Pulmonary arterial hypertension in the emergency department: A focus on medication management.

Pulmonary arterial hypertension (PAH) is a chronic progressive incurable condition associated with a high degree of morbidity and mortality. With over five drug classes FDA approved in the last decade, the significant advancements in the pharmacologic management of PAH has improved long-term outcomes. Drug therapies have been developed to directly target the underlying pathogenesis of PAH including phosphodiesterase type-5 inhibitors (PDE-5i), endothelin-receptor antagonists (ERAs), guanylyl-cyclase inhibitors, prostacyclin analogues, and prostacyclin receptor agonists. Although these agents offer remarkable benefits, there are significant challenges with their use such as complexities in medication dosing, administration, and adverse effects. Given these consequences, PAH medications are classified as high-risk, and the transitions of care process to and from the hospital setting are a vulnerable area for medication errors in this population. Thus, it is crucial for the emergency department provider to appropriately identify, manage, and triage these patients through close collaboration with a multidisciplinary team to ensure safe and effective medication management for PAH patients in the acute care setting.

Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 µg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Salvage therapies for refractory hypoxemia in ARDS.

Acute Respiratory Distress Syndrome (ARDS) is a condition of varied etiology characterized by the acute onset (within 1 week of the inciting event) of hypoxemia, reduced lung compliance, diffuse lung inflammation and bilateral opacities on chest imaging attributable to noncardiogenic (increased permeability) pulmonary edema. Although multi-organ failure is the most common cause of death in ARDS, an estimated 10-15% of the deaths in ARDS are caused due to refractory hypoxemia, i.e.- hypoxemia despite lung protective conventional ventilator modes. In these cases, clinicians may resort to other measures with less robust evidence -referred to as "salvage therapies". These include proning, 48 h of paralysis early in the course of ARDS, various recruitment maneuvers, unconventional ventilator modes, inhaled pulmonary vasodilators, and Extracorporeal membrane oxygenation (ECMO). All the salvage therapies described have been associated with improved oxygenation, but with the exception of proning and 48 h of paralysis early in the course of ARDS, none of them have a proven mortality benefit. Based on the current evidence, no salvage therapy has been shown to be superior to the others and each of them is associated with its own risks and benefits. Hence, the order of application of these therapies varies in different institutions and should be applied following a risk-benefit analysis specific to the patient and local experience. This review explores the rationale, evidence, advantages and risks behind each of these strategies.

Selexipag, an Oral Prostacyclin-Receptor Agonist for Pulmonary Arterial Hypertension.

OBJECTIVE: To evaluate the data supporting the approval of selexipag and discuss its potential place in therapy for managing pulmonary arterial hypertension (PAH). DATA SOURCES: A systematic review of the literature for all relevant articles was performed through January 16, 2017, using MEDLINE and SCOPUS. A manual search of references from reports of clinical trials, review articles, and recent conference abstracts was performed to identify additional relevant studies. STUDY SELECTION AND DATA EXTRACTION: Eligible citations included in vitro or in vivo evaluations of selexipag, with no restrictions on patient population or indication. Data related to the patient populations and outcomes of interest were extracted from each citation. DATA SYNTHESIS: Single phase II and phase III trials have been published evaluating selexipag in patients with PAH. In 43 patients, the phase II trial showed that selexipag significantly reduced pulmonary vascular resistance by 30% versus placebo ( P = 0.0045) and improved 6-minute walk distance by 24 m ( P < 0.05). The larger phase III trial enrolled 1156 patients with PAH, showing that selexipag lowered the incidence of death or PAH-related complications by 40% versus placebo ( P < 0.001). Selexipag also improved 6-minute walk distance and lowered hospitalization risk. Common adverse events included headache, diarrhea, nausea, and jaw pain. CONCLUSIONS: The specific role of selexipag for managing PAH patients is unclear because of its modest efficacy, lack of mortality reduction, and cost similar to intravenous prostacyclins. Additional clinical trials exploring combination therapy as well as its role in other types of pulmonary hypertension are needed.

Pulmonary Arterial Hypertension: A Focus on Infused Prostacyclins.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and cell proliferation in the pulmonary vasculature. Guideline-driven interventions with infused prostacyclin treatment are the mainstay for patients with advanced symptoms. Infused prostacyclin therapy is complex. It is critical to manage prostacyclin therapy with precision because boluses or interruptions can be fatal. Education of patients and inpatient staff nurses is necessary to prevent negative outcomes. Nurses are an essential part of the multidisciplinary team caring for patients with PAH. The diagnostic evaluation and treatment of PAH are reviewed here, and challenges associated with the care of patients on prostacyclin therapy are discussed.

High-flow oxygen therapy and other inhaled therapies in intensive care units.

In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

The evolution of prostacyclins in pulmonary arterial hypertension: from classical treatment to modern management.

Prostacyclins for the treatment of pulmonary arterial hypertension (PAH) have historically been covered under the insurance medical benefit because they require durable medical equipment and are administered by an intravenous, subcutaneous, or inhalation route. However, more treatment options that target the prostacyclin pathway have become available. As the number and type of options expand, an improved understanding of these drugs will aid managed care decision makers in evaluating new treatment options and making clinically sound and cost-effective treatment decisions. PAH is a progressive disease of pulmonary vascular remodeling that increases pulmonary vascular resistance and often results in right-side heart failure and death if left untreated. Adverse event profiles, the complexity of administration modalities, and potential complications must be considered when administering prostacyclin therapy. Traditional modes of administration, with their potential challenges and complications, may have contributed to the unmet need for an oral agent. Another consideration for managed care decision makers is that oral agents are generally covered under the insurance pharmacy benefit. Access to oral medications with long-term outcomes data, as well as the improved convenience of oral therapy, may help patients with PAH maximize function by maintaining a more convenient and consistent therapeutic regimen.

Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterised by increased pulmonary vascular resistance, which leads to restricted pulmonary arterial blood flow and elevated pulmonary arterial pressure. In patients with PAH, pulmonary concentrations of prostacyclin, a prostanoid that targets several receptors including the IP prostacyclin receptor, are reduced. To redress this balance, epoprostenol, a synthetic prostacyclin, or analogues of prostacyclin have been given therapeutically. These therapies improve exercise capacity, functional class and haemodynamic parameters. In addition, epoprostenol improves survival among patients with PAH. Despite their therapeutic benefits, treatments that target the prostacyclin pathway are underused. One key factor is their requirement for parenteral administration: continuous intravenous administration can lead to embolism and thrombosis; subcutaneous administration is associated with infusion-site pain; and inhalation is time consuming, requiring multiple daily administrations. Nevertheless, targeting the prostacyclin pathway is an important strategy for the management of PAH. The development of oral therapies for this pathway, as well as more user-friendly delivery devices, may alleviate some of the inconveniences. Continued improvements in therapeutic options will enable more patients with PAH to receive medication targeting the prostacyclin pathway.

Inhaled Therapies for Pulmonary Hypertension.

The inhaled route has a number of attractive features for treatment of pulmonary hypertension, including delivery of drug directly to the target organ, thus enhancing pulmonary specificity and reducing systemic adverse effects. It can also improve ventilation/perfusion matching by dilating vessels supplying ventilated regions, thus improving gas exchange. Furthermore, it can achieve higher local drug concentrations at a lower overall dose, potentially reducing drug cost. Accordingly, a number of inhaled agents have been developed to treat pulmonary hypertension. Most in current use are prostacyclins, including epoprostenol, which has been cleared for intravenous applications but is used off-label in acute care settings as a continuously nebulized medication. Aerosolized iloprost and treprostinil are both prostacyclins that have been cleared by the FDA to treat pulmonary arterial hypertension (PAH). Both require frequent administration (6 and 4 times daily, respectively), and both have a tendency to cause airway symptoms, including cough and wheeze, which can lead to intolerance. These agents cannot be used to substitute for the infused routes of prostacyclin because they do not permit delivery of medication at high doses. Inhaled nitric oxide (INO) is cleared for the treatment of primary pulmonary hypertension in newborns. It is also used off-label to test acute vasoreactivity in PAH during right-heart catheterization and to treat acute right-heart failure in hospitalized patients. In addition, some studies on long-term application of INO either have been recently completed with results pending or are under consideration. In the future, because of its inherent advantages in targeting the lung, the inhaled route is likely to be tested using a variety of small molecules that show promise as PAH therapies.

Management of the patient with pulmonary arterial hypertension receiving intravenous prostacyclin: an expert nurse practical guide.

Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by elevated pulmonary artery pressure ultimately leading to right heart failure and death. Treatment options have significantly increased over the past decade. Intravenous prostacyclins remain the treatment of choice for advanced PAH, leading to long-term clinical benefits and improved survival. Their administration requires a high level of nursing competency and presents considerable challenges for patients and caregivers. This article reviews the characteristics of currently available intravenous prostacyclins and provides a practical guide for nurses who may have had limited exposure to intravenous prostacyclins and their unique dosing, side effects, and titration characteristics.

Prostacyclins.

Prostacyclins have a favourable pharmacological profile for treatment of pulmonary hypertension as they possess vasodilative, antiproliferative, antiaggregatory, and anti-inflammatory properties that may compensate the main pathologic changes in the small pulmonary arteries. In severe pulmonary hypertension these vessels show a deficit in the endogenous prostacyclin secretion. The therapeutic potential of prostacyclin for pulmonary hypertension has been known since 30 years, and since nearly 20 years prostacyclin has been approved for idiopathic PAH. There are intravenous, subcutaneous, and inhaled approaches of different substances who share many but not all pharmacologic properties. However, none of these approaches are easy and free of adverse effects. Long-term experience and careful decision-making are instrumental to achieve favourable clinical long-term results.

Safety recommendations for administering intravenous prostacyclins in the hospital.

Prostacyclins are a high-risk category of continuous intravenous infusions increasingly used in hospitals to treat advanced pulmonary arterial hypertension, a rare condition characterized by vasoconstriction and vascular proliferation of the pulmonary arteries. Prostacyclins are given in doses of nanograms per kilogram per minute and have a narrow therapeutic dosing range for each patient. Sudden increases or decreases in dose can be life threatening. Previous studies revealed errors in the administration of these high-risk infusions, which in some instances led to serious adverse events, including death. The literature was reviewed for safety measures in administration of high-risk intravenous medications and input was obtained from leading experts in pulmonary arterial hypertension to create a set of safety recommendations for infusion of prostacyclins.

Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies.

Pulmonary arterial hypertension (PAH), which is a subset of pulmonary hypertension, is a group of diseases distinguished by vascular remodeling of the small pulmonary arteries with associated elevated pulmonary arterial pressure and right ventricular failure. This progressive and sometimes fatal disease occurs as an idiopathic disease or as a component of other disease states. Estimates of the incidence of PAH have varied from 5 to 52 cases/1 million population. Symptoms begin with shortness of breath with exertion and progress to dyspnea with normal activities and, finally, dyspnea at rest. Untreated patients with PAH have a 1-, 3-, and 5-year survival rate of 68%, 48%, and 34%, respectively. Treated, the survival rates improve to 91% to 97% after 1 year and 84% to 91% after 2 years. The current definition of PAH consists of 3 specific hemodynamic assessments confirmed by right heart catheterization findings. One of several important pathophysiologic mechanisms involved in PAH is pulmonary vascular remodeling, which is caused by endothelial and smooth muscle cell hyperproliferation. This is coincident with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide and prostacyclin, which further impedes proper vasomotor tone, among other effects. Prostacyclin therapies augment the decreased prostacyclin levels in patients with PAH. The currently approved prostacyclins for the treatment of PAH include epoprostenol, iloprost, and treprostinil. Among the 3 medications, the delivery options include intravenous infusion, subcutaneous infusion, and inhaled formulations. Epoprostenol has been shown to have a positive effect on survival in patients with PAH. All prostacyclins have demonstrated improvements in functional class, exercise tolerance, and hemodynamics in patients with PAH. Intravenously and subcutaneously administered formulations of prostacyclins require continuous infusion pump administration, which presents clinical challenges for both the patient and the care provider. Dosing must be individualized and also presents a clinical challenge. Inhaled formulations seem efficacious in moderately symptomatic patients with PAH and might be appropriate when combined with an oral medication. Combination therapies are commonly used in clinical practice, with the decision to do so based on randomized controlled trial data and case study evidence. The present report provides an overview of PAH, the scientific rationale for treatment with prostacyclin therapy, and the benefits and risks of prostacyclin therapy, both as monotherapy and combined with other medications approved for the treatment of PAH.

Iloprost inhalation in mild asthma.

OBJECTIVE: To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma. METHODS: Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.5 or 5 µg for 14 days. Spirometry, asthma questionnaires, peak flow diaries, measurement of methacholine responsiveness, and exhaled nitric oxide concentrations were obtained prior to and after the treatment period. RESULTS: Chronic inhalation of iloprost (2.5-5 µg) did not alter spirometry or methacholine responsiveness. CONCLUSION: Inhaled iloprost in carefully selected volunteers with mild asthma appears to be a suitable intervention to explore the effects of prostacyclin in human asthma.

Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy.

Pulmonary arterial hypertension (PAH) is a rare but serious condition, which if untreated, is associated with a 2-3-year median survival time. A number of treatment options are available for PAH, leading to improvements in exercise capacity, symptoms, and hemodynamics. However, the disease remains incurable and most patients will ultimately progress to right heart failure and death. Three classes of drugs are currently available to improve PAH outcomes, although this review will focus solely on a class of potent vasodilators known as prostacyclins. Currently, four prostacyclin analogs are licensed for the treatment of PAH: epoprostenol, treprostinil, and iloprost in the USA and some European countries, and beraprost in Japan and Korea. Prostacyclins have become the treatment of choice in patients with severe PAH, but there is also evidence to suggest that their earlier use may also benefit patients with mild-to-moderate disease. This review discusses the advantages of prostacyclins in terms of their usefulness in patients whose condition has deteriorated following monotherapy with other agents, and their integral role in combination therapy. The latter appears to offer the potential for pulmonary vasculature remodeling and could be regarded as an emerging paradigm to treat and prevent the progression of PAH.

Emerging drugs for pulmonary hypertension.

IMPORTANCE OF THE FIELD: Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by structural narrowing of the small pulmonary arteries that often culminates in fatal right heart failure. AREAS COVERED IN THIS REVIEW: PubMed was searched for PAH and treatment. Data from scientific meetings and pharmaceutical websites are also included. There are currently eight FDA approved drugs for PAH that fall into one of three classes: prostacyclins, endothelin-receptor antagonists and PDE-5 inhibitors. All have important limitations and morbidity and mortality remain high. Several new agents with similar mechanisms of action are in clinical development. Multiple novel therapeutic targets are being explored. New applications for PAH therapies, such as pulmonary hypertension due to left heart and lung disease, are also being investigated. WHAT THE READER WILL GAIN: An understanding of currently available drugs and those in clinical development for pulmonary hypertension. TAKE HOME MESSAGE: Drugs targeting the pulmonary vasculature have been an extremely active area of basic and clinical research for the past 20 years and will continue to be so for the foreseeable future. Considerable progress has been made, and yet there continues to be a great unmet medical need for developing more efficacious therapies.

Are inhaled vasodilators useful in acute lung injury and acute respiratory distress syndrome?

In patients with acute respiratory distress syndrome (ARDS), inhaled vasodilator can result in important physiologic benefits (eg, improved hypoxemia, lower pulmonary arterial pressure, and improved right-ventricular function and cardiac output) without systemic hemodynamic effects. Inhaled nitric oxide (INO) and aerosolized prostacyclins are currently the most frequently used inhaled vasodilators. Inhaled prostacyclins are as effective physiologically as INO and cost less. Randomized controlled trials of INO in the treatment of ARDS have shown short-term physiologic benefits, but no benefit in long-term outcomes. No outcome studies have been reported on the use of prostacyclin in patients with ARDS. There is no role for the routine use of inhaled vasodilators in patients with ARDS. Inhaled vasodilator as a rescue therapy for severe refractory hypoxemia in patients with ARDS may be reasonable, but is controversial.

Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy.

The present review aims to examine the effect of specific drugs on long-term outcome of pulmonary arterial hypertension (PAH), to critically review the available data, and to derive useful information for daily patient care. PAH is an intrinsic disease of the pulmonary circulation with a malignant evolution as a consequence of progressive right heart failure. Without specific therapy, median survival is only 2.8 yrs. The intravenous prostacyclin analogue epoprostenol is the only treatment with a demonstrated effect on survival, observed during a single 12-week randomised placebo-controlled trial. Three long-term observational studies have also shown that median survival is raised above 6 yrs with this therapy. Subcutaneous treprostinil appears to have similar beneficial effects on survival, as reported in two long-term observational studies. This is not the case for inhaled iloprost, as shown in one study in which a high proportion of patients needed the addition of, or the switch to, another therapy. Among the oral agents, long-term data have only been published for bosentan. The three studies including patients from expert centres also showed very good survival data, but again with a broad use of combination therapy. In less expert hands, with limited access to more complex therapies, reported survival seems much worse. In these studies, baseline New York Heart Association class and 6-min walk distance are repeatedly shown to be important predictors of survival. Finally, there is emerging data that prostanoid therapy results in a tendency to normalise C-reactive protein levels, a factor associated with improved long-term outcomes.

Inhalation therapy in invasive and noninvasive mechanical ventilation.

PURPOSE OF REVIEW: The aim of this article is to discuss the various factors that influence aerosol delivery in mechanically ventilated patients and clarify optimal techniques for aerosol administration in this patient population. Clinical use of various inhaled therapies in patients receiving invasive and noninvasive mechanical ventilation is also discussed. RECENT FINDINGS: With optimal techniques for using pressurized metered-dose inhalers and nebulizers in ventilator circuits, the efficiency of inhaled drug delivery in mechanically ventilated patients is comparable to that in ambulatory patients. Techniques for enhancing inhaled drug delivery during noninvasive positive pressure ventilation are also being investigated. SUMMARY: Pressurized metered-dose inhalers of bronchodilator and corticosteroid aerosols are more efficient and convenient to use than nebulizers for routine therapy in ventilated patients. Nebulizers are, however, more versatile and are employed to generate aerosols of bronchodilators, corticosteroids, antibiotics, prostaglandins, surfactant, and mucolytic agents. Factors influencing drug delivery during noninvasive positive pressure ventilation are not fully understood as yet, and further work is needed to enhance drug delivery in this setting. Improvements in drug formulations and the design and efficiency of aerosol generating devices have led to increasing application of inhaled therapies in mechanically ventilated patients.