Pulmonary hypertension (PH) is comprised of a group of clinical conditions associated with elevated pressure in the pulmonary vascular bed. This hemodynamic state is characterized by a concomitant mean pulmonary artery pressure (mPAP) greater than 20 mm Hg, pulmonary artery occlusion pressure (PAOP) equal to or less than 15 mm Hg, and pulmonary vascular resistance (PVR) equal to or greater than 3 Woods Units at rest.1 Generally, it is a rare progressive disease in which elevated pulmonary vascular pressure leads to right ventricular (RV) failure and death. The exact incidence is unknown. Some estimates indicate the number is in the hundreds of thousands and may represent 1% of the world's population and 10% of individuals over age 65.2 PH occurs more often in females.2 If left untreated, the mean survival rate is 2.8 years. Approximately 200,000 patients are hospitalized each year with a primary or secondary diagnosis of PH. Approximately 15,000 individuals die of PH each year.2
PH is classified based on pathophysiology, hemodynamics, and therapeutic options. In 2013, the World Health Organization (WHO) classified the principal forms of PH into 5 groups. WHO Group 1 includes the most common form of PH, pulmonary arterial hypertension (PAH). WHO Group 2 includes patients with PH resulting from left heart disease. WHO Group 3 addresses patients who have lung disease or hypoxia. WHO Group 4 includes patients with chronic thromboembolic disease. WHO Group 5 includes those with multifactorial PH.1-4 For the 2018 WHO update to the clinical classification of PH, see https://erj.ersjournals.com/content/erj/early/2018/10/11/13993003.01913-2018.full.pdf. This article will focus on the WHO Group 1 form of PAH.
PAH, a type of PH, is characterized by an mPAP of 20 mm Hg or greater (the former threshold was defined as 25 mm Hg or greater) at rest or a pulmonary artery systolic pressure greater than 40 mm Hg, measured during a right heart catheterization. Historically PAH was a condition that affected a few individuals and was overlooked by the medical and pharmaceutical communities. In 1973, WHO held the first international conference on primary PH. WHO organized the conference because of a significant increase in the incidence of PH related to a weight-loss medication. The hemodynamic definition of PH was established at that meeting. Additionally, the National Institutes of Health launched the first PH registry. The second international conference was held 25 years later. Scientists attending that meeting established the clinical classifications of PH. Since then, there have been additional international conferences with each one establishing standards of care for the patient with PH.5 More recently, the 6th World Symposium on Pulmonary Hypertension convened a task force that proposed changing the definition of PH and added a new subgroup to Group I classification of PH.1 Additionally, there have been numerous registries at several centers in the US and the world that have contributed to the identification of patient characteristics and predicted patient outcomes. For example, female patients with greater than 6-minute walk distance and higher cardiac outputs are more likely to survive.5,6
PAH can be caused by a single factor or in combination with other disease processes. Idiopathic PAH has no known hereditary link or other causative risk factor. Heritable PAH occurs in familial lines with or without a genetic mutation.6 Drugs or toxins can cause PAH. Examples of medications associated with the development of PAH are aminorex fumarate and derivatives of fenfluramine. Aminorex fumarate and fenfluramine were drugs used for obesity management but because of post-marketing adverse drug events, both drugs have been withdrawn from the US market. Because of its vasoconstrictive properties, cocaine is an example of a toxin that can cause PAH. The strength of the associations between these drugs and toxins and the development of PAH vary.7 For the 2018 update on the classification of drugs and toxins associated with PAH, see https://erj.ersjournals.com/content/erj/early/2018/10/11/13993003.01913-2018.full.pdf. Connective tissue diseases can also lead to the development of PAH and account for 15% to 25% of cases worldwide.6 Examples of connective tissue diseases include systemic lupus erythematosus and systemic sclerosis. Patients with HIV, portal hypertension, congenital heart diseases, and schistosomiasis are all at an increased risk for developing PAH.6
PAH affects the small resistance vessels in the pulmonary vascular bed (see Vessel changes in PAH). Recall that the arterial wall consists of three layers of tissue, the intima, media, and adventitia. PAH is characterized by thickening of the intimal lining, hypertrophy of the medial layer, and proliferation of the adventitia, resulting in an inflammatory state. The inflammation activates the intrinsic clotting cascade resulting in thrombosis of the small arterial vessels.8 Production of vasoconstricting substances increases, including thromboxane, endothelin, and serotonin; and production of vasodilators decreases, including nitric oxide and prostacyclin. PVR increases, which in turn increases RV afterload and subsequent RV hypertrophy.
It is interesting to note that long-term outcomes of PAH are determined by the response of the right ventricle to the increased afterload. It may be adaptive with the development of ventricular concentric hypertrophy while maintaining a normal ejection fraction and cardiac output. A maladaptive response includes an eccentric dilatation and increased fibrosis of the right ventricle, resulting in a reduced ejection fraction and cardiac output. Researchers are still investigating the underlying mechanisms that mediate the switch from the adaptive form to the maladaptive state.8 RV dysfunction can be attributed to several pathologic changes including a shift from oxidative to anaerobic metabolism, presence of ischemia, calcium mishandling at the cellular level, and sarcomere remodeling.8 As the disease process continues, the right ventricle may fail and cause cardiogenic shock.
Signs and symptoms
Progressive exercise intolerance is the primary sign of PAH. The vagueness of this initial sign can lead to a diagnosis delay of months to years from the initial onset of symptoms. Other corresponding initial symptoms can include unexplained exhaustion and fatigue.2 As the disease progresses, worsening symptoms, such as shortness of breath with daily activities, weakness, syncope, palpitations, and angina can develop. With the involvement of the right ventricle, signs and symptoms of RV failure develop. These can include peripheral edema, ascites, and hepatomegaly, feeling of fullness early after starting to eat, and pleural effusions.6 The WHO Functional Assessment for PAH is modeled somewhat after the New York Heart Association functional classification and is used by healthcare providers to identify and diagnose the disease. (See WHO functional assessment for PH.)
A high index of suspicion is required to diagnose PAH because of the vague, common, early symptoms of dyspnea, fatigue, and exercise intolerance. It is important to consider the diagnosis in patients with a chronic illness who have symptoms that are disproportionate to the underlying disease or are poorly responsive to treatment. Noninvasive echocardiography with Doppler imaging is essential for screening. Although imperfect, the echocardiogram will reveal the presence of RV or right atrial enlargement or dilation. Additionally, the study can evaluate for cardiac causes of PAH, including valvular heart disease, left ventricular dysfunction, or pericardial effusion; or use a bubble study to evaluate for shunt lesions.4,6
Right heart catheterization is necessary for a PAH diagnosis, based on the pulmonary artery systolic pressure and the mPAP. It is the gold standard for diagnosis of PAH. Normal mPAP is 14 mm Hg ± 3. Per the 6th World Symposium, PAH is present when the mPAP is greater than 20 mm Hg. An mPAP greater than 40 mm Hg is considered severe PAH.1,4,6
Pulmonary vasodilator testing should be performed and include a decrease in mPAP to 40 mm Hg or less, a decrease of 20 mm Hg in mPAP and unchanged or increased cardiac output. A lack of response does not indicate a lack of response to PAH therapies. Additionally, a volume challenge of 10 mL/kg of warm 0.9% sodium chloride infused over 10 minutes can be performed if there is still a suspicion of PAH. A positive response would include an increase of the mPAP of 20 mm Hg or greater while the PAOP remains at 15 mm Hg or less.1,4,6
Patients with PAH should be referred to a center with a PH program. Treatment goals include initiating oxygen therapy for patients with a PaO2 less than 60 mm Hg.2 If the patient is unstable, other treatment considerations include invasive hemodynamic monitoring, maintaining systolic blood pressure (SBP) greater than 90 mm Hg, maintaining central venous pressure (CVP) 8 to 10 mm Hg with diuretics and judicious fluid resuscitation, RV contractility support with inotropes if needed, and pulmonary vasodilators.6 Mechanical RV assist devices can be used in the short term in patients with PAH to support the right ventricle, and in severe cases extracorporeal membrane oxygenation (ECMO) can be used.
General guidelines. The management of PAH is determined by identifying and treating the underlying cause. Counseling and educating the patient and family about the disease are important components in the care of patients with PAH. Patients should be encouraged to participate in a low-level graded exercise appropriate for their physical condition, such as walking, and to avoid heavy physical exertion and isometric exercise, which may cause exertional syncope. Patients also should be encouraged to participate in a pulmonary rehabilitation program. Supplemental oxygen to maintain an oxygen saturation greater than 90% at rest as well as with physical activity and sleep. Going to higher altitudes is not recommended because of lower oxygen levels.6 Instruction on a low-sodium diet is appropriate for most patients with PAH.
Guidelines recommend anticoagulation with warfarin titrated to an international normalized ratio of 1.5 to 2.5, particularly if the patient has a history of pulmonary emboli.4 A diuretic may be indicated to address volume overload or peripheral edema related to RV failure. Calcium channel blockers have been found to be helpful in a subgroup of patients (10% to 15%) with an acute response to vasodilator testing.6 Patients who are not vasoreactive should never be placed on calcium channel blockers, as they will worsen their disease progression.6 However, very few of these patients do well on a long-term basis.6
Lung or heart-lung transplant remains the best treatment option for patients with PAH. Patients should be referred and evaluated for a transplant early before severe right heart failure develops. In some centers, ECMO is being used as a bridge to recovery or a bridge to transplant.
Pulmonary vasoactive medications. Pulmonary vasoactive medications often are initiated when the patient is experiencing symptoms with physical activity or routine daily activity (WHO PH functional class II–III). Combination oral therapy or augmented therapy may be used. As the disease progresses and the patient experiences symptoms at rest with severe symptoms associated with any activity (WHO PH functional class IV), care providers will initiate I.V. or subQ infusion therapy. These medications are expensive, high risk, and must be handled carefully. Many pulmonary vasoactive medications have drug-drug interactions and may also be contraindicated in certain pathologic states such as hepatic failure. PAH medications work on one of three pathways in the pulmonary vasculature: endothelin, prostacyclin, and nitric pathways. (See PAH medications, pathways, nursing considerations, and adverse reactions.)
Prostacyclins. Endogenous prostacyclin is produced in the endothelial cells and is a vasodilator with antiproliferative effects. Prostacyclin production is reduced in patients with PAH. This class of medications has been the mainstay of the management of PAH for 20 years. Medications in this group work by directly dilating the pulmonary vascular vessels, inhibiting platelet aggregation in the pulmonary circulation and working as an antiproliferative agent to prevent fibrosis of the pulmonary vessels. Prostacyclin therapy can be administered intravenously, subcutaneously, or via inhalation. This class of medications includes epoprostenol (continuous I.V. infusion), treprostinil (continuous I.V. infusion, subcutaneous infusion, intermittent inhaled, and oral), and iloprost, a synthetic analogue of prostacyclin (intermittent inhaled).4,9
Epoprostenol is most commonly delivered by continuous I.V. infusion through a central venous catheter using an infusion device. Epoprostenol sodium (Flolan), one of the earlier preparations, has a relatively short half-life (approximately 6 minutes); caution should be taken not to abruptly discontinue the infusion because of the risk of rebound PH, which can cause RV failure, shock, and cardiac arrest. Flolan that is reconstituted with the Flolan sterile diluent must be used with a cold pouch if not administered within 8 hours, however Flolan that is reconstituted with the Flolan pH 12 sterile diluent does not require the use of a cold pouch. A more stable epoprostenol preparation, Veletri, is available and is stable at room temperature and does not require use of a cold pouch.10 Treprostinil (Tyvaso) is approved for oral inhalation use and treprostinil (Orenitram) extended-release tablets are approved for oral use.6,9
Endothelin receptor antagonists (ERAs). Endothelin is released from the epithelial cells lining the blood vessels. It produces vasoconstriction of the pulmonary blood vessels. The ERAs block the endothelin receptors on the smooth muscle of the pulmonary blood vessels. The result is less vasoconstriction as well as a reduction in smooth muscle proliferation and thickening of the blood vessels. Examples include ambrisentan (Letairis), macitentan (Opsumit), and bosentan (Tracleer). These drugs are given orally.6,9
Phosphodiesterase type-5 (PDE5) inhibitors. This class of medications increases intracellular nitric oxide levels, which will dilate the pulmonary vascular bed. Medications in this class include sildenafil (Revatio) and tadalafil (Adcirca).6,9
Soluble guanylate cyclase stimulator and prostacyclin receptor agonists are the last two classes of pulmonary vascular vasodilators. Both will produce vasodilation of the pulmonary blood vessels through different mechanisms.9
There are many nursing considerations when caring for a patient with PAH. This is a progressive and deadly disease requiring routine monitoring and a strict medication regimen. Early diagnosis, initiation of therapy, and adherence to therapy improve mobility and help maintain quality of life while slowing disease progression.11 An understanding of diagnostics, pharmacologic treatments, and strong assessment skills are vital to providing safe and effective nursing care and effective education to a patient with PAH. Nursing considerations should be based on the symptoms present and the current progression of the disease. The goal is to prevent complications and optimize the patient to decrease symptoms improving their quality of life. The assessment of the patient with PAH should be a full head-to-toe assessment. The nurse must monitor for signs and symptoms of RV failure.
When the patient with PAH is decompensated necessitating admission to the hospital, a primary treatment goal is to initiate oxygen therapy for a PaO2 less than 60 mm Hg.2 This may be accomplished by delivering supplemental oxygen through a nasal cannula, use of high-flow oxygen or, in some cases, endotracheal intubation with mechanical ventilator support. Patients admitted to the ICU will require invasive monitoring and pharmacologic support to maintain an SBP of greater than 90 mm Hg, maintain a CVP at 8 to 10 mm Hg with diuretics and judicious fluid resuscitation, RV contractility support with inotropes if needed, and pulmonary vasodilators.6 If RV failure is severe, mechanical RV assist devices may be used in the short term to offload and support the right ventricle. In severe cases, ECMO using the veno-veno cannulation may be appropriate. In this situation, the goal is to oxygenate the blood.
A multidisciplinary approach to patient mobility is important because patients in advanced stages of PAH are at an increased risk for syncope. Activity tolerance should be assessed, and adequate rest periods should be provided. These patients are at risk for skin breakdown because of poor appetite and decreased ambulation. Skin surveillance and implementation of preventive measures are required. Patients with PAH require meticulous infectious disease prevention including the administration of appropriate vaccinations. Care must be taken to prevent a central line-associated bloodstream infection (CLABSI) if a pulmonary arterial catheter or other central line is present.9
An important aspect of nursing care of these patients is the initiation and/or maintenance of pulmonary vasodilator medications. Depending on the patient's disease progression, medication therapy may start out as monotherapy. When patients no longer respond to oral therapies, initiate inhaled, subcutaneous, or I.V. infusion therapies. PAH medications are high-risk and should be handled with care. Each patient may respond differently to the medications and may experience different adverse reactions to drug therapy. To aid in adherence and appropriate dosing, the nurse should be proactive in reporting medication adverse reactions to the provider and administering as-needed medications to decrease adverse reactions such as nausea and diarrhea. Clinical nurses and the clinical pharmacists have a unique role in collaborating to provide patient and family education about medication adverse reactions, specifically what symptoms to look for and when to notify their physician. This education will help patients increase their adherence to PAH medication regimen.
Discharge planning should begin at admission because a comprehensive care team will be needed to care for the patient with PAH in and out of the hospital. This comprehensive care includes social work and case management staff to assist with financial and community resources that may be required, particularly as it relates to the patient's social support, quality of life, and use of pulmonary vasodilator medications after discharge. If a patient is discharged on a pulmonary vasodilator continuous infusion, the nurse caring for the patient should contact the pulmonary hypertension ambulatory clinic to pursue obtaining financial clearance for the medication and to arrange for a home infusion services company to provide the medication after the patient is discharged. Patients requiring I.V. or subcutaneous therapy at home require education about how to manage their pump and insertion site prior to discharge. Generally, the specialty home infusion services will provide this education with the acute care nurse reinforcing the skills and knowledge. Because this is a progressively fatal disease without a lung transplant, palliative care is a useful resource for the patient and his or her family to drive goals of care. Prior to discharge, the patient with PAH should be referred to a PAH outpatient clinic for ongoing care and postdischarge monitoring.
Patients with PAH on home infusion are commonly readmitted to the hospital. The nurse's understanding of how to manage the patient's home subcutaneous or I.V. pump is important for patient safety. Some medical facilities may require that the patient be switched from his or her home I.V. pump to a hospital-provided infusion pump or the patient condition may dictate that the patient needs to be switched from subcutaneous to I.V. medications. Many facilities will allow the patient's infusion to complete prior to changing over to the hospital infusion pump because of the high cost of the medications used to treat PH. The nurse may need to contact the readmitted patient's home infusion services company to obtain information about the current medication dosing. When changing from a home infusion pump to the hospital device, the drug concentration and half-life must be considered. This process is considered a very high-risk situation. If the infusion is interrupted for longer than expected, the patient may abruptly decompensate and experience an abrupt increase in pulmonary vascular pressures characterized by the onset of oxygen desaturation and acute respiratory distress. It is advisable that the nurse partner with the clinical pharmacist using a checklist to assure appropriate steps are taken.
Although knowledge about the epidemiology and pathophysiology of PAH have increased significantly over the past 20 years, PAH continues to be a debilitating disease with poor survival rates and high economic burden. The nurses caring for these patients have a unique role in ongoing comprehensive assessment, assisting with goal planning, medication management, and patient/family education. Meanwhile, many unanswered questions about the trajectory of this disease require further research.
Vessel changes in PAH
(A) Normal pulmonary artery. (B) Mild pulmonary hypertension with thickening of the media of the pulmonary artery. (C) Pulmonary artery with extensive intimal fibrosis and thickening of vascular smooth muscle. (D) Micrograph of a small pulmonary artery that is virtually occluded by concentrically thickened intimal fibrosis and thickening of the media because of pulmonary arterial hypertension.