Epoprostenol Use for Pulmonary Arterial Hypertension in the Palliative Care Setting

Introduction

Pulmonary arterial hypertension (PAH) is an incurable and often debilitating condition. It is accompanied by high symptom and social burdens and diminished overall quality of life (QOL).^1–3 Although patients with PAH and their families are ideal candidates for benefit from palliative medicine, few have palliative specialists involved in their care. ³ Epoprostenol infusion is a common treatment for severe PAH and has been shown to provide both improved QOL ² and increased survival. ⁴ The complexity of its administration and its cost, and the lack of familiarity that many palliative providers have with the medication, have limited its use in palliative care and hospice settings. In fact, being on epoprostenol may limit access to palliative hospice care. We present a case illustrating the challenges associated with caring for a patient with idiopathic PAH on epoprostenol near the end of life, and we present our guidelines for its use created as a result of this patient case.

Case Report

Ms. F was a 52-year-old woman with primary pulmonary hypertension who had been on epoprostenol infusion for over a year. Her mother was her primary caregiver in her home. She had been admitted to the hospital and managed in the intensive care unit (ICU) multiple times for progressive exacerbations of pulmonary symptoms and delirium.

On this admission, the patient presented to the emergency department with severe tachypnea, diaphoresis, and somnolence. The patient's mother and pulmonologist both supported the avoidance of cardiopulmonary resuscitation or mechanical ventilation, but favored continued measures that might prolong her life without undue burden. With this goal in mind, Palliative Care was involved for assistance with symptom management and social and existential support. The patient was admitted to our inpatient unit and in conjunction with her pulmonologist her epoprostenol was continued and antibiotics initiated for a possible pneumonia.

Ms F's mental status eventually improved, which afforded an opportunity for careful discussion of goals of care among the patient, her mother, her pulmonologist, and the palliative care team. Her high symptom burden and oxygen requirement precluded discharge to home, however, and we were unable to find a hospice facility that could provide the epoprostenol due to its considerable expense. Despite its help in alleviating her dyspnea, the patient nonetheless felt as if she were a prisoner to the medication. With her mother's support, Ms. F decided to discontinue epoprostenol despite the likelihood that it was prolonging her life. She wanted aggressive management of her symptoms as they arose, and wanted to return home if possible or look for placement.

To allow time for symptom management and stabilization prior to further decreases, we reduced the epoprostenol by 10% daily. Ms. F tolerated these decreases remarkably well, and, in fact, the drug was weaned completely. Thirty minutes after the final 10% was discontinued she became severely dyspneic and delirious. Hydromorphone, midazolam, and nebulized fentanyl alleviated her dyspnea, and her mental status temporarily returned to baseline. She enjoyed several hours of interaction with her family, thereafter before becoming comatose and dying peacefully with her mother at the bedside.

Discussion

PAH is caused by progressive obliteration of the pulmonary arterioles. Over time, despite recent advances in medical treatment, patients develop progressive right ventricular failure with resultant dyspnea, volume overload, palpitations, syncope, and eventual death.^1,4,5

PAH occurs in a variety of disease states and conditions. It can be idiopathic, occur in association with collagen vascular disease, or result from underlying lung disease, thromboembolic disease, left ventricular failure, human immunodeficiency virus (HIV), or drug or toxin exposure. ¹ The exact pathogenesis is incompletely elucidated, and disease subtypes are indistinguishable clinically or histologically regardless of etiology.^1,2

Idiopathic PAH is a rare disorder, with reports estimating its prevalence at between 15 and 52 cases per one million patients. ⁶ It initially presents as dyspnea, which may be variably accompanied by dizziness, chest pain, or fatigue. ² PAH currently remains incurable, and patients typically experience a trajectory of progressive dyspnea, declining function and QOL, and ultimately death. ¹ Mean time from symptom onset to diagnosis is 34 months, and median time from diagnosis to death is 2.8 years. ³

There is little information in the medical literature about palliative or end-of-life management in PAH. Although patients demonstrate a moderate awareness of palliative care and hospice resources, only 11% have palliative-trained specialists involved in their care, and more than three times as many patients die in an ICU than die at home. ³

The impairments associated with PAH extend beyond physical symptoms to multiple QOL domains. Even with optimized treatment, when compared with population norms, patients with PAH report moderate-to-severe decreases in emotional well-being and energy, and increased isolation, anorexia, insomnia, and pain.^2,3 Treatment, furthermore, is complex, expensive, and relies heavily on caregiver support, potentially leading to further social stress. The incurable and progressive nature of the disease, in turn, may create profound existential distress. Although advances in medical treatment are improving the symptom burden and survival in PAH, it remains a severely life-limiting illness. As such, patients with PAH and their families are excellent candidates for palliative care and can benefit from the expertise in symptom management, goals of care determination, coordinated social and existential support, and end-of-life care.

Prostacyclin is a naturally occurring metabolite of arachidonic acid with vasodilatory, anti-platelet aggregation, and cytoprotective effects. ¹ Among the three classes of pulmonary artery-specific vasodilators currently available in the United States, the intravenous (IV) prostacyclin analogues are most often used for patients with severe disease and have been shown in randomized controlled trials to improve exercise capacity, pulmonary hemodynamics, and survival. ⁴ Compared with patients on alternative therapies, those receiving epoprostenol have been shown to have improved energy and dyspnea threshold, and less depression, anxiety, and emotional distress. ²

Epoprostenol (Flolan®), the first such medication on the U.S. market, was FDA approved in May 1995. A generic version is now available. It must be prepared daily under sterile conditions, stored under refrigeration, and given by continuous infusion through a central vein. Dosing is frequently initiated and titrated with telemetry monitoring in an intermediate care unit or ICU. Generic and name-brand versions, while similar, should not be interchanged. Due to the short half-life of approximately 6 minutes and risk of potentially life-threatening rebound pulmonary hypertension, the medication should not be abruptly discontinued.^1,7

Due to the short half-life and requirement for refrigeration and protection from light, outpatient administration is achieved via a continuous ambulatory delivery device (CADD) pump, which couples a cassette containing the drug with an ice pack to ensure drug stability. High levels of social support are mandatory, with patients and caregivers being taught to manage the pump in the outpatient setting, including drug dilution, cassette preparation, and dose adjustment as directed by their physician.

An additional prostaglandin analog treprostinil (Remodulin®) was FDA approved subsequently in 2002. Treprosinil has a longer half-life, and it can be delivered via subcutaneous (or IV) infusion, minimizing some of the potential complications of central venous infusion. ⁸ Velitiri®, a room-temperature stable formulation of epoprostenol, is also now available. ⁹ As our initial experience involved a patient on epoprostenol, our guidelines are for its use; however, they can readily be adapted to treprostinil or temperature-stabilized epoprostenol use if necessary.

Patients on epoprostenol face unique challenges with respect to end-of-life care. Due to the drug's relative newness and complexity of use, the treatment itself may constitute an impediment to patients with PAH benefiting from palliative expertise. Epoprostenol's role as a life-prolonging therapy may inhibit initial palliative care consultation, and its expense may contribute to a belief that patients are not appropriate candidates for hospice. However, our experience in the case described above suggests that this need not be the case. Rather, with appropriate planning, interdepartmental coordination, consultation, and education, patients can safely benefit from palliative expertise and primary management.

Prior to the case above, epoprostenol had rarely been used within our institution in a nontelemetry-monitored environment. Using the patient's own medication and infusion equipment from home was contrary to our unit policy and considered unsafe, as our nurses are not trained to operate the home pump. Furthermore, this would have limited our goal of providing respite for the patient's mother by requiring that she continue to provide direct management of the medication on a full-time basis. Additionally, we were unable to find any published guidelines for use of epoprostenol in a palliative care setting. When the decision to wean the patient's epoprostenol was reached, we again consulted the literature, but found that published weaning protocols for epoprostenol similarly do not exist.

Several key issues emerged through our experience in this case and the subsequent development of our protocol and are shown in Table 1. Our guidelines are presented in Table 2.

Conclusion

Epoprostenol offers both a survival and QOL benefit to patients with PAH, but its inpatient use is often restricted to a dedicated intermediate care unit or ICU environment. By extending its use and that of other prostacyclin analogues to the palliative care setting, patients and families of those with PAH can be afforded greater choice regarding location of care, expert symptom management, and enhanced access to other elements of palliative care. Careful coordination and predetermined protocols for the use of epoprostenol in a palliative care environment are essential to ensure safe delivery. The institutional guidelines we have developed to utilize epoprostenol on our palliative unit are presented here. These policies are a first step, and further study and continued interspecialty collaboration are required to optimize care in PAH.