Intravenous Prostacyclin Analogues Research Articles

Compression Stockings Improve Lower Legs Symptom in Patients with Pulmonary Artery Hypertension Treated by Pulmonary Vasodilators—A Pilot Study

Pulmonary vasodilators have improved pulmonary arterial hypertension (PAH) symptoms and prognosis; however, the drugs cause some side effects, including lower legs pain, which impair quality of life (QOL). The present study examined if compression stockings improved lower extremity symptoms and QOL caused by pulmonary vasodilators in PAH patients. We retrospectively enrolled consecutively ten patients with PAH treated by pulmonary vasodilators, who were regularly followed in Kurume University Hospital from January 2022 to June 2022. Oral questionnaire surveys, the Numeric Rating Scale for Pain (NRS) and the Pain Disability Assessment Scale (PDAS), were conducted regarding lower extremity symptoms before wearing elastic stockings and one month later, to evaluate how the lower extremity symptoms affected daily life. All ten patients were female, with a mean age of 50.2 ± 11.5 years, out of whom intravenous prostacyclin analogue (PGI2) was administered in five patients. In no intravenous PGI2 group, NRS score was significantly improved from 4.6 ± 2.3 to 2.8 ± 1.2 (p = 0.037), while from 9.4 ± 1.2 to 5.4 ± 1.6 (p = 0.002) in intravenous PGI2 group. PDAS score was also significantly improved [no intravenous PGI2 group; 18.0 (15.0-24.0) to 15.0 (10.0-19.0), intravenous PGI2 group; 25.0 (17.0-37.0) to 17.0 (5.0-27.0)]. Lower extremity symptoms in patients using pulmonary vasodilators were improved by wearing compression stockings.

Efficacy and safety of selexipag in real-life in patients with pulmonary arterial hypertension: early results of RAMPHA study

Abstract Background Pulmonary arterial hypertension (PAH) is a syndrome characterized by marked remodeling of the pulmonary vasculature and leading to right heart failure and death. Selexipag, an oral prostacyclin IP receptor agonist, has been shown to decrease morbidity and mortality compared to patients treated with placebo. Purpose Our aim was to evaluate the efficacy and safety of Selexipag in patients with PAH in real-life. Methods The RAMPHA study was a multicenter, observational and retrospective trial of patients who had PAH and began taking Selexipag between 2017–2021. We analyzed baseline characteristics, risk profiles, clinical assessments that were used for risk stratification and events in follow-up time. Results 29 patients aged 48±14 were initially studied. 23 (79%) were women. Within the pulmonary hypertension-classification, 10 (34,5%) had PAH associated-congenital heart disease, 9 (31%) had idiopathic HAP, 7 (24,1%) had PAH associated with connective tissue disease, 1 had PAH associated to HIV and 2 heritable PAH. The time from PAH diagnoses to the beginning of Selexipag treatment was 54 months (IQR 89). 89,7% (26) were in treatment with doubled combination therapy with PDE5i+ARE; Sildenafil was the most widely used PDE5i and bosentan (37,9%) the most used ARE. No patients were under treatment with intravenous prostacyclin analogue, but 3 were with Treprostinil (1 of them subcutaneous and 2 inhaled) and 2 patients with iloprost. Most patients were categorized in intermediate risk profile (figure 1), using the risk stratification strategy of ESC/ERS PH guidelines. In the approach of risk assessment before start with Selexipag, clinical, functional, exercise (with 6MWT) and echocardiographic variables were used in all the patients. Biochemical variables with NT-proBNP were used in 93% of the patients. Only 15 patients had a right catheterization to get haemodynamic parameters before the treatment. At follow up, 11 patients (38%) improved functional class, only 1 patient got worst (p=0,001). 3 patients improved risk-profile in the exercise test and, in the others, a quantitative improvement was found. NT-proBNP levels were not significant better (924ng/l IQR 1209 vs 760ng/l IQR 1397). There were not changes in RV function in the echocardiographic parameters. Selexipag was well-tolerated, 86% of the patients experienced side effects, but none had to discountinue the treatment. The most common side effect was headache. The titration lasted 68 days (IQR 72) and 38% of the patients got maximum doses. At the medium-term follow-up of 52 months, the free-event survival (worsening of PAH that resulted in hospitalization; initiation of parenteral prostanoid therapy or death to PAH; or any cause) was 80% (Figure 2). Conclusion Selexipag, added as triple combination therapy in patients with PAH intermediate risk, improved risk variables, was well tolerated and achieved a medium-long-term free-event survival greater than 80%. Funding Acknowledgement Type of funding sources: None.

Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension - A review of the past, present and future.

Therapy with intravenous prostacyclin analogues in patients with pulmonary arterial hypertension (PAH) has been established for decades and is an integral component of the current guidelines for the treatment of pulmonary hypertension. Initially, these drugs were infused by external pump systems via tunnelled right atrial catheters with the need for cooling and frequent exchange of drug reservoirs. Associated complications included, among others, catheter-related infections. More recently, fully implantable pump systems have been developed with drug reservoirs that are filled transcutaneously, allowing intervals between refills of several weeks. This technique results in a low rate of infections. Epoprostenol, iloprost and treprostinil have all been used intravenously in PAH, but titration, dosing and dose escalation in long-term therapy are not standardized. Intravenous prostacyclin analogues are still under-used, despite available data suggesting that early and broad application of these therapies as part of risk-oriented, guideline-directed combination therapy for patients with PAH may lead to a survival benefit. This review provides a detailed overview of the drugs, infusion systems and dosing strategies used for intravenous therapy in patients with PAH.

Pharmacological treatment for Buerger's disease.

Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The aetiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularisation to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain.This is an update of the review first published in 2016. To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 15 October 2019. The review authors searched LILACS, ISRCTN, Australian New Zealand Clinical Trials Registry, EU Clinical Trials Register, clincialtrials.gov and the OpenGrey Database to 5 January 2020. We included randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease. Two review authors, independently assessed the studies, extracted data and performed data analysis. No new studies were identified for this update. Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid. Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; 1 study; moderate-certainty evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; 1 study; moderate-certainty evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; 1 study; moderate-certainty evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; 2 studies; I² = 0%; very low-certainty evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; 1 study; low-certainty evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; 1 study; moderate-certainty evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; 1 study; moderate-certainty evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; 1 study; moderate-certainty evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; 1 study; moderate-certainty evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; 1 study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; 1 study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low-certainty evidence). Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study. Overall, the certainty of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information (for example regarding baseline tobacco exposure). Moderate-certainty evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Very low and low-certainty evidence suggests there is no clear difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very low-certainty evidence suggests there is no clear difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. Further well designed RCTs assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Targeted therapy of pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018

In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available. The treatment algorithm for PAH was modified based on the observation that there are now many patients diagnosed with IPAH who are at an advanced age and have significant cardiopulmonary comorbidities. For patients newly diagnosed with classic forms of PAH, i.e. younger patients without significant cardiopulmonary comorbidities, the consensus-based recommendation was to use initial combination therapy as the standard approach. The use of monotherapies was no longer considered appropriate in such patients. The choice of treatment strategies should be based on the risk assessment as proposed in the European guidelines. In patients presenting with a low or intermediate risk, oral combination therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors or soluble guanylate cyclase stimulators, respectively, should be used. In high-risk patients, triple combination therapy including a subcutaneous or intravenous prostacyclin analogue should be considered. For patients who suffer from PAH and significant cardiopulmonary comorbidities, initial monotherapy is recommended and the use of combination therapies should be considered on an individual basis. The latter recommendations are based on the scarcity of evidence supporting the use of combination therapy and the higher risk of drug-related adverse events in such patients.

Infection de cathéter veineux central tunnelisé survenue sous traitement par époprosténol

Pulmonary arterial hypertension is a pulmonary vascular disease with a poor prognosis. Continuous intravenous treatment with prostacyclin analogues requires the placement of a tunnelled catheter. The occurrence of catheter-related infections in this context is unusual due to the alkaline pH of the prostacyclin analogue solutions. A 50-year-old patient with inherited pulmonary artery hypertension, treated with bosentan, sildenafil and epoprostenol, experienced generalized malaise associated with a weight loss of 9kg over a 12-month period without evidence of a source of infection or malignancy. There was no evidence of hemodynamic disturbance. The diagnosis was made after 1year of follow-up, when the patient presented with a 38° fever and a biological inflammatory syndrome. Repeated peripheral blood cultures were positive for Dietzia, an alkalophilic coryneform bacillus. The patient's condition responded favourably to antibiotic therapy. Infection of a tunneled intravenous catheter should be considered in the case of non-specific symptoms or where there is evidence of sepsis, in patients treated with intravenous prostacyclin analogues administered intravenously. In this context, the laboratory should be warned to search for slow-growing organisms.

Pharmacological treatment for Buerger's disease.

Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain. To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease. The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies. Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease. Two review authors, independently assessed the studies, extracted data and performed data analysis. Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid.Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I² = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low quality evidence).Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure. Moderate quality evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Verylow and low quality evidence suggests there is no difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very-low quality evidence suggests there is no difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Pharmacological treatment for Buerger's disease.

Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain. To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease. The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies. Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease. Two review authors, independently assessed the studies, extracted data and performed data analysis. Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid.Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I² = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low quality evidence).Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure. Moderate quality evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Verylow and low quality evidence suggests there is no difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very-low quality evidence suggests there is no difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Hypertension pulmonaire : définition, classification et traitements

Pulmonary hypertension (PH) is a cardio-pulmonary disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. Its definition is an increase in mean pulmonary artery pressure (mPAP) \hbox{$\geqslant $} ⩾ 25 mmHg at rest, leading to right heart failure and ultimately death. The clinical classification of pulmonary hypertension (PH) categorizes PH into groups which share similar pathophysiological and hemodynamic characteristics and treatments. Five groups of disorders that cause PH are identified: pulmonary arterial hypertension (Group 1) which is a pre-capillary PH, defined by a normal pulmonary artery wedge pressure (PAWP) \hbox{$\leqslant $} ⩽ 15 mmH, due to remodelling of the small pulmonary arteries (<500 μm); pulmonary hypertension due to left heart disease (Group 2) which is a post-capillary PH, defined by an increased pulmonary artery wedge pressure (PAWP) >15 mmHg; pulmonary hypertension due to chronic lung disease and/or hypoxia (Group 3); chronic thrombo-embolic pulmonary hypertension (Group 4); and pulmonary hypertension due to unclear and/or multifactorial mechanisms (Group 5). PAH (PH group 1) can be treated with agents targeting three dysfunctional endothelial pathways of PAH: nitric oxide (NO) pathway, endothelin-1 pathway and prostacyclin pathway. Patients at low or intermediate risk can be treated with either initial monotherapy or initial oral combination therapy. In patients at high risk initial combination therapy including intravenous prostacyclin analogues should be considered. Patients with inadequate clinical response to maximum treatment (triple therapy with an intravenous prostacyclin) should be assessed for lung transplantation. Despite progresses, PAH remains a fatal disease with a 3-year survival rate of 58%. Treatment of group 2, group 3 and group 5 PH is the treatment of the causal disease and PAH therapeutics are not recommended. Treatment of group 4 PH is pulmonary endarteriectomy if patients are eligible, otherwise balloon pulmonary angioplasty and/or medical therapy can be considered.

Intravenous prostacyclin analogue iloprost (Ilomedin®) in the treatment of a patient with Buerger’s disease

Buerger’s disease, or thromboangiitis obliterans, is a severe disabling systemic disease of vessels. The paper describes a case of thromboangiitis obliterans in a patient with three extremities amputated during vascular therapy. The course intravenous administration of the stable prostacyclin analogue iloprost (Ilomedin®) allows the only extremity to be preserved.

Advanced Pulmonary Hypertension: Considerations for Care Planning at End of Life (427)

Objectives 1. Explain the pathophysiology of and symptoms associated with advanced pulmonary hypertension including the mechanisms of action of medications commonly used for advanced pulmonary hypertension and their impact on symptoms. 2. Discuss the current literature on managing patients with advanced pulmonary hypertension at the end-of-life. 3. Propose a guideline for providing end-of-life care for patients with advanced pulmonary hypertension. The survival of patientswithWorldHealthOrganization functional class IV pulmonary hypertension is less than one year if untreated. Although initiation of prostacyclin analogues improves functional status and survival, class IV pulmonary hypertension remains a terminal illness. Unfortunately, there is little evidence on how best to manage these patients at the end-oflife. This session will use case studies of patients admitted to our MICU on continous IV prostacyclin analogues to discuss the challenges and considerations inherent in providing care to patients dying with advanced pulmonary hypertension. Briefly, we will describe the pathophysiology of advanced pulmonary hypertension including a review of associated symptoms. Next, we will outline the pharmacokinetics of intravenous prostacyclin analogues (epoprostenol and trepostinil) used for patients with class IV pulmonary hypertension, including the impact of these medications on patient symptoms. Given the dearth of literature on end-oflife care for patients with class IV pulmonary hypertension, we will propose general guidelines for medical management by extrapolating from studies examining discontinuation or transitions off of other medications with similar mechanisms (eg, nitric oxide, sildenafil, and prostacyclin) as well as from our own experiences. Finally, we will use these cases to examine various psychosocial challenges associated with patients dying from pulmonary hypertension, including considerations for place of death (eg, hospital setting, home hospice, inpatient hospice). A detailed handout will be provided that outlines our proposed medical management guidelines for care of patients dying from advanced pulmonary hypertension.

Hemoptysis Requiring Bronchial Artery Embolization in Pulmonary Arterial Hypertension

Hemoptysis is an uncommon complication in patients with pulmonary arterial hypertension (PAH). Although the mechanism of hemoptysis is unknown, treatment with bronchial artery embolization (BAE) is proposed to be a safe and reliable method of treatment. We report our experience in treating PAH patients presenting with acute hemoptysis that required multiple BAEs. Three female and one male PAH patients, ages 45 + or - 9 years (mean + or - standard deviation [SD]) presented with acute hemoptysis. Right ventricular systolic pressure and cardiac index at the time of the first episode of hemoptysis were 85 + or - 17 mm Hg and 2.7 + or - 0.7 L/min/m, respectively. Two of the four patients had recurrent episodes of hemoptysis, requiring multiple BAEs. All four were on intravenous prostacyclin analogue. None were receiving warfarin or endothelin receptor antagonists at the time of the episode. During each episode of hemoptysis, international normalized ratio (INR) was 1.09 + or - 0.11 units, and platelet count was 124,000 + or - 47,000 per microliter. Each episode of hemoptysis was acutely terminated with BAE. In the majority of cases, patients had multiple aberrant bronchial arteries embolized, and an average of 2.3 arteries was embolized per session (1-4 embolized arteries). Each BAE was performed utilizing polyvinyl alcohol particles, ranging from 250-500 microns. There were no reported complications of the 14 BAE procedures performed. Although the incidence of hemoptysis is unknown and likely underreported, we report our experience in which recurrent hemoptysis was treated with multiple BAE procedures. This report emphasizes the efficacy and safety of BAE in terminating episodes of recurrent hemoptysis in patients with severe PAH.

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&emsp14;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&emsp14;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.

Characteristics and Outcome of Portopulmonary Hypertension

Purpose: Pulmonary artery (PA) hypertension developing in patients with portal hypertension (PH), also called portopulmonary hypertension (PPHTN), caries significant mortality in patients undergoing liver transplant (OLT). With OLT becoming the standard of care, implications of PPHTN are increasingly recognized. However, PPHTN remaines rather poorly characterized. Aim: To define the clinical, biochemical, homodynamic and outcome characteristics of PPHT. Methods: PPHTN was defined as PA systolic pressure ≥ 40 mm Hg (PAs), PA mean pressure ≥ 25 mm Hg (PAm), Pulmonary capillary wedge pressure (PCW) <15 mm Hg, Pulmonary vascular resistance (PVR) ≥ 120 dynes.s.cm−5. During evaluation of candidates for OLT eleven patients identified to have PPHTN were followed for 19 to 48 months. Their clinical, biochemical, hemodynamic parameters, natural history and outcome were analyzed. Results: There were 8 females and 3 males with age of 51.4 ± 2.3 years. Etiology of liver disease was alcoholism and autoimmune hepatitis in one each, cryptogenic in 2, Primary sclerosing cholangitis in 2 and chronic hepatitis C in 5. Shortness of breath was experienced by one, 9 had ascites, and 6 had significant splanchnic varices. Biochemical parameters revealed MELD score of 13.2 ± 1.0 (range 8–18), total s. bilirubin 2.0 ± 0.3 mg%, s. albumin 3.3 ± 0.2 Gm%, AST 109.4 ± 28.3 IU and ALT 72.4 ± 20.5 IU. Cardiac output was 7.4 ± 0.9 L/min (range 4.6–11.4), PAs was 57.5 ± 4.2 mm Hg, PAm was 33.8 ± 3.7 mm Hg, PCW was 13.5 ± 2.1 mm Hg, PVR was 299.5 dynes.s.cm−5, 2-D echocardiography showed tricuspid regurgitation (TR) in all. Treatment (calcium channel blockers, sildenafils, endothelin receptor antagonists, or intravenous prostacyclin analogue) for 19.4 ± 4.3 months (range 1–48) dropped the PAs to 49.1 ± 4.6 mm Hg. Four patients were given OLT, seven denied OLT because of high PA pressure. From the time diagnosis of PPHTN was made, six are alive for 33.3 ± 4.1 months and 5 died after 17.6 ± 6.3 months. Conclusions: PPHTN occurs in patients with cirrhosis of all etiologies with significant PH and is more frequent in females. PA hypertension remains asymptomatic in most patients. All of the patients have hyperdynamic cardiac hemodynamics and increased PVR. The finding of TR on 2 D echocardiography is a good screening indicator of PA hypertension. Response to treatment is variable and less than desirable. Significant PPHTN often prohibits OLT and those not transplanted have decreased survival.

Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension.

Pulmonary hypertension can occur either as primary or secondary disease following cardiac or pulmonary illnesses. In either cases, histological lung biopsies reveal vascular remodelling i.e. smooth muscle cells proliferation with medial hypertrophy, arteriolar muscularization and endothelial cell proliferation. Subsequent intimal thickening, fibrosis and in situ thrombosis, altogether lead to vaso-occlusive alterations referred to as plexiform lesions. Theories concerning the detailed physiopathology of pulmonary hypertension have focused on endothelial and smooth muscle cells' chemical factors production and response to different mediators. The endothelium produces vasoconstrictor and growth-promoting factor such as endothelin-1 (ET-1) as well as vasodilator and growth-inhibitor factors like prostacyclin and nitric oxide (NO). ET-1 has been noted in high concentrations in some clinical cases and experimental models of pulmonary hypertension, coupled with ET-1 receptors' modulation and altered endothelin converting enzyme activities, suggesting their active role in both arteriolar vasoconstriction and occlusion. Vascular thrombosis which has been noted by pathologists in pulmonary hypertension, could be related to an imbalance between thrombotic inducing factors (such as anti-phospholipid antibodies, ET-1 and thromboxane) and decreased fibrinolytic activity and antiaggregant endothelial factors (like prostacyclin, NO, thrombomodulin). The discovery of an endothelial cells' monoclonal proliferation in plexiform lesions of patients with primary pulmonary hypertension may reinforce the cellular proliferation hypothesis to understand the histopathology of this disease. In view of these new findings, the treatments available for pulmonary hypertension have been expanded from the previously employed oxygen therapy, calcium-channel blockers and anticoagulants, to intravenous prostacyclin analogues (epoprostenol) and inhaled nitric oxide.