling can be a long term sequelae due to chronic hypoxia and can persist despite the removal of the hypoxic stimulus of altitude.
Additionally, endothelial nitrous oxide (NO) is theorized to play a role in the development of HAPH. We know that longstanding hypoxia decreases NO synthesis contributing to the development of pulmonary hypertension. When comparing different subpopulations, research has shown that increased concentrations of NO in pulmonary endothelium have resulted in a lower prevalence of HAPH. Specifically, the literature has shown that individuals from Tibet have recorded high concentrations of NO, which correlates with a lower prevalence of HAPH when compared to the South American Andean population.
The presentation of high altitude pulmonary hypertension is similar to other causes of pulmonary hypertension. The patient might describe 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. 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 PH (autoimmune pathology, valvular heart disease, drug-induced PH, and infectious disease) are necessary when evaluating patients for suspected HAPH.
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 make a diagnosis of high altitude pulmonary hypertension, the patient must reside at an elevation greater than 2,500 meters. It is also important to rule out other diagnoses. Work up, and diagnostics include EKG, echocardiogram, chest x-ray, pulmonary function tests, and right-sided heart catheterization with pulmonary angiography.
EKG will 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 will reveal dilated right ventricle and right atrium, as well as an increase in pulmonary artery pressure. It is important 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, and 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. Of note, it is important to attempt the catheterization and angiography at the altitude of residence, if possible.
Currently, there is limited data regarding the long term management of high altitude pulmonary hypertension. In several studies, some treatments have been shown to improve symptoms and mPAPs, many of which are recommended for the treatment of pulmonary hypertension due to other causes.
Specific for high altitude pulmonary hypertension, it is recommended that patients move to lower altitudes. Some studies have shown that mPAPs have normalized within two years after returning to low lands from areas of elevation . Phosphodiesterase inhibitors like the well-known medication sildenafil have shown promising benefits in the treatment of HAPH. These medications inhibit the breakdown of NO, which leads to pulmonary artery vasodilation and a decrease in mPAP. Endothelin receptor blockers such as bosentan have also been used in the treatment of pulmonary hypertension. Acetazolamide is useful in the prevention of AMS. Some studies have shown that it can decrease pulmonary vascular resistance. That being said, it has not been studied specifically for the treatment of HAPH, and benefits may be minimal. Yet, due to its low side effect profile, it is safe to incorporate it as a treatment option.
In the acute setting, some research suggests that venovenous extracorporeal membrane oxygenation (ECMO) can be beneficial in severe cases. Despite all efforts and recommendations, if an individual develops irreversible pulmonary hypertension, the mainstay of treatment is pulmonary transplantation.
Patients with high altitude pulmonary hypertension will present with dyspnea on exertion, fatigue, chest pain, and peripheral edema. All causes of heart failure and pulmonary hypertension should be considered, such as valvular disease, congenital heart disease, COPD, asthma, interstitial lung disease, connective tissue disorders, and systolic or diastolic dysfunction.
For pulmonary hypertension of any cause, early recognition and treatment are critical for successful treatment outcomes. 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 who will develop irreversible pulmonary hypertension and require pulmonary transplantation. After transplantation, patients have a median survival of 10.7 years. If unsuccessful, there are a variety of palliative procedures that can aid in maximizing right ventricular cardiac output.
Few long term studies have been performed to assess 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.
The most common complication is exercise intolerance, which most patients will experience some degree, despite appropriate management and therapy. Unfortunately, the worst complications are the advancement of the disease, right ventricular failure, and death.
Patient education is key in successfully managing any cause of pulmonary hypertension. Giving the appropriate medications and explaining the importance of adhering to the regimen provides the patient with the best chance for the best clinical outcome. Providers must also take care to accurately manage patient expectations of treatment outcomes as some will still experience significant exercise intolerance and ultimately require pulmonary transplantation.
Specific for high altitude pulmonary hypertension, emphasizing that pulmonary artery pressures can improve with returning to lower altitudes should be a key motivator for patient management. If the patient understands the progression and severity of the disease, urging them to return to lower altitudes can significantly improve their quality of life and prognosis.
High altitude pulmonary hypertension is a life-threatening condition if unrecognized and untreated. Enhancing patient outcomes first comes from early recognition and treatment. Primary care providers who serve communities at high altitudes can provide a great deal of information and education to their patients. If they have a high index of suspicion for altitude-related illness, in this case, HAPH, early detection, and treatment can significantly improve the prognosis. Strongly urging patients to descend to lower elevations can lower their pulmonary artery pressures, and cannot be emphasized enough. 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 with the diagnosis of HAPH. Although treatment recommendations are based on cohort and case-control studies, it is believed that patients will benefit from pulmonary vasodilators, possibly acetazolamide, and descent to lower altitudes. [Level 3]. More studies need to be done on maximizing the treatment modalities of pulmonary hypertension of all causes, and specifically of HAPH.
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